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Hydrogels are three-dimensional polymeric networks filled with water and mimic tissue environments. Therefore, they are considered optimal to deliver cells and engineer damaged tissues. The hydrogel networks have been significantly modified to endow biochemical functionality with adhesive ligands, growth factors, or degradable sites that are helpful to drive proper cell functions. Recently, some of the biophysical properties of hydrogels have emerged as key players in dictating cell fate. Beyond static stiffness, time-dependent stress/strain changes in the interaction with cells and the cell-mediated degradation and matrix synthesis have been demonstrated to shape cell status and tissue repair process. We highlight here the emerging biophysical properties of hydrogels that can motivate tissue engineers to design and develop hydrogels optimally for tissue regeneration.

HighlightsNanozyme-based approaches to produce therapeutic hydrogels.Enzymatic mechanisms and multifunctional roles of nanozyme-engineered hydrogels for skin therapy.Therapeutic actions of nanozyme-engineered hydrogels in inflamed skin tissues.Mechanical and immunological aspects of skin therapy guided by nanozyme-engineered hydrogels.Promising directions and challenges of nanozyme-inspired hydrogel platforms.Inflammatory skin disorders can cause chronic scarring and functional impairments, posing a significant burden on patients and the healthcare system. Conventional therapies, such as corticosteroids and nonsteroidal anti-inflammatory drugs, are limited in efficacy and associated with adverse effects. Recently, nanozyme (NZ)-based hydrogels have shown great promise in addressing these challenges. NZ-based hydrogels possess unique therapeutic abilities by combining the therapeutic benefits of redox nanomaterials with enzymatic activity and the water-retaining capacity of hydrogels. The multifaceted therapeutic effects of these hydrogels include scavenging reactive oxygen species and other inflammatory mediators modulating immune responses toward a pro-regenerative environment and enhancing regenerative potential by triggering cell migration and differentiation. This review highlights the current state of the art in NZ-engineered hydrogels (NZ@hydrogels) for anti-inflammatory and skin regeneration applications. It also discusses the underlying chemo-mechano-biological mechanisms behind their effectiveness. Additionally, the challenges and future directions in this ground, particularly their clinical translation, are addressed. The insights provided in this review can aid in the design and engineering of novel NZ-based hydrogels, offering new possibilities for targeted and personalized skin-care therapies.

The clustered regularly interspaced short palindromic repeats (CRISPR)/associated protein 9 (CRISPR/Cas9) gene editing technology, as a revolutionary breakthrough in genetic engineering, offers a promising platform to improve the treatment of various genetic and infectious diseases because of its simple design and powerful ability to edit different loci simultaneously. However, failure to conduct precise gene editing in specific tissues or cells within a certain time may result in undesirable consequences, such as serious off-target effects, representing a critical challenge for the clinical translation of the technology. Recently, some emerging strategies using genetic regulation, chemical and physical strategies to regulate the activity of CRISPR/Cas9 have shown promising results in the improvement of spatiotemporal controllability. Herein, in this review, we first summarize the latest progress of these advanced strategies involving cell-specific promoters, small-molecule activation and inhibition, bioresponsive delivery carriers, and optical/thermal/ultrasonic/magnetic activation. Next, we highlight the advantages and disadvantages of various strategies and discuss their obstacles and limitations in clinical translation. Finally, we propose viewpoints on directions that can be explored to further improve the spatiotemporal operability of CRISPR/Cas9.

Mesoporous bioactive nanoparticles (MBNs) have been developed as promising additives to various types of bone or dentin regenerative material. However, biofunctionality of MBNs as dentin regenerative additive to dental materials have rarely been studied. We investigated the uptake efficiency of MBNs-NH2 with their endocytosis pathway and the role of MBNs-NH2 in odontogenic differentiation to clarify inherent biofunctionality. MBNs were fabricated by sol-gel synthesis, and 3% APTES was used to aminate these nanoparticles (MBNs-NH2) to reverse their charge from negative to positive. To characterize the MBNs-NH2, TEM, XRD, FTIR, zeta(ξ)-potential measurements, and Brunauer-Emmett-Teller analysis were performed. After primary cultured rat dental pulp stem cells (rDPSCs) were incubated with various concentrations of MBNs-NH2, stem cell viability (24 hours) with or without differentiated media, internalization of MBNs-NH2 in rDPSCs (~4 hours) via specific endocytosis pathway, intra or extracellular ion concentration and odontoblastic differentiation (~28 days) were investigated. Incubation with up to 50 μg/mL of MBNs-NH2 had no effect on rDPSCs viability with differentiated media (p>0.05). The internalization of MBNs-NH2 in rDPSCs was determined about 92% after 4 hours of incubation. Uptake was significantly decreased with ATP depletion and after 1 hour of pre-treatment with the inhibitor of macropinocytosis (p<0.05). There was significant increase of intracellular Ca and Si ion concentration in MBNs-NH2 treated cells compared to no-treated counterpart (p<0.05). The expression of odontogenic-related genes (BSP, COL1A, DMP-1, DSPP, and OCN) and the capacity for biomineralization (based on alkaline phosphatase activity and alizarin red staining) were significantly upregulated with MBNs-NH2. These results indicate that MBNs-NH2 induce odontogenic differentiation of rDPSCs and may serve as a potential dentin regenerative additive to dental material for promoting odontoblast differentiation.

Multistack and multimotor powertrain systems have significant potential for improving the efficiency and performance of fuel cell electric vehicles (FCEVs) compared to conventional powertrain systems. To achieve a superior powertrain system, the major components such as the stack, motor, and transmission of the multistack and multimotor systems should be optimized. To analyze the energy efficiency and dynamic performance of the FCEV, an FCEV analysis model was developed. This model included a two‐stack and two‐motor powertrain system (2S2M) employing a stack power and motor torque distribution strategy. An optimization problem was formulated with stack transition power, motor torque distribution, and transmission gear ratios as the optimization variables and hydrogen consumption and acceleration time as the objectives for efficiency and performance measures, respectively. An artificial neural network (ANN) model‐based optimization method was used to address the computational burden of multiobjective optimization. The optimization results highlighted the Pareto front for the FCEV employing 2S2M, showing a trade‐off relationship between the efficiency and performance of the FCEV. Compared to the conventional powertrain system, the 2S2M can reduce hydrogen consumption and acceleration time by up to 7.9% and 6.2%, respectively. An analysis of the distribution of optimal solutions and a comparison of the Pareto fronts for each optimization variable highlighted the necessity for the proposed system optimization method. Furthermore, a comparison between the FCEV and ANN models in terms of computational time for the optimization demonstrated the effectiveness of the ANN model‐based multiobjective optimization.

Although PMMA-based biomaterials are widely used in clinics, a major hurdle, namely, their poor antimicrobial (i.e., adhesion) properties, remains and can accelerate infections. In this study, carboxylated multiwalled carbon nanotubes (CNTs) were incorporated into poly(methyl methacrylate) (PMMA) to achieve drug-free antimicrobial adhesion properties. After characterizing the mechanical/surface properties, the anti-adhesive effects against 3 different oral microbial species ( Staphylococcus aureus , Streptococcus mutans , and Candida albicans ) were determined for roughened and highly polished surfaces using metabolic activity assays and staining for recognizing adherent cells. Carboxylated multiwalled CNTs were fabricated and incorporated into PMMA. Total fracture work was enhanced for composites containing 1 and 2% CNTs, while other mechanical properties were gradually compromised with the increase in the amount of CNTs incorporated. However, the surface roughness and water contact angle increased with increasing CNT incorporation. Significant anti-adhesive effects (35~95%) against 3 different oral microbial species without cytotoxicity to oral keratinocytes were observed for the 1% CNT group compared to the PMMA control group, which was confirmed by microorganism staining. The anti-adhesive mechanism was revealed as a disconnection of sequential microbe chains. The drug-free antimicrobial adhesion properties observed in the CNT-PMMA composite suggest the potential utility of CNT composites as future antimicrobial biomaterials for preventing microbial-induced complications in clinical settings (i.e., Candidiasis).

In recent years, multidrug-resistant (MDR) bacteria have increased rapidly, representing a major threat to human health. This problem has created an urgent need to identify alternatives for the treatment of MDR bacteria. The aim of this study was to identify the antibacterial activity of selenium nanoparticles (SeNPs) and selenium nanowires (SeNWs) against MDR bacteria and assess the potential synergistic effects when combined with a conventional antibiotic (linezolid). SeNPs and SeNWs were characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), zeta potential, and UV-visible analysis. The antibacterial effects of SeNPs and SeNWs were confirmed by the macro-dilution minimum inhibitory concentration (MIC) test. SeNPs showed MIC values against methicillin-sensitive S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), vancomycin-resistant S. aureus (VRSA), and vancomycin-resistant enterococci (VRE) at concentrations of 20, 80, 320, and >320 μg/mL, respectively. On the other hand, SeNWs showed a MIC value of >320 μg/mL against all tested bacteria. Therefore, MSSA, MRSA, and VRSA were selected for the bacteria to be tested, and SeNPs were selected as the antimicrobial agent for the following experiments. In the time-kill assay, SeNPs at a concentration of 4X MIC (80 and 320 μg/mL) showed bactericidal effects against MSSA and MRSA, respectively. At a concentration of 2X MIC (40 and 160 μg/mL), SeNPs showed bacteriostatic effects against MSSA and bactericidal effects against MRSA, respectively. In the synergy test, SeNPs showed a synergistic effect with linezolid (LZD) through protein degradation against MSSA and MRSA. In conclusion, these results suggest that SeNPs can be candidates for antibacterial substitutes and supplements against MDR bacteria for topical use, such as dressings. However, for use in clinical situations, additional experiments such as toxicity and synergistic mechanism tests of SeNPs are needed.

The aim of this study was to investigate the biomineralization of a newly introduced bioactive glass-incorporated light-curable pulp capping material using human dental pulp stem cells (hDPSCs). The product (Bioactive® [BA]) was compared with a conventional calcium hydroxide-incorporated (Dycal [DC]) and a light-curable (Theracal® [TC]) counterpart. Eluates from set specimens were used for investigating the cytotoxicity and biomineralization ability, determined by alkaline phosphatase (ALP) activity and alizarin red staining (ARS). Cations and hydroxide ions in the extracts were measured. An hDPSC viability of less than 70% was observed with 50% diluted extract in all groups and with 25% diluted extract in the DC. Culturing with 12.5% diluted BA extract statistically lowered ALP activity and biomineralization compared to DC (p<0.05), but TC did not (p>0.05). Ca (~110 ppm) and hydroxide ions (pH 11) were only detected in DC and TC. Ionic supplement-added BA, which contained similar ion concentrations as TC, showed similar ARS mineralization compared to TC. In conclusion, the BA was similar to, yet more cytotoxic to hDPSCs than, its DC and TC. The BA was considered to stimulate biomineralization similar to DC and TC only when it released a similar amount of Ca and hydroxide ions.

Advancing the technologies for cellular reprogramming with high efficiency has significant impact on regenerative therapy, disease modeling, and drug discovery. Biophysical cues can tune the cell fate, yet the precise role of external physical forces during reprogramming remains elusive. Here the authors show that temporal cyclic‐stretching of fibroblasts significantly enhances the efficiency of induced pluripotent stem cell (iPSC) production. Generated iPSCs are proven to express pluripotency markers and exhibit in vivo functionality. Bulk RNA‐sequencing reveales that cyclic‐stretching enhances biological characteristics required for pluripotency acquisition, including increased cell division and mesenchymal‐epithelial transition. Of note, cyclic‐stretching activates key mechanosensitive molecules (integrins, perinuclear actins, nesprin‐2, and YAP), across the cytoskeletal‐to‐nuclear space. Furthermore, stretch‐mediated cytoskeletal‐nuclear mechano‐coupling leads to altered epigenetic modifications, mainly downregulation in H3K9 methylation, and its global gene occupancy change, as revealed by genome‐wide ChIP‐sequencing and pharmacological inhibition tests. Single cell RNA‐sequencing further identifies subcluster of mechano‐responsive iPSCs and key epigenetic modifier in stretched cells. Collectively, cyclic‐stretching activates iPSC reprogramming through mechanotransduction process and epigenetic changes accompanied by altered occupancy of mechanosensitive genes. This study highlights the strong link between external physical forces with subsequent mechanotransduction process and the epigenetic changes with expression of related genes in cellular reprogramming, holding substantial implications in the field of cell biology, tissue engineering, and regenerative medicine.

Restoration of hard tissue in conjunction with adhesive is a globally challenging issue in medicine and dentistry. Common clinical therapies involving application of adhesive and substitute material for functional or anatomical recovery are still suboptimal. Biomaterials with bioactivity and inhibitory effects of enzyme-mediated adhesive degradation can render a solution to this. Here, we designed a novel copper-doped bioactive glass nanoparticles (CuBGn) to offer multifunction: metalloproteinases (MMP) deactivation and remineralization and incorporated the CuBGn in resin-dentin adhesive systems, which showed most common failure of MMP mediated adhesive degradation among hard tissue adhesives, to evaluate proposed therapeutic effects. A sol-gel derived bioactive glass nanoparticles doping 10 wt% of Cu (Cu-BGn) for releasing Cu ions, which were well-known MMP deactivator, were successfully created and included in light-curing dental adhesive (DA), a filler-free co-monomer resin blend, at different concentrations (up to 2 wt%). These therapeutic adhesives (CuBGn-DA) showed enhanced (a)cellular bioactivity, cytocompatibility, microtensile bond strength and MMP deactivation-ability. In conclusion, the incorporation of Cu ions releasing nano-bioactive glass demonstrated multifunctional properties at the resin-dentin interface; MMP deactivation and remineralization, representing a suitable strategy to extend the longevity of adhesive-hard tissue (i.e. resin-dentin) interfaces.