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Wound healing is a multifaceted process that involves hemostasis, inflammation, proliferation, and remodeling stages. Diabetic wounds affect the transition of the organized phases and result in delayed healing due to impaired angiogenesis, chronic inflammation, bacterial infection, and insufficient growth factors. Multifunctional heterostructural nanoparticles enriched minimally invasive hydrogels for on-demand procedural distribution to aid wound healing at various stages has become a promising strategy. Herein, silk fibroin-hyaluronic acid based injectable hydrogels incorporated with mace-like Au-CuS heterostructural nanoparticles (gAu-CuS HSs) were used to cure diabetic wounds. SF-HA and the rough surface of gAu-CuS HSs confer a synergistic hemostatic phase with a nano-bridge effect and rapidly close the wounds. During the inflammation stage, gAu-CuS HSs perform in-space resonance energy transfer under 808 nm laser irradiation which in return produces reactive oxygen species for bacterial destruction. The unusual mace-like rough structure of nanoparticles causes macrophage transfer to the M2 phenotype, regulates cytokine expression (interleukin 6, transforming factor-β1, interferon γ, and interleukin-10), promotes angiogenesis, and promotes cell multiplication and fibroblast emigration to the wound area during the proliferation and remodeling phase. Overall, the gAu-CuS HSs reinforced injectable hydrogel programmatically accelerates wound healing and could represent a versatile strategy for advanced diabetic wound healing.

Hydrogel-based wound dressings with tissue adhesion abilities are widely used for wound closure. However, currently developed hydrogel adhesives are still poor at continuing to seal wounds while bleeding is ongoing. Herein, we demonstrate an antibacterial and hemostatic hydrogel adhesive with low-swelling properties and toughness for wound healing. The hydrogel was composed of Pluronic F127 diacrylate, quaternized chitosan diacrylate, silk fibroin, and tannic acid, and it was not only able to maintain good tissue adhesion abilities in a moist environment but it also showed guaranteed tissue adhesion and mechanical strength after absorbing water due to its low-swelling and toughness properties. Furthermore, in vitro and in vivo tests demonstrated that the hydrogel also had antibacterial, antioxidant, and hemostatic properties, which could promote tissue regeneration. All these findings demonstrate that this hydrogel with multifunctional properties is a promising material for clinical wound healing applications.

Wound healing is a complex dynamic process. During the occurrence of skin injury, the excessive reactive oxygen species (ROS) level is associated with sustained inflammatory response, which limits efficient wound repair. Although multifunctional hydrogels are considered ideal wound dressings due to their unique advantages, the development of hydrogel dressings with rapid gelling rates, shape adaptation, and antioxidant function is still a vital challenge. In this work, a ROS-responsive injectable polyethylene glycol hydrogel containing thioketal bonds (PEG-TK hydrogel) was synthesized and utilized to deliver epidermal growth factor (EGF). We adopted bio-orthogonal click chemistry for crosslinking the polymer chains to obtain the EGF@PEG-TK hydrogel with fast gelation time, injectability and shape-adaptability. More interestingly, the thioketal bonds in the PEG-TK hydrogel not only scavenged excessive ROS in the wound sites but also achieved responsive and controlled EGF release to facilitate regeneration. The EGF@PEG-TK hydrogel treatment offered the benefits of protecting cells from oxidative stress, accelerating wound closure, and reducing scar formation in the full-thickness skin defect model. This work provides a promising strategy for developing antioxidant hydrogel dressing for facilitating the repair of wounds.

Artificial small-diameter blood vessels (SDBVs) are extremely limited in their thrombosis and still present significant clinical challenges worldwide. In recent years, 3D-bio-printing has offered a powerful technique to fabricate vessel channels in tissue engineering applications. Hydrogels are attractive bio-inks for SDBVs 3D-bio-printing, but they usually present weak mechanical properties. To overcome the weak mechanical properties of hydrogel bio-inks, a printable human umbilical vein endothelial cell (HUVEC)-laden polyrotaxane-alginate (PR-Alg) double-network (DN) hydrogel was fabricated. The PR-Alg DN hydrogel consists of a Ca 2+ cross-linked alginate network to form the first network rapidly, and a photo-cross-linked slide-ring network was designed as the second network. By combining special hydrogel structures of slide-ring (SR) and double network (DN), we significantly improved the mechanical properties of hydrogels. The PR-Alg DN hydrogel provides excellent stress (199 ± 20 kPa) and strain (1239 ± 58%), and the fracture energy reaches 668 ± 80 J/m 2 . Additionally, due to the presence of biocompatible materials and the gentle 3D-bio-printing process, the 3D-bio-printed channels showed outstanding biocompatibility, particularly in HUVECs' survival and proliferation. We anticipate that this work will expand the application of hydrogels with improved mechanical properties in biomedicine, particularly for artificial SDBVs.

Hyaluronic acid (HA) based hydrogels are one of most functional natural biomaterials in the field of cartilage tissue engineering (CTE). Even with the promising advantages of HA hydrogels, the complicated mechanical properties of the native cartilage have not been realized, and fabricating HA hydrogels with excellent mechanical properties to make them practical in CTE still remains a current challenge. Here, a strategy that integrates hydrogels and nanomaterials is shown to form a HA hydrogel with sufficient mechanical loading for cartilage tissue production and recombination. Cellulose nanofibrils (CNFs) are promising nanomaterial candidates as they possess high mechanical strength and excellent biocompatibility. In this study, we developed methacrylate-functionalized CNFs that are able to photo-crosslink with methacrylated HA to fabricate HA/CNF nanocomposite hydrogels. The present composite hydrogels with a compressive modulus of 0.46 ± 0.05 MPa showed adequate compressive strength (0.198 ± 0.009 MPa) and restorability, which can be expected to employ as a stress-bearing tissue such as articular cartilage. Besides, this nanocomposite hydrogel could provide a good microenvironment for bone marrow mesenchymal stem cell proliferation, as well as chondrogenic differentiation, and exhibit prominent repair effect in the full-thickness cartilage defect model of SD rats. These results suggest that the HA/CNF nanocomposite hydrogel creates a new possibility for fabricating a scaffold in CTE.

The success of complex tissue and internal organ reconstruction relies principally on the fabrication of a 3D vascular network, which guarantees the delivery of oxygen and nutrients in addition to the disposal of waste. In this study, a rapidly forming cell-encapsulated double network (DN) hydrogel is constructed by an ultrasonically activated silk fibroin network and bioorthogonal-mediated polyethylene glycol network. This DN hydrogel can be solidified within 10 s, and its mechanical property gradually increases to ∼20 kPa after 30 min. This work also demonstrates that coencapsulation of human umbilical vein endothelial cells (HUVECs) and umbilical cord-derived mesenchymal stem cells (UCMSCs) into the DN hydrogel can facilitate the formation of more mature vessels and complete the capillary network in comparison with the hydrogels encapsulated with a single cell type both in vitro and in vivo . Taking together, the DN hydrogel, combined with coencapsulation of HUVECs and UCMSCs, represents a strategy for the construction of a functional vascular network.

Wound dressings are widely used to promote wound healing. Traditional dressings need the help of tape to fix onto the wounds, which are not suitable in the human body. In addition, hemostasis of internal wounds is usually treated with direct sutures which will cause secondary trauma to the patient and increase the risk of infection. Therefore, development of new dressings with high tissue adhesion and biocompatibility is of great clinical significance. The highly adhesive wound dressings can firmly attach to external and internal wounds, and form a barrier to prevent bacterial invasion, accelerate healing, and avoid secondary damage caused by sutures. Hydrogels are soft materials that possess a 3D network structure with tunable physical and chemical properties, which provides ideal conditions to support the wound healing process. In this review, we summarize the recent advances in developing hydrogel-based wound dressings as well as their adhesion mechanism. Moreover, the prospects of these wound dressings over the coming years are also covered.

Tissue engineering is an important field of regenerative medicine, which combines scaffolds and cell transplantation to develop substitute tissues and/or promote tissue regeneration. Hydrogels, a three-dimensional network with high water content and biocompatibility, have been widely used as scaffolds to mimic the structure and properties of tissues. However, the low mechanical strength and limited functions of traditional hydrogels greatly limited their applications in tissue engineering. Recently, nanocomposite hydrogels, with its advantages of high mechanical property and some unique properties (such as electrical conductivity, antibacterial, antioxidation, magnetic responsiveness), have emerged as the most versatile and innovative technology, which provides a new opportunity as a unique tool for fabricating hydrogels with excellent properties. In this review, we summarize the recent advances in fabricating nanocomposite hydrogels and their applications in tissue engineering. In addition, the future and prospects of nanocomposite hydrogels for tissue engineering are also discussed.

An injectable BMSC-encapsulated double network (DN) hydrogel was fabricated via silk fibroin (SF) and poly(ethylene glycol) (PEG), which could efficiently support the survival and proliferation of BMSCs in vitro as well as cartilage repair in vivo, and provides a new strategy for cartilage tissue engineering.

Articular cartilage has limited self-healing ability due to its lack of abundant nutrients and progenitor cells. In this study, an injectable hydrogel system consisting of collagen type I-tyramine (Col-TA) and hyaluronic acid-tyramine (HA-TA) was fabricated as the bone marrow mesenchymal stem cell (BMSC)-laden hydrogel system for cartilage regeneration. Next, the physiochemical properties of this hydrogel system were well characterized and optimized, including gelation time, stiffness, water absorption and degradability. Further, the proliferation and differentiation of BMSCs within the Col-HA hydrogel were evaluated, and the ability of in vivo cartilage repair was also examined in the presence of the transforming growth factor-β1 (TGF-β1). These results illustrate that this hydrogel can offer a great microenvironment for BMSC growth and cartilage differentiation both in vitro and in vivo, and the Col-HA hydrogel can serve as an ideal hydrogel for cartilage tissue regeneration.

Bone-marrow-derived mesenchymal stem cells possess great potential for tissue engineering and regenerative medicine. In the work, an injectable BMSCs-laden hydrogel system was formed by enzyme-catalyzed crosslinking of hyaluronic acid-tyramine and chondroitin sulfate-tyramine in the presence of hydrogen peroxide and horseradish peroxidase, which was used as a 3D scaffold to explore the behavior of the mesenchymal stem cells. Afterward, the gelation rate, mechanical properties, as well as the degradation process of the scaffold were well characterized and optimized. Furthermore, bone morphogenetic protein-2 was encapsulated in the scaffold, which was used to improve the osteogenic properties. The results illustrated that such a BMSCs-laden hydrogel not only offered a proper microenvironment for the adhesion, proliferation and differentiation of mesenchymal stem cells in vitro, but also promoted bone regeneration in vivo. Therefore, this injectable BMSCs-laden hydrogel may serve as an efficient 3D scaffold for bone repair and regeneration., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Many patients suffer from bone injury and self-regeneration is not effective. Developing new strategies for effective bone injury repair is highly desired. Herein, collagen, an important component of the extracellular matrix, was modified with glycidyl methacrylate. The water solubility and photochemical cross-linking ability of the resulting collagen derivative was then improved. Thereafter, BMSC-laden hydrogel was fabricated using collagen modified with glycidyl methacrylate and hyaluronic acid modified with methacrylic anhydride under UV light in the presence of I 2959. The physicochemical properties were characterized suggesting that the hydrogel had great potential for enhancing cell adhesion and proliferation. Furthermore, without adding the bone morphogenetic protein-2, the collagen also promoted osteogenic differentiation of BMSCs within the hydrogel. Altogether, this hydrogel system provides a general strategy to fabricate cell-encapsulating hydrogel based on collagen and could be used as 3D scaffold for bone injury repair., (Copyright © 2018 Elsevier B.V. All rights reserved.)

An injectable in situ fast-forming hydrogel was easily fabricated through the inverse electron demand Diels-Alder click reaction between trans-cyclooctene and tetrazine. This hydrogel system simultaneously encapsulated bone morphogenetic protein-2 and BMSCs which showed potential applications in 3D bio-printing and tissue engineering.

Spinal cord injury (SCI) often causes severe and permanent disabilities due to the complexity of injury progression. The promising methods are generally based on tissue engineering technology using biocompatible hydrogels to achieve SCI repair. However, hydrogels are commonly incapable of close contact with the damaged spinal cord stumps and fail to support neural regeneration in SCI. Therefore, it is still a challenge to achieve stable contact with the transected nerve stumps and accelerate neural regeneration in the lesion microenvironment. Here, an in situ forming glycidyl methacrylated silk fibroin/ laminin-acrylate (SF-GMA/LM-AC) hydrogel was fabricated for SCI repair. The polymer chains formed a network quickly after ultraviolet (UV)-light trigger, in topological entanglement with the spinal cord, stitching the hydrogel and wet tissues together like a suture at the molecular scale. The SF-GMA/LM-AC hydrogel also provided a favorable environment for the growth of cells due to the incorporation of LM-AC. Compared with physical entrapment of LM, LM-AC immobilized in the hydrogel by covalent technology provided better microenvironments for neural stem cells (NSCs) growth. The repair of complete transection SCI in rats demonstrated that this hydrogel guided and promoted neural regeneration over 8 weeks, leading to hind limb locomotion recovery. This adhesive and bioactive SF-GMA/LM-AC hydrogel may open many opportunities in various therapeutic indications, including SCI. Many materials have been developed for building transplanted scaffolds, but it is still a challenge to fabricate bioactive scaffolds and adhesion to wet tissues. In this study, we successfully developed an in situ forming SF-GMA/LM-AC hydrogel for SCI repair. This in situ forming hydrogel formed significant adhesion to the native spinal cord, stitching hydrogel and tissue together like a suture at the molecular scale. In addition, covalent immobilized LM-AC was used as the contact guidance biochemical cues for axonal outgrowth and had much better bioactive effects than physically entangled LM. Moreover, this universal strategy would open an avenue to fabricate adhesive and bioactive hydrogel for various disease treatments including SCI. [Display omitted] [ABSTRACT FROM AUTHOR]

Hydrogels, especially injectable hydrogels, are promising materials due to their high water content and mechanical properties similar to natural tissues. Compared to the traditional hydrogels, injectable hydrogels can form in situ and reduce the invasiveness, which in turn reduces surgical and recovery costs. The past few years have seen a significant interest in the development of injectable hydrogels in research and clinical treatment. However, how to construct injectable biocompatible hydrogels rapidly and efficiently with proper mechanical properties remains a challenge. The 'Click' reaction, with its property of easy preparation and rapid reaction rate, has emerged as the most versatile and innovative technology, especially the bio-orthogonal reactions which provide a new opportunity as a unique tool for fabricating fast-forming injectable biocompatible hydrogels. In this review, we summarize the recent advances in fabricating injectable hydrogels via bio-orthogonal reactions. [ABSTRACT FROM AUTHOR]

Summary Many DNA and RNA regulatory proteins contain polypeptide domains that are unstructured when analyzed in cell lysates. These domains are typified by an over-representation of a limited number of amino acids and have been termed prion-like, intrinsically disordered or low-complexity (LC) domains. When incubated at high concentration, certain of these LC domains polymerize into labile, amyloid-like fibers. Here, we report methods allowing the generation of a molecular footprint of the polymeric state of the LC domain of hnRNPA2. By deploying this footprinting technique to probe the structure of the native hnRNPA2 protein present in isolated nuclei, we offer evidence that its LC domain exists in a similar conformation as that described for recombinant polymers of the protein. These observations favor biologic utility to the polymerization of LC domains in the pathway of information transfer from gene to message to protein. [ABSTRACT FROM AUTHOR]