Due to their intrinsic injectable and self-healing characteristics, dynamic hydrogels, based on dynamic covalent bonds, have gained a great attention. In this study, a novel dynamic hydrogel based on the boronic ester dynamic covalent bond is facilely developed using phenylboronic acid-modified hyaluronic acid (HA–PBA) and plant-derived polyphenol-tannic acid (TA). The dynamic hydrogel gelated quickly under mild conditions and had favorable viscoelastic properties with good self-healing and shear-thinning capabilities. Moreover, the simultaneous utilization of TA as a reductant for the green synthesis of silver nanoparticles (AgNP) inspired the preparation of a TA-reduced AgNP hybrid dynamic hydrogel with potent and broad-spectrum antibacterial activities. The dynamic hydrogels could also be applied for pH- and reactive oxygen species (ROS)-responsive release of loaded protein molecules without showing evident cytotoxicity and hemolysis in vitro. In addition, the dynamic hydrogels showed the anti-oxidative properties of high free radical and ROS scavenging capacity, which was verified by the DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) free radical assay and ROS fluorescence staining. Overall, this novel class of cytocompatible, self-healing, dual stimuli responsive, antibacterial, anti-oxidative, and injectable hydrogels could be promising as a wound dressing for chronic wound healing.

3D bioprinting holds great potential for use in tissue engineering to treat degenerative joint disorders, such as osteoarthritis. However, there is a lack of multifunctional bioinks that can not only support cell growth and differentiation, but also offer protection to cells against injuries caused by the elevated oxidative stress; this conditions is a common characteristic of the microenvironment of the osteoarthritis disease. To mitigate oxidative stress-induced cellular phenotype change and malfunction, an anti-oxidative bioink derived from an alginate dynamic hydrogel was developed in this study. The alginate dynamic hydrogel gelated quickly via the dynamic covalent bond between the phenylboronic acid modified alginate (Alg-PBA) and poly (vinyl alcohol) (PVA). It presented good self-healing and shear-thinning abilities because of the dynamic feature. The dynamic hydrogel supported long-term growth of mouse fibroblasts after stabilization with a secondary ionic crosslinking between introduced calcium ions and the carboxylate group in the alginate backbone. In addition, the dynamic hydrogel showed good printability, resulting in the fabrication of scaffolds with cylindrical and grid structures with good structural fidelity. Encapsulated mouse chondrocytes maintained high viability for at least 7 days in the bioprinted hydrogel after ionic crosslinking. Most importantly, in vitro studies implied that the bioprinted scaffold could reduce the intracellular oxidative stress for embedded chondrocytes under H₂O₂ exposure; it could also protect the chondrocytes from H₂O₂-induced downregulation of extracellular matrix (ECM) relevant anabolic genes (ACAN and COL2) and upregulation of a catabolic gene (MMP13). In summary, the results suggest that the dynamic alginate hydrogel can be applied as a versatile bioink for the fabrication of 3D bioprinted scaffolds with an innate antioxidative ability; this technique is expected to improve the regenerative efficacy of cartilage tissues for the treatment of joint disorders.

Injectable hydrogels show great promise for bone tissue engineering applications due to their high biocompatibility and drug delivery capabilities. The bone defects in osteoporosis are usually characterized by an oxidative and inflammatory microenvironment that impairs the regeneration capability of bone tissues. To attenuate the reactive oxygen species (ROS) and promote bone regeneration, an anti-oxidative hydrogel with osteogenic capacity was developed in this study. The poorly water soluble, natural antioxidant, resveratrol, was encapsulated in thiolated Pluronic F-127 micelles with over 50-times-enhanced solubility. The injectable hydrogel was facilely formed because of the new thioester bond between the free thiol group in modified F-127 and the arylate group in hyaluronic acid (HA)–acrylate. The resveratrol-loaded hydrogel showed good viscoelastic properties and in vitro stability and was cyto-compatible with bone-marrow-derived mesenchymal stem cells (BMSCs). The hydrogel allowed for a sustained release of resveratrol for at least two weeks and effectively enhanced the osteogenic differentiation of BMSCs by the up-regulation of osteogenic markers, including ALP, OCN, RUNX-2, and COL1. Moreover, the hydrogel exhibited anti-oxidative and anti-inflammatory abilities through the scavenging of intracellular ROS in RAW264.7 cells and inhibiting the gene expression and secretion of pro-inflammatory cytokines TNF-α and IL-1β under LPS exposure. In summary, the results suggest that our multifunctional hydrogel loaded with resveratrol bearing osteogenic, anti-oxidative, and anti-inflammatory actions is easily prepared and represents a promising resveratrol delivery platform for the repair of osteoporotic bone defects.

Chikungunya virus (CHIKV) is a positive-sense, single-stranded RNA virus, spread by the Aedes species (sp.) mosquitoes. Chikungunya virus (CHIKV) causes a condition characterized by high fever, headache, rash, and joint pain. Recent investigations reveal presence of bone lesions and erosive arthritis in the joints of CHIKV infected patients, indicating an association of bone pathology with CHIKV infection. However, the molecular mechanism underlying CHIKV-induced bone pathology remains poorly defined. Bone marrow derived mesenchymal stem cells (BMSCs) contribute to bone homeostasis by differentiating into osteogenic cells which later mature to form the bone. Disruption of osteogenic differentiation and function of BMSCs lead to bone pathologies. Studies show that virus infections can alter the properties and function of BMSCs. However, to date, pathogenesis of CHIKV infection in this context has not been studied. In the current study, we investigated the susceptibility of BMSCs and osteogenic cells to CHIKV and studied the effect of infection on these cells. To our knowledge, for the first time we report that CHIKV can productively infect BMSCs and osteogenic cells. We also observed a decreased gene expression of the major regulator of osteogenic differentiation, RUNX2 in CHIKV infected osteogenic cells. Furthermore, impaired functional properties of osteogenic cells i.e. decreased production and activity of alkaline phosphatase (ALP) and matrix mineralization were observed in the presence of CHIKV infection. Thus, we conclude that CHIKV likely impairs osteogenic differentiation of BMSCs indicating a possible role of BMSCs in altering bone homeostasis during CHIKV infection. Importance: Presently, no vaccines or treatment options are available for CHIKV infection. Joint pain is one of the major concerns. Although studies have shown an association between bone pathology and infection, the molecular pathogenesis in context of bone pathology is poorly defined. Here, we demonstrate for the first time that BMSCs and BMSC-derived osteogenic cells are susceptible to CHIKV infection and infection likely alters function of the osteogenic cells. This study highlights altered osteogenic differentiation as a possible mechanism for causing the bone pathology observed in CHIKV pathogenesis.

Chikungunya virus (CHIKV) is a positive-sense, single-stranded RNA virus, belonging to the genus alphavirus in the family Togaviridae . The virus is spread by the Aedes species (sp.) mosquitoes in tropical and subtropical regions of the world. CHIKV causes Chikungunya fever (CHIKF), where the acute stage of infection is characterized by high fever, headache, rash, and polyarthralgia. In 30-40% of cases, patients develop a chronic stage with debilitating joint pain persisting for months to years imposing a burden on the population in terms of disability adjusted life years (DALY). Presently, no vaccines or treatment options are available for this infection. Prior investigations reveal that CHIKV infection is associated with bone pathology; however, the molecular mechanism underlying CHIKV-induced bone pathology remains poorly defined. Studies show that disruption of osteogenic differentiation and function of bone marrow-derived mesenchymal stem cells (BMMSCs) can lead to bone pathologies. However, to date pathogenesis of CHIKV infection in this context has not been studied. In the current study, we investigated the susceptibility of BMMSCs to CHIKV and studied the effect of infection on BMMSCs-derived osteogenic cells. To our knowledge, for the first time we report that CHIKV can productively infect BMMSCs. We observed a decrease in the intracellular and extracellular alkaline phosphatase (ALP) activity and reduction in calcium phosphate deposition in infected cells compared to mock-infected control. Thus, we conclude that CHIKV infects BMMSCs and disrupts function of osteogenic cells. Importance: Although studies have shown association of bone pathology and CHIKV infection, the pathogenesis of infection causing altered bone homeostasis is not fully understood. Here, we demonstrate for the first time that BMMSCs are susceptible to CHIKV infection. Furthermore, we observe that infection causes disruption in the function of BMMSC- derived osteogenic cells. Impaired function of these osteogenic cells will likely lead to a disruption in bone homeostasis and in part, provides a mechanism for the observed bone pathology associated with CHIKV pathogenesis.