Smart Hydrogels for Tissue Regeneration.

The rapid growth in the portion of the aging population has led to a consequent increase in demand for biomedical hydrogels, together with an assortment of challenges that need to be overcome in this field. Smart hydrogels can autonomously sense and respond to the physiological/pathological changes of the tissue microenvironment and continuously adapt the response according to the dynamic spatiotemporal shifts in conditions. This along with other favorable properties, make smart hydrogels excellent materials for employing toward improving the precision of treatment for age-related diseases. The key factor during the smart hydrogel design is on accurately identifying the characteristics of natural tissues and faithfully replicating the composition, structure, and biological functions of these tissues at the molecular level. Such hydrogels can accurately sense distinct physiological and external factors such as temperature and biologically active molecules, so they may in turn actively and promptly adjust their response, by regulating their own biological effects, thereby promoting damaged tissue repair. This review summarizes the design strategies employed in the creation of smart hydrogels, their response mechanisms, as well as their applications in field of tissue engineering; and concludes by briefly discussing the relevant challenges and future prospects.

Corrigendum to "Development of methods for detecting the fate of mesenchymal stem cells regulated by bone bioactive materials" [Bioact. Mater. 6(3) (2021) 613-626].

[This corrects the article DOI: 10.1016/j.bioactmat.2020.08.035.].

Status, distribution, source, and risk of polychlorinated biphenyl levels in soils of five cities from the Hexi Corridor, Northwest China.

Few studies have been performed on the persistent organic pollutant contamination in soil from the plateau and remote areas, particularly the mid-latitude arid and semi-arid regions of Northwest China. The occurrence, spatial distribution, source, and potential risk of 12 polychlorinated biphenyls (PCBs) were investigated in soil collected from five Hexi Corridor cities in Northwest China. All of the PCBs were detected individually in the soil samples. The concentration of Σ12PCBs in the Hexi Corridor ranged from 2.0 to 148.5 ng/g, with an average of 21.3 ng/g. The tetra-CBs and hexa-CBs were the dominant PCB components in the soil. Higher PCB levels were found in the industrial city of Jiuquan, and the fewest PCBs were detected at Jinchang. Source analysis by principal component analysis showed that the dominant sources of PCBs were automobile exhaust, paint additives, insulation materials, and other industrial products. The carcinogenic health risk of PCBs in the Hexi Corridor soil was within acceptable levels, but the exposure risk of PCBs in soil for children was higher than that for adults.

Corrigendum to "Mussel-inspired nanozyme catalyzed conductive and self-setting hydrogel for adhesive and antibacterial bioelectronics" [Bioact. Mater. 6 (2021) 2676-2687 / 452].

[This corrects the article DOI: 10.1016/j.bioactmat.2021.01.033.].

Adhesive Gelatin-Catechol Complex Reinforced Poly(Acrylic Acid) Hydrogel with Enhanced Toughness and Cell Affinity for Cartilage Regeneration.

The repair of cartilage damage caused by trauma, wear, or degenerative deformation remains a major challenge in modern medicine. Therefore, it is essential to develop a mechanically compatible and bioactive scaffold for cartilage tissue regeneration. In this study, a mussel-inspired, tough, adhesive polydopamine/gelatin-poly(acrylic acid) (PDA/Gel-PAA) composite hydrogel was developed for cartilage regeneration. The hydrogel achieved a high compressive strength of up to 0.67 MPa and a toughness of 420 J/m2 because of the unique chemical-physical cross-linking structure by introducing the PDA/Gel complex into the PAA network. PAA chains with rich carboxyl groups mimic the negatively charged glycosaminoglycans (GAGs) in the natural cartilage extracellular matrix (ECM), leading to strong water retention in the hydrogel. The incorporation of the PDA/Gel complex with catechol groups on PDA and arginine-glycine-aspartic acid (RGD) sequences on gelatin chains provided abundant adhesive motifs to improve the cell affinity and tissue adhesiveness of PAA, thereby facilitating the adhesion and proliferation of bone marrow stromal cells (BMSCs). In addition, transforming growth factor-ß3 (TGFß3) was stably immobilized and released from the PDA/Gel-PAA hydrogel. Thus, adhesive hydrogels can provide a suitable microenvironment to promote cell migration in the defect area and induce chronogenesis for cartilage regeneration.

Mussel-inspired nanozyme catalyzed conductive and self-setting hydrogel for adhesive and antibacterial bioelectronics.

Adhesive hydrogels have broad applications ranging from tissue engineering to bioelectronics; however, fabricating adhesive hydrogels with multiple functions remains a challenge. In this study, a mussel-inspired tannic acid chelated-Ag (TA-Ag) nanozyme with peroxidase (POD)-like activity was designed by the in situ reduction of ultrasmall Ag nanoparticles (NPs) with TA. The ultrasmall TA-Ag nanozyme exhibited high catalytic activity to induce hydrogel self-setting without external aid. The nanozyme retained abundant phenolic hydroxyl groups and maintained the dynamic redox balance of phenol-quinone, providing the hydrogels with long-term and repeatable adhesiveness, similar to the adhesion of mussels. The phenolic hydroxyl groups also afforded uniform distribution of the nanozyme in the hydrogel network, thereby improving its mechanical properties and conductivity. Furthermore, the nanozyme endowed the hydrogel with antibacterial activity through synergistic effects of the reactive oxygen species generated via POD-like catalytic reactions and the intrinsic bactericidal activity of Ag. Owing to these advantages, the ultrasmall TA-Ag nanozyme-catalyzed hydrogel could be effectively used as an adhesive, antibacterial, and implantable bioelectrode to detect bio-signals, and as a wound dressing to accelerate tissue regeneration while preventing infection. Therefore, this study provides a promising approach for the fabrication of adhesive hydrogel bioelectronics with multiple functions via mussel-inspired nanozyme catalysis.

An Injectable, Bifunctional Hydrogel with Photothermal Effects for Tumor Therapy and Bone Regeneration.

Significant attention has been focused on bone tumor therapy recently. At present, the treatment in clinic typically requires surgical intervention. However, a few tumor cells remain around bone defects after surgery and subsequently proliferate within several days. Thus, fabrication of biomaterials with dual functions of tumor therapy and bone regeneration is significant. Herein, the injectable hydrogel containing cisplatin (DDP) and polydopamine-decorated nano-hydroxyapatite is prepared via Schiff base reaction between the aldehyde groups on oxidized sodium alginate and amino groups on chitosan. The hydrogel exhibits sustained release properties for DDP due to the immobilization of DDP via abundant functional groups on polydopamine (PDA). Additionally, given the intense absorption of PDA in the near-infrared region, the hydrogel exhibits excellent photothermal effects when exposed to the NIR laser (808 nm). Based on the properties, the hydrogel effectively ablates tumor cells (4T1 cells) in vitro and suppresses tumor growth in vivo. Furthermore, the hydrogel promotes the adhesion and proliferation of bone mesenchymal stem cells in vitro due to the abundant functional groups on PDA and further induces bone regeneration in vivo. Therefore, the study extends research on novel biomaterials with dual functions of tumor therapy and bone regeneration.

Mussel-Inspired Electroactive and Antioxidative Scaffolds with Incorporation of Polydopamine-Reduced Graphene Oxide for Enhancing Skin Wound Healing.

Wound repair and tissue regeneration are complex processes that involve many physiological signals. Thus, employing novel wound dressings with potent biological activity and physiological signal response ability to accelerate wound healing is a possible solution. Herein, inspired by mussel chemistry, we developed a polydopamine (PDA)-reduced graphene oxide (pGO)-incorporated chitosan (CS) and silk fibroin (SF) (pGO-CS/SF) scaffold with good mechanical, electroactive, and antioxidative properties as an efficient wound dressing. First, pGO with good dispersibility and cell affinity was obtained upon reduction by PDA under alkali conditions. Second, pGO was dispersed into a CS/SF mixture, and then CS and SF chains were dual-cross-linked by poly(ethylene glycol) diglycidyl ether and glutaraldehyde to obtain a pGO-incorporated gel. Finally, the gel underwent a freeze-dry process to obtain the pGO-CS/SF scaffold. Owing to PDA reduction and functionalization, pGO in the scaffold plays important roles for the performances of the scaffolds. First, the pGO acts as nanoreinforcement to enhance the mechanical properties of the scaffold by combining the dual-cross-linked CS/SF network. Second, the uniformly distributed pGO in the scaffolds comprises a well-connected electric pathway, which can provide a channel for the transmission of electrical signals in the scaffold. Moreover, pGO in the scaffolds serves as an antioxidant agent to scavenge reactive oxygen species (ROS) and therefore terminates excessive ROS oxidation. In vitro studies show that electroactive pGO-CS/SF scaffolds can respond to electrical signals and promote cytological behavior. In addition, the pGO-CS/SF scaffolds can reduce cellular oxidation by removing excessive ROS. The in vivo full-thickness skin defect model demonstrates that the electroactive and antioxidative pGO-CS/SF scaffold can efficiently enhance wound healing. In summary, the pGO-CS/SF scaffold is a promising wound dressing because of its ability to promote physiological electrical signal transmission for cell growth and reduce ROS oxidation, resulting in an improved wound regeneration effect.

A resilient and flexible chitosan/silk cryogel incorporated Ag/Sr co-doped nanoscale hydroxyapatite for osteoinductivity and antibacterial properties.

Cryogels from natural biopolymers, especially chitosan (CS) and silk fibroin (SF), have attracted significant attention for bone tissue engineering due to their good biocompatibility and tissue affinity. However, they are still not widely applied in clinics because of their poor mechanical properties, and lack of osteoinductivity and antibacterial properties. Here, by integrating a physico-chemical hybrid-crosslinking strategy and a freeze-drying method, the authors have prepared a resilient and flexible chitosan/silk cryogel with Ag and Sr co-doped hydroxyapatite (AgSrHA). The cryogel exhibits super resilience and flexibility, which guarantees the mechanical strength required for bone repair. Furthermore, the cryogel possesses long-term effective antibacterial properties and osteoinductivity due to the slow release of Ag and Sr ions. The physico-chemical hybrid-crosslinking points were introduced into a CS/SF network by treating with a mixture of alkaline and polyethylene glycol glycidyl ether (PEGDE) at 60 °C, which endowed the cryogel with super resilience and flexibility. Nanoscale AgSrHA was incorporated into the CS/SF network to further enhance the mechanical properties of the cryogel. In addition, Ag and Sr were doped into the HA crystal lattice, which not only prevents cytotoxicity by avoiding the ion burst release behavior, but also can achieve antibacterial and osteoinductive properties for a long period of time. In short, the AgSrHA/CS/SF cryogel with excellent mechanical properties and long-term effective dual-biofunction of antibacterial properties and osteoinductivity would be an ideal candidate for successful bone repair in clinics.

Mussel-inspired nano-building block assemblies for mimicking extracellular matrix microenvironments with multiple functions.

The assembly of nano-building blocks is an effective way to produce artificial extracellular matrix microenvironments with hierarchical micro/nano structures. However, it is hard to assemble different types of nano-building blocks, to form composite coatings with multiple functions, by traditional layer-by-layer (LbL) self-assembly methods. Inspired by the mussel adhesion mechanism, we developed polydopamine (PDA)-decorated bovine serum albumin microspheres (BSA-MS) and nano-hydroxyapatite (nano-HA), and assembled them to form bioactive coatings with micro/nano structures encapsulating bone morphogenetic protein-2 (BMP-2). First, PDA-decorated nano-HA (nano-pHA) was obtained by oxidative polymerization of dopamine on nano-HA. Second, BMP-2-encapsulated BSA microspheres were prepared through desolvation, and then were also decorated by PDA (pBSA-MS). Finally, the nano-pHA and pBSA-MS were assembled using the adhesive properties of PDA. Bone marrow stromal cell cultures and in vivo implantation, showed that the pHA/pBSA (BMP-2) coatings can promote cell adhesion, proliferation, and benefited for osteoinductivity. PDA decoration was also applied to assemble various functional nanoparticles, such as nano-HA, polystyrene, and Fe3O4 nanoparticles. In summary, this study provides a novel strategy for the assembly of biofunctional nano-building blocks, which surpasses traditional LbL self-assembly of polyelectrolytes, and can find broad applications in bioactive agents delivery or multi-functional coatings.

Polydopamine mediated assembly of hydroxyapatite nanoparticles and bone morphogenetic protein-2 on magnesium alloys for enhanced corrosion resistance and bone regeneration.

Magnesium alloys have the great potential to be used as orthopedic implants due to their biodegradability and mechanical resemblance to human cortical bone. However, the rapid degradation in physiological environment with the evolution of hydrogen gas release hinders their clinical applications. In this study, we developed a novel functional and biocompatible coating strategy through polydopamine mediated assembly of hydroxyapatite nanoparticles and growth factor, bone morphogenetic protein-2 (BMP-2), onto the surface of AZ31 Mg alloys. Such functional coating has strong bonding with the substrate and can increase surface hydrophilicity of magnesium alloys. In vitro electrochemical corrosion and hydrogen evolution tests demonstrate that the coating can significantly enhance the corrosion resistance and therefore slow down the degradation of AZ31 Mg alloys. In vitro cell culture reveals that immobilization of HA nanoparticles and BMP-2 can obviously promote cell adhesion and proliferation. Furthermore, in vivo implantation tests indicate that with the synergistic effects of HA nanoparticles and BMP-2, the coating does not cause obvious inflammatory response and can significantly reduce the biodegradation rate of the magnesium alloys and induce the new bone formation adjacent to the implants. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2750-2761, 2017.

Studies on the regulation of lipid metabolism and its mechanism of the iridoids rich fraction in Valeriana jatamansi Jones.

Valeriana jatamansi Jones, a plant with heart-shaped leaves in the Valeriana genus of Valerianaceae, is widely used in Chinese folk medicine. Iridoid is an important constituent of V. jatamansi that contributes to the pharmacological efficacy of the herb. This study aims to investigate the regulation of lipid metabolism and its mechanism of the iridoids rich fraction in V. jatamansi (IRFV). A high fat diet was used to establish the hyperlipidemia rat model, with 2mg/kg/d of simvastatin as a positive control, fed with 7.5, 15, and 30mg/kg/d of IRFV for 20days to investigate the lipid regulation activity and mechanism of IRFV. Body weight, liver index, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in both serum and liver, as well as total bile acid (TBA), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) in serum were measured. The lipoprotein lipase (LPL) and hepatic lipase (HL) activities and the apoprotein A5 (ApoA5), peroxisome proliferator-activated receptor α (PPAR-α), sterol regulatory element-binding proteins (SREBP-1c), and liver X receptor α (LXR-α) protein expressions were observed. Liver pathology was described through hematoxylin-eosin (HE) staining. Compared with the model group, three different IRFV dosages can slow down the weight gain of rats, reduce the contents of TG, and increase the contents of HDL-C in serum. Low IRFV dosage can significantly reduce the AST and ALT contents in serum, liver index, and the TG contents in liver, enhance LPL activity. Medium IRFV dosage can significantly decrease the TG and LDL-C contents in liver. High IRFV dosage can significantly reduce LDL-C, TBA, AST, and ALT contents in serum, and enhance HL activity. Three different IRFV dosages can significantly increase the ApoA5 and PPAR-α protein expression and decrease the SREBP-1c protein expression. Furthermore, the LXR-α protein expression decreased in low- and high-dose groups. Liver tissue pathological observation showed that IRFV can improve cell degeneration to a certain extent. These results strongly suggest that IRFV play significant roles in regulating lipid metabolism, the mechanism may be related to the increased ApoA5 protein expression.