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Highlights Derived from silica photonic crystals, inverse opal microspheres have a regularly connected porous structure and inherit structural color properties. Combined with the stable scaffold and the photothermal phase-transition of the secondary filling material, the inverse opal composite microspheres are endowed with self-healing properties and the ability for controllable drug release. Inverse opal microspheres were significantly treated for diabetic wound, via promoting tissue regeneration, collagen deposition and angiogenesis. Meanwhile, the release of drugs could be monitored by the structural color characteristic.

Highlights: Derived from silica photonic crystals, inverse opal microspheres have a regularly connected porous structure and inherit structural color properties. Combined with the stable scaffold and the photothermal phase-transition of the secondary filling material, the inverse opal composite microspheres are endowed with self-healing properties and the ability for controllable drug release. Inverse opal microspheres were significantly treated for diabetic wound, via promoting tissue regeneration, collagen deposition and angiogenesis. Meanwhile, the release of drugs could be monitored by the structural color characteristic. Chronic diabetic wounds confront a significant medical challenge because of increasing prevalence and difficult-healing circumstances. It is vital to develop multifunctional hydrogel dressings, with well-designed morphology and structure to enhance flexibility and effectiveness in wound management. To achieve these, we propose a self-healing hydrogel dressing based on structural color microspheres for wound management. The microsphere comprised a photothermal-responsive inverse opal framework, which was constructed by hyaluronic acid methacryloyl, silk fibroin methacryloyl and black phosphorus quantum dots (BPQDs), and was further re-filled with a dynamic hydrogel. The dynamic hydrogel filler was formed by Knoevenagel condensation reaction between cyanoacetate and benzaldehyde-functionalized dextran (DEX-CA and DEX-BA). Notably, the composite microspheres can be applied arbitrarily, and they can adhere together upon near-infrared irradiation by leveraging the BPQDs-mediated photothermal effect and the thermoreversible stiffness change of dynamic hydrogel. Additionally, eumenitin and vascular endothelial growth factor were co-loaded in the microspheres and their release behavior can be regulated by the same mechanism. Moreover, effective monitoring of the drug release process can be achieved through visual color variations. The microsphere system has demonstrated desired capabilities of controllable drug release and efficient wound management. These characteristics suggest broad prospects for the proposed composite microspheres in clinical applications. [ABSTRACT FROM AUTHOR]

Bone defects induced by trauma, infection, and tumors present a significant challenge for treatment in clinical trials. Biomaterial-based tissue engineering strategy has shown great promise in bone defect repair. However, multiple functions inherent in the extracellular matrix (ECM) are rarely covered in the design of scaffold materials associated with bone grafting procedures. These deficiencies significantly limit its potential application in pathologic bone defect therapy. In this work, we constructed a hydrogel scaffold mimicking the dynamic features of ECM with the combination of antimicrobial and osteogenic capabilities as well, to investigate its applications in the therapy of infected radial defects. The hydrogel scaffold enables not only minimally invasive implantation but also adaptability and adhesion to irregular defect shapes. Both in vitro and in vivo assays have indicated that the hydrogel scaffold could rapidly eradicate bacteria, restore the infection-induced localized inflammatory microenvironment. Further loading osteogenic growth peptide (OGP) to recruit stem cells promotes osteogenic differentiation and ultimately enhances bone regeneration in the defect region. In summary, our work indicated that hydrogels with ECM-related inherent bioactivities and dynamic inner structures represent a feasible solution as a tissue bionic substitute for the therapy of infected bone defects.

Introduction: Over-activation of oxidative stress due to impaired antioxidant functions in nucleus pulpous (NP) has been identified as a key factor contributing to intervertebral disc degeneration (IVDD). While Kartogenin (KGN) has previously demonstrated antioxidant properties on articular cartilage against osteoarthritis, its effects on NP degeneration have yet to be fully understood. Objectives: This study aimed to investigate the protective effects of KGN on nucleus pulpous cells (NPCs) against an inflammatory environment induced by interleukin (IL)-1β, as well as to explore the therapeutic potential of KGN-enhanced dynamic hydrogel in preventing IVDD. Methods: NPCs were isolated from rat caudal IVDs and subjected to treatment with KGN at varying concentrations (ranging from 0.01 to 1 ​μM) in the presence of IL-1β. The expression of extracellular matrix (ECM) anabolism markers was quantitatively assessed at both the mRNA and protein levels. Additionally, intracellular reactive oxygen species and antioxidant enzyme expression were evaluated, along with the role of nuclear factor erythroid 2-related factor 2 (NRF2). Based on these findings, a dynamic self-healing hydrogel loaded with KGN was developed through interconnecting networks. Subsequently, KGN-enhanced dynamic hydrogel was administered into rat caudal IVDs that had undergone puncture injury, followed by radiographic analysis and immunohistochemical staining to evaluate the therapeutic efficacy. Results: In vitro treatments utilizing KGN were observed to maintain ECM synthesis and inhibit catabolic activities in IL-1β-stimulated NPCs. The mechanism behind this protective effect of KGN on NPCs was found to involve the asctivation of NRF2 and downstream antioxidant enzymes, including glutathione peroxidase 1 and heme oxygenase 1. This was further supported by the loss of both antioxidant and anabolic effects upon pharmacological inhibition of NRF2. Furthermore, a self-healing hydrogel was developed and loaded with KGN to achieve localized and sustained release of the compound. The injection of KGN-enhanced hydrogel effectively ameliorated the degradation of NP ECM and mitigated inflammation in a rat model of puncture-induced IVDD. Conclusions: Our results indicate that KGN exhibits potential as a therapeutic agent for NP degeneration, and that KGN-enhanced dynamic hydrogel represents a novel approach for treating IVDD by restoring redox homeostasis in NP.The translational potential of this article: The dysregulation of oxidant and antioxidant balance has been shown to impede the repair and regeneration of NP, thereby hastening the progression of IVDD following injury. The present investigation has demonstrated that the sustained release of KGN promotes the synthesis of ECM in vitro and mitigates the progression of IVDD in vivo by restoring redox equilibrium, thereby presenting a novel therapeutic candidate based on the antioxidant properties of KGN for the treatment of IVDD.

Bioprinting is a booming technology, with numerous applications in tissue engineering and regenerative medicine. However, most biomaterials designed for bioprinting depend on the use of sacrificial baths and/or non‐physiological stimuli. Printable biomaterials also often lack tunability in terms of their composition and mechanical properties. To address these challenges, the authors introduce a new biomaterial concept that they have termed "clickable dynamic bioinks". These bioinks use dynamic hydrogels that can be printed, as well as chemically modified via click reactions to fine‐tune the physical and biochemical properties of printed objects after printing. Specifically, using hyaluronic acid (HA) as a polymer of interest, the authors investigate the use of a boronate ester‐based crosslinking reaction to produce dynamic hydrogels that are printable and cytocompatible, allowing for bioprinting. The resulting dynamic bioinks are chemically modified with bioorthogonal click moieties to allow for a variety of post‐printing modifications with molecules carrying the complementary click function. As proofs of concept, the authors perform various post‐printing modifications, including adjusting polymer composition (e.g., HA, chondroitin sulfate, and gelatin) and stiffness, and promoting cell adhesion via adhesive peptide immobilization (i.e., RGD peptide). The results also demonstrate that these modifications can be controlled over time and space, paving the way for 4D bioprinting applications. [ABSTRACT FROM AUTHOR]

Abstract Bioprinting is a booming technology, with numerous applications in tissue engineering and regenerative medicine. However, most biomaterials designed for bioprinting depend on the use of sacrificial baths and/or non‐physiological stimuli. Printable biomaterials also often lack tunability in terms of their composition and mechanical properties. To address these challenges, the authors introduce a new biomaterial concept that they have termed “clickable dynamic bioinks”. These bioinks use dynamic hydrogels that can be printed, as well as chemically modified via click reactions to fine‐tune the physical and biochemical properties of printed objects after printing. Specifically, using hyaluronic acid (HA) as a polymer of interest, the authors investigate the use of a boronate ester‐based crosslinking reaction to produce dynamic hydrogels that are printable and cytocompatible, allowing for bioprinting. The resulting dynamic bioinks are chemically modified with bioorthogonal click moieties to allow for a variety of post‐printing modifications with molecules carrying the complementary click function. As proofs of concept, the authors perform various post‐printing modifications, including adjusting polymer composition (e.g., HA, chondroitin sulfate, and gelatin) and stiffness, and promoting cell adhesion via adhesive peptide immobilization (i.e., RGD peptide). The results also demonstrate that these modifications can be controlled over time and space, paving the way for 4D bioprinting applications.

Poly(acrylic acid‐co‐N‐vinylcaprolactam) (PAN) hydrogels containing multiple hydrogen bonds can exhibit pH‐induced reversible dynamic responsive behaviors. When placing a transparent hydrogel in an acid bath, as hydrogen bonds between comonomer units involving protonated COOH groups are formed faster than water diffusion, a nonequilibrium light‐scattering state is formed to turn the hydrogel opaque, while as the swelling equilibrium is reached over time, the hydrogel regains its transparency. Likewise, when the transparent, hydrogen‐bonded hydrogel is subsequently immersed in DI water, faster water absorption occurs in where more COOH groups are deprotonated, which also generates a light‐scattering state leading to opacity, while the transparency is slowly recovered after equilibrium. Using such two‐way dynamic transparency evolution, a PAN‐based hydrogel material is prepared to demonstrate a dynamic memory system for information memorizing‐forgetting and recalling‐forgetting. [ABSTRACT FROM AUTHOR]

A dynamic hydrogel was prepared from N,O‐carboxymethyl chitosan (NOCC) and oxidized aldehyde‐containing hyaluronic acid (A‐HA) by Schiff base reaction. The resulted NOCC/A‐HA hydrogels were characterized by Fourier transform infrared spectroscopy and scanning electron microscopy (SEM). The rheological, swelling, and self‐healing properties of hydrogels were determined. The hydrogels present interconnected porous structure, high swelling rate, and outstanding self‐healing capacity. The biocompatibility of hydrogels was evidenced by MTT assay and zebrafish embryonic toxicity test. Human umbilical cord blood mononuclear cells (CB‐MNC) were encapsulated in the hydrogel. High cell viability above 50% was obtained after 21 days culture. A mouse scald model was realized to evaluate the potential of cell laden hydrogel in wound healing. Compared to the control group and the hydrogel group, the cell laden hydrogel group exhibits faster epidermal regeneration, reduced inflammation and more neovascularization. Therefore, NOCC/A‐HA hydrogels encapsulating CB‐MNC could be a promising therapy in the treatment of burns or scalds. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Flexible hydrogels containing various osteogenic inorganic constituents, which can accommodate complicated shape variations, are considered as ideal grafts for craniofacial bone defect reconstruction. However, in most hybrid hydrogels, poor interaction between the polymer network and particles has detrimental effects on hydrogel rheological and structural properties, clinical manipulation and repair efficacy. In this article, we designed and prepared a series of hyaluronic acid composite hydrogel containing Cu-doped bioactive glass (CuBG) and phosphoserine (PS), in which hyaluronic acid was modified by methacrylate groups and phenylboronic acid groups to form a double crosslinked network. PS acted as an interaction bridge of CuBG particles and HAMA-PBA network to improve the mechanical properties of the composite hydrogels. The CuBG/PS hydrogels exhibited suitable rheological properties (injectable, self-healing, shape-adaptable), bone tissue integrating ability and anti-bacterial property. Meanwhile, we found that CuBG and PS have synergistic effect on improving osteogenic efficiency both in vitro and in vivo , particularly when the ratio of CuBG to PS is lower than 3 (9CB/3PS). This work provided a versatile and scalable approach to enhanced the interaction within inorganic particles and polymer network in hydrogels without extra modification on components. [ABSTRACT FROM AUTHOR]

[Display omitted] • A low-cost homogeneous microsphere production device was designed. • Porous microsphere with good biocompatibility were produced for cell loading. • Controlled release of MSCs-laden microspheres using the microenvironment response mechanism. • The spatiotemporal delivery of hydrogel platform promotes abdominal wall repair. Healing the wounds of abdominal wall defects characterised by severe complications represents a significant clinical challenge. Mesenchymal stem cells (MSC)-based therapies have emerged as a promising strategy for tissue regeneration. However, the low engraftment and survival rates limit their application owing to the complicated wound microenvironment and large wound areas in abdominal wall defects. Inspired by focal biointerfaces, the present research engineered a spatiotemporal delivery microenvironment-responsive therapeutic platform, termed MSC-GSM@HG, for abdominal wall repair. The constructed platform proved capable of dissolving HA-PBA/Gel-DA (HG) hydrogels in response to in vivo inflammatory responses and subsequently releasing MSC-laden gelatine and silk fibroin microspheres (GSMs). Meanwhile, the HG hydrogels can not only protect the MSCs from excessive reactive oxygen species but also exhibit haemostatic and anti-inflammatory properties. Strikingly, this microsphere-releasing hydrogel platform actively enhanced the repair of abdominal wall defects in vivo , by reducing inflammatory response, facilitating angiogenesis and promoting collagen deposition. Therefore, the microenvironment-responsive platform represents a promising strategy for MSC-based therapies for abdominal wall defects through spatiotemporal delivery mechanisms. [ABSTRACT FROM AUTHOR]

[Display omitted] • A polyphenol-mediated and ZIF-8 nanoparticle-enhanced hydrogel for diabetic wound healing. • The hydrogel exhibited injectable, adhesion and self-healing properties for irregular wounds. • The QCT-ZIF-8 system improved mitochondrial dysfunction and ER stress in hyperglycaemia. • The hydrogel promoted HUVECs angiogenesis and alleviated vascular dysfunction. • The hydrogel collapsed bacterial membrane and induced content loss to control infection. An important challenge in the chronic wound healing of diabetes is delayed healing stages with impaired cellular functions, attributed to mitochondrial dysfunction and excessive endoplasmic reticulum (ER) stress. Here, we describe a quercetin (QCT)-loaded zeolitic imidazolate framework (ZIF-8) incorporated into a polyphenol-mediated carboxymethyl chitosan/tannic acid (CT) dynamic hydrogel to promote diabetic wound healing by regulating subcellular and cellular functions. ZIF-8 endows the hydrogel with excellent antibacterial properties. By alleviating mitochondrial function and ER stress, the hydrogel fundamentally improves the cellular function damage induced by hyperglycemia and is endowed with reactive oxygen species (ROS)-scavenging and anti-apoptosis activities to promote cell proliferation, extension and keratinocyte differentiation. Moreover, sustained release of QCT and Zn2+ from the QCT@ZIF-8 system not only promotes vascular endothelial cell migration but also alleviates tubular dysfunction, thus achieving excellent angiogenesis. Accordingly, these features create a favorable environment for skin regeneration and synergistically accelerate diabetic wound healing. Therefore, our findings reveal a potential multi-effect therapeutic strategy for diabetic wound healing. Potential design principles targeting subcellular and cell function open up new avenues for other metabolic and inflammatory diseases. [ABSTRACT FROM AUTHOR]

Hydrogels containing thermosensitive polymers such as poly(N‐isopropylacrylamide) (P(NIPAm)) may contract during heating and show great promise in fields ranging from soft robotics to thermosensitive biosensors. However, these gels often exhibit low stiffness, tensile strength, and mechanical toughness, limiting their applicability. Through copolymerization of P(NIPAm) with poly(Acrylic acid) (P(AAc)) and introduction of ferric ions (Fe3+) that coordinate with functional groups along the P(AAc) chains, here a thermoresponsive hydrogel with enhanced mechanical extensibility, strength, and toughness is introduced. Using both experimentation and constitutive modeling, it is found that increasing the ratio of m(AAc):m(NIPAm) in the prepolymer decreases strength and toughness but improves extensibility. In contrast, increasing Fe3+ concentration generally improves strength and toughness with little decrease in extensibility. Due to reversible coordination of the Fe3+ bonds, these gels display excellent recovery of mechanical strength during cyclic loading and self‐healing ability. While thermosensitive contraction imbued by the underlying P(NIPAm) decreases slightly with increased Fe3+ concentration, the temperature transition range is widened and shifted upward toward that of human body temperature (between 30 and 40 °C), perhaps rendering these gels suitable as in vivo biosensors. Finally, these gels display excellent adsorptive properties with a variety of materials, rendering them possible candidates in adhesive applications. [ABSTRACT FROM AUTHOR]

Constructing hydrogels with spatially heterogeneous structures are crucial for unlocking novel applications. To this end, selectively removing a specific portion of hydrogels by facile and intricate destructive strategies is worth exploring. Herein, a "contact-destructive" hydrogel actuator is presented, composed of a dynamic hydrogel network doped with hydrophilic polyethylene glycol (PEG). The destructive behavior of the hydrogel actuator is attributed to the surface tension-induced spreading effect and the enhanced water absorption due to the additive PEG. Parameters that act on these mechanisms are used to control the destruction of the hydrogel. During the destructive process, the hydrogel actuator exhibits locomotion routes predetermined by the graphic pattern with the aid of 3D printing. Additionally, such self-destructive behavior can be terminated by UV light irradiation when PEG is replaced with poly(ethylene glycol) diacrylate (PEGDA). Significantly, diverse applications including controllable 3D structures collapse, self-erasing, and on-demand cell release, are realized with such self-destructive hydrogel. These results demonstrate that the present hydrogel has great values in soft robotics, anti-counterfeiting, controlled drug delivery, and other related fields., (© 2024 Wiley‐VCH GmbH.)

Engineered living materials (ELMs) are a new class of materials in which living organism incorporated into diffusive matrices uptake a fundamental role in material's composition and function. Understanding how the spatial confinement in 3D can regulate the behavior of the embedded cells is crucial to design and predict ELM's function, minimize their environmental impact and facilitate their translation into applied materials. This study investigates the growth and metabolic activity of bacteria within an associative hydrogel network (Pluronic‐based) with mechanical properties that can be tuned by introducing a variable degree of acrylate crosslinks. Individual bacteria distributed in the hydrogel matrix at low density form functional colonies whose size is controlled by the extent of permanent crosslinks. With increasing stiffness and elastic response to deformation of the matrix, a decrease in colony volumes and an increase in their sphericity are observed. Protein production follows a different pattern with higher production yields occurring in networks with intermediate permanent crosslinking degrees. These results demonstrate that matrix design can be used to control and regulate the composition and function of ELMs containing microorganisms. Interestingly, design parameters for matrices to regulate bacteria behavior show similarities to those elucidated for 3D culture of mammalian cells. [ABSTRACT FROM AUTHOR]

Abstract Engineered living materials (ELMs) are a new class of materials in which living organism incorporated into diffusive matrices uptake a fundamental role in material's composition and function. Understanding how the spatial confinement in 3D can regulate the behavior of the embedded cells is crucial to design and predict ELM's function, minimize their environmental impact and facilitate their translation into applied materials. This study investigates the growth and metabolic activity of bacteria within an associative hydrogel network (Pluronic‐based) with mechanical properties that can be tuned by introducing a variable degree of acrylate crosslinks. Individual bacteria distributed in the hydrogel matrix at low density form functional colonies whose size is controlled by the extent of permanent crosslinks. With increasing stiffness and elastic response to deformation of the matrix, a decrease in colony volumes and an increase in their sphericity are observed. Protein production follows a different pattern with higher production yields occurring in networks with intermediate permanent crosslinking degrees. These results demonstrate that matrix design can be used to control and regulate the composition and function of ELMs containing microorganisms. Interestingly, design parameters for matrices to regulate bacteria behavior show similarities to those elucidated for 3D culture of mammalian cells.

Most adhesives lose adhesion in the presence of sweat. A sweat-adaptive adhesive hydrogel was developed here through dynamic hydrogen bond networks. The sodium chloride released during sweating functions as the salting in effect which decouples hydrogen bonds of the polymer network exposing more polar groups which contributes to enhanced interfacial adhesion, enabling higher adhesion energy at the hydrogel-tissue interface. [Display omitted] • The enabling sweat-adaptive adhesive hydrogel via dynamic hydrogen bond networks. • Cellulose contributes a lot to adhesive properties of the hydrogel. • The hydrogel combines high interfacial toughness and adhesion strength. • Tough bioadhesion toward advanced bioelectronics for EMG monitoring upon sweating. Adhesive hydrogels offer an appealing way to the demand for flexible epidermal electronics. Despite the significant advances of adhesive hydrogel electronics, the unavoidable degradation of adhesion and associated diminished detection on sweaty skin are two long-standing bottlenecks for their practical applications. Herein, we present a sweat-adaptive adhesive poly(acrylamide)/cellulose (PAAm/Cel) hydrogel electronic via dynamic hydrogen bond networks. Increased sweat promotes the decoupling of hydrogen bonds within the hydrogel between PAAm and cellulose, leading to enhanced skin-hydrogel interfacial adhesion due to the strong binding of exposed abundant polar groups to the skin. The resulting PAAm/Cel hydrogel exhibits robust bioadhesion on sweating skin, with 268.3 J m−2 in interfacial toughness, 201.7 kPa in tensile strength, and 31.7 kPa in shear strength. Furthermore, the conformable and adhesive PAAm/Cel hydrogel electronics are demonstrated to produce high-quality and stable electromyogram (EMG) signals worked on persistent sweating skin. We believe that our designed adhesive hydrogel with dynamic hydrogen bond networks coupled with sweat is promising for tough bioadhesive electronics and enables bioadhesive technologies with high-level adaptivity in daily activities. [ABSTRACT FROM AUTHOR]

Wound healing in diabetic patients presents significant challenges in clinical wound care due to high oxidative stress, excessive inflammation, and a microenvironment prone to infection. In this study, we successfully developed a multifunctional tandem dynamic covalently cross-linked hydrogel dressing aimed at diabetic wound healing. This hydrogel was constructed using cyanoacetic acid functionalized dextran (Dex-CA), 2-formylbenzoylboric acid (2-FPBA) and natural oligomeric proanthocyanidins (OPC), catalyzed by histidine. The resulting Dex-CA/OPC/2-FPBA (DPOPC) hydrogel can be dissolved triggered by cysteine, thereby achieving "controllable and non-irritating" dressing change. Furthermore, the incorporation of OPC as a hydrogel building block endowed the hydrogel with antioxidant and anti-inflammatory properties. The cross-linked network of the DPOPC hydrogel circumvents the burst release of OPC, enhancing its biosafety. In vivo studies demonstrated that the DPOPC hydrogel significantly accelerated the wound healing process in diabetic mice compared to a commercial hydrogel, achieving an impressive wound closure rate of 98 % by day 14. The DPOPC hydrogel effectively balanced the disrupted inflammatory state during the healing process. This dynamic hydrogel based on natural polyphenols is expected to be an ideal candidate for dressings intended for chronic wounds. [ABSTRACT FROM AUTHOR]

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.

• A comprehensive overview of the design and applications of dynamic hydrogels. • Elucidating physicochemical mechanisms for various crosslinking methods. • Discussing the full factorial design of nanocomposite hydrogels for drug release. • Highlights of multi-scale biomedical applications of dynamic hydrogels. • Delving into the challenges and future prospects of dynamic hydrogels in clinical practice. Hydrogels have emerged in various biomedical applications, including tissue engineering and medical devices, due to their ability to imitate the natural extracellular matrix (ECM) of tissues. However, conventional static hydrogels lack the ability to dynamically respond to changes in their surroundings to withstand the robust changes of the biophysical microenvironment and to trigger on-demand functionality such as drug release and mechanical change. In contrast, multifunctional dynamic hydrogels can adapt and respond to external stimuli and have drawn great attention in recent studies. It is realized that the integration of nanomaterials into dynamic hydrogels provides numerous functionalities for a great variety of biomedical applications that cannot be achieved by conventional hydrogels. This review article provides a comprehensive overview of recent advances in designing and fabricating dynamic hydrogels for biomedical applications. We describe different types of dynamic hydrogels based on breakable and reversible covalent bonds as well as noncovalent interactions. These mechanisms are described in detail as a useful reference for designing crosslinking strategies that strongly influence the mechanical properties of the hydrogels. We also discuss the use of dynamic hydrogels and their potential benefits. This review further explores different biomedical applications of dynamic nanocomposite hydrogels, including their use in drug delivery, tissue engineering, bioadhesives, wound healing, cancer treatment, and mechanistic study, as well as multiple-scale biomedical applications. Finally, we discuss the challenges and future perspectives of dynamic hydrogels in the field of biomedical engineering, including the integration of diverse technologies. [ABSTRACT FROM AUTHOR]

[Display omitted] • Natural derived strategy. • ECM-like remodeling capacity and antimicrobial properties. • Regulating bone repair microenvironment. Bone defects induced by trauma, infection, and tumors present a significant challenge for treatment in clinical trials. Biomaterial-based tissue engineering strategy has shown great promise in bone defect repair. However, multiple functions inherent in the extracellular matrix (ECM) are rarely covered in the design of scaffold materials associated with bone grafting procedures. These deficiencies significantly limit its potential application in pathologic bone defect therapy. In this work, we constructed a hydrogel scaffold mimicking the dynamic features of ECM with the combination of antimicrobial and osteogenic capabilities as well, to investigate its applications in the therapy of infected radial defects. The hydrogel scaffold enables not only minimally invasive implantation but also adaptability and adhesion to irregular defect shapes. Both in vitro and in vivo assays have indicated that the hydrogel scaffold could rapidly eradicate bacteria, restore the infection-induced localized inflammatory microenvironment. Further loading osteogenic growth peptide (OGP) to recruit stem cells promotes osteogenic differentiation and ultimately enhances bone regeneration in the defect region. In summary, our work indicated that hydrogels with ECM-related inherent bioactivities and dynamic inner structures represent a feasible solution as a tissue bionic substitute for the therapy of infected bone defects. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The paper focuses on the synthesis and characterization of new drug delivery systems for local therapy. They were prepared by in situ hydrogelation of chitosan biopolymer with nitrosalicylaldehyde in the presence of a model drug, varying the crosslinking density. The structural, supramolecular and morphological characteristics of the systems were studied by FTIR spectroscopy, X-ray diffraction and, POM and SEM microscopy. In vitro release of the drug has been explored in simulated physiological conditions and in vivo release was investigated by the somatic pain model on rats. Information on the biodegradation of the systems was gain by simulating experiments of enzymatic degradation. The systems were biodegradable and showed a prolonged drug release, assuring an in vivo efficient therapeutic effect over 5 days, with no systemic toxicity. All these findings demonstrated that the new hydrogels based on nitrosalicyl-imine-chitosan provides a practical approach for sustained drug delivery for local chemotherapy. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) governs all aspects of cancer progression and in vitro 3D cell culture platforms are increasingly developed to emulate the interactions between components of the stromal tissues and cancer cells. However, conventional cell culture platforms are inadequate in recapitulating the TME, which has complex compositions and dynamically changing matrix mechanics. In this study, we developed a dynamic gelatin-hyaluronic acid hybrid hydrogel system through integrating modular thiol-norbornene photopolymerization and enzyme-triggered on-demand matrix stiffening. In particular, gelatin was dually modified with norbornene and 4-hydroxyphenylacetic acid to render this bioactive protein photo-crosslinkable (through thiol-norbornene gelation) and responsive to tyrosinase-triggered on-demand stiffening (through HPA dimerization). In addition to the modified gelatin that provides basic cell adhesive motifs and protease cleavable sequences, hyaluronic acid (HA), an essential tumor matrix, was modularly and covalently incorporated into the cell-laden gel network. We systematically characterized macromer modification, gel crosslinking, as well as enzyme-triggered stiffening and degradation. We also evaluated the influence of matrix composition and dynamic stiffening on pancreatic ductal adenocarcinoma (PDAC) cell fate in 3D. We found that either HA-containing matrix or a dynamically stiffened microenvironment inhibited PDAC cell growth. Interestingly, these two factors synergistically induced cell phenotypic changes that resembled cell migration and/or invasion in 3D. Additional mRNA expression array analyses revealed changes unique to the presence of HA, to a stiffened microenvironment, or to the combination of both. Finally, we presented immunostaining and mRNA expression data to demonstrate that these irregular PDAC cell phenotypes were a result of matrix-induced epithelial-mesenchymal transition (EMT). [ABSTRACT FROM AUTHOR]

Hydrogels with spatiotemporally tunable mechanical properties have been increasingly employed for studying the impact of tissue mechanics on cell fate processes. These dynamic hydrogels are particularly suitable for recapitulating the temporal stiffening of a tumor microenvironment. To this end, we have reported an enzyme-mediated stiffening hydrogel system where tyrosinase (Tyrase) was used to stiffen orthogonally crosslinked cell-laden hydrogels. Herein, a mathematical model was proposed to describe enzyme diffusion and reaction within a highly swollen gel network, and to elucidate the critical factors affecting the degree of gel stiffening. Briefly, Fick’s second law of diffusion was used to predict enzyme diffusion in a swollen poly(ethylene glycol) (PEG)-peptide hydrogel, whereas the Michaelis–Menten model was employed for estimating the extent of enzyme-mediated secondary crosslinking. To experimentally validate model predictions, we designed a hydrogel system composed of 8-arm PEG-norbornene (PEG8NB) and bis-cysteine containing peptide crosslinker. Hydrogel was crosslinked in a channel slide that permitted one-dimensional diffusion of Tyrase. Model predictions and experimental results suggested that an increasing network crosslinking during stiffening process did not significantly affect enzyme diffusion. Rather, diffusion path length and the time of enzyme incubation were more critical in determining the distribution of Tyrase and the formation of additional crosslinks in the hydrogel network. Finally, we demonstrated that the enzyme-stiffened hydrogels exhibited elastic properties similar to other chemically crosslinked hydrogels. This study provides a better mechanistic understanding regarding the process of enzyme-mediated dynamic stiffening of hydrogels.

Introduction: Over-activation of oxidative stress due to impaired antioxidant functions in nucleus pulpous (NP) has been identified as a key factor contributing to intervertebral disc degeneration (IVDD). While Kartogenin (KGN) has previously demonstrated antioxidant properties on articular cartilage against osteoarthritis, its effects on NP degeneration have yet to be fully understood., Objectives: This study aimed to investigate the protective effects of KGN on nucleus pulpous cells (NPCs) against an inflammatory environment induced by interleukin (IL)-1β, as well as to explore the therapeutic potential of KGN-enhanced dynamic hydrogel in preventing IVDD., Methods: NPCs were isolated from rat caudal IVDs and subjected to treatment with KGN at varying concentrations (ranging from 0.01 to 1 ​μM) in the presence of IL-1β. The expression of extracellular matrix (ECM) anabolism markers was quantitatively assessed at both the mRNA and protein levels. Additionally, intracellular reactive oxygen species and antioxidant enzyme expression were evaluated, along with the role of nuclear factor erythroid 2-related factor 2 (NRF2). Based on these findings, a dynamic self-healing hydrogel loaded with KGN was developed through interconnecting networks. Subsequently, KGN-enhanced dynamic hydrogel was administered into rat caudal IVDs that had undergone puncture injury, followed by radiographic analysis and immunohistochemical staining to evaluate the therapeutic efficacy., Results: In vitro treatments utilizing KGN were observed to maintain ECM synthesis and inhibit catabolic activities in IL-1β-stimulated NPCs. The mechanism behind this protective effect of KGN on NPCs was found to involve the asctivation of NRF2 and downstream antioxidant enzymes, including glutathione peroxidase 1 and heme oxygenase 1. This was further supported by the loss of both antioxidant and anabolic effects upon pharmacological inhibition of NRF2. Furthermore, a self-healing hydrogel was developed and loaded with KGN to achieve localized and sustained release of the compound. The injection of KGN-enhanced hydrogel effectively ameliorated the degradation of NP ECM and mitigated inflammation in a rat model of puncture-induced IVDD., Conclusions: Our results indicate that KGN exhibits potential as a therapeutic agent for NP degeneration, and that KGN-enhanced dynamic hydrogel represents a novel approach for treating IVDD by restoring redox homeostasis in NP.The translational potential of this article: The dysregulation of oxidant and antioxidant balance has been shown to impede the repair and regeneration of NP, thereby hastening the progression of IVDD following injury. The present investigation has demonstrated that the sustained release of KGN promotes the synthesis of ECM in vitro and mitigates the progression of IVDD in vivo by restoring redox equilibrium, thereby presenting a novel therapeutic candidate based on the antioxidant properties of KGN for the treatment of IVDD., Competing Interests: A conflict of interest occurs when an individual's objectivity is potentially compromised by a desire for financial gain, prominence, professional advancement or a successful outcome. The Editors of the Journal of Orthopaedic Translation strive to ensure that what is published in the Journal is as balanced, objective and evidence-based as possible. Since it can be difficult to distinguish between an actual conflict of interest and a perceived conflict of interest, the Journal requires authors to disclose all and any potential conflicts of interest., (© 2023 The Authors.)

Bioprinting techniques allow for the recreation of 3D tissue-like structures. By deposition of hydrogels combined with cells (bioinks) in a spatially controlled way, one can create complex and multiscale structures. Despite this promise, the ability to deposit customizable cell-laden structures for soft tissues is still limited. Traditionally, bioprinting relies on hydrogels comprised of covalent or mostly static crosslinks. Yet, soft tissues and the extracellular matrix (ECM) possess viscoelastic properties, which can be more appropriately mimicked with hydrogels containing reversible crosslinks. In this study, we have investigated aldehyde containing oxidized alginate (ox-alg), combined with different cross-linkers, to develop a small library of viscoelastic, self-healing, and bioprintable hydrogels. By using distinctly different imine-type dynamic covalent chemistries (DCvC), (oxime, semicarbazone, and hydrazone), rational tuning of rheological and mechanical properties was possible. While all materials showed biocompatibility, we observed that the nature of imine type crosslink had a marked influence on hydrogel stiffness, viscoelasticity, self-healing, cell morphology, and printability. The semicarbazone and hydrazone crosslinks were found to be viscoelastic, self-healing, and printable—without the need for additional Ca2+ crosslinking—while also promoting the adhesion and spreading of fibroblasts. In contrast, the oxime cross-linked gels were found to be mostly elastic and showed neither self-healing, suitable printability, nor fibroblast spreading. The semicarbazone and hydrazone gels hold great potential as dynamic 3D cell culture systems, for therapeutics and cell delivery, and a newer generation of smart bioinks.

Electro-responsive dynamic hydrogels, which possess robust mechanical properties and precise spatiotemporal resolution, have a wide range of applications in biomedicine and energy science. However, it is still challenging to design and prepare electro-responsive hydrogels (ERHs) which have all of these properties. Here, we report one such class of ERHs with these features, based on the direct current voltage (DCV)-induced rearrangement of sodium dodecyl sulfate (SDS) micelles, where the rearrangement can tune the hydrogel networks that are originally maintained by the SDS micelle-assisted hydrophobic interactions. An enlarged mesh size is demonstrated for these ERHs after DCV treatment. Given the unique structure and properties of these ERHs, hydrophobic cargo (thiostrepton) has been incorporated into the hydrogels and is released upon DCV loading. Additionally, these hydrogels are highly stretchable (>6000%) and tough (507 J/m 2 ), showing robust mechanical properties. Moreover, these hydrogels have a high spatiotemporal resolution. As the cross-links within our ERHs are enabled by the non-covalent ( i.e. , hydrophobic) interactions, these hydrogels are self-healing and malleable. Considering the robust mechanical properties, precise spatiotemporal resolution, dynamic nature ( e.g. , injectable and self-healing), and on-demand drug delivery ability, this class of ERHs will be of great interest in the fields of wearable bioelectronics and smart drug delivery systems.

Presented here is the synthesis of a 3D printable nano-polysaccharide self-healing hydrogel for flexible strain sensors. Consisting of three distinct yet complementary dynamic bonds, the crosslinked network comprises imine, hydrogen, and catecholato-metal coordination bonds. Self-healing of the hydrogel is demonstrated by macroscopic observation, rheological recovery, and compression measurements. The hydrogel was produced via imine formation of carboxyl methyl chitosan, oxidized cellulose nanofibers, and chitin nanofibers followed by two subsequent crosslinking stages: immersion in tannic acid (TA) solution to create hydrogen bonds, followed by soaking in FeIII solution to form catecholato-metal coordination bonds between TA and FeIII. The metal coordination bonds were critical to imparting conductivity to the hydrogel, a requirement for flexible strain sensors. The hydrogel exhibits excellent shear-thinning and dynamic properties with high autonomous self-healing (up to 89%) and self-recovery (up to 100%) at room temperature without external stimuli. Furthermore, it shows good printability, biocompatibility, and strain sensing ability. [Display omitted] [ABSTRACT FROM AUTHOR]

Postoperative abdominal adhesions are a common problem after surgery and can produce serious complications. Current antiadhesive strategies focus mostly on physical barriers and are unsatisfactory and inefficient. In this study, we designed and synthesized advanced injectable cream-like hydrogels with multiple functionalities, including rapid gelation, self-healing, antioxidation, anti-inflammation, and anti-cell adhesion. The multifunctional hydrogels were facilely formed by the conjugation reaction of epigallocatechin-3-gallate (EGCG) and hyaluronic acid (HA)-based microgels and poly(vinyl alcohol) (PVA) based on the dynamic boronic ester bond. The physicochemical properties of the hydrogels including antioxidative and anti-inflammatory activities were systematically characterized. A mouse cecum-abdominal wall adhesion model was implemented to investigate the efficacy of our microgel-based hydrogels in preventing postoperative abdominal adhesions. The hydrogels, with a high molecular weight HA, significantly decreased the inflammation, oxidative stress, and fibrosis and reduced the abdominal adhesion formation, compared to the commercial Seprafilm group or Injury-only group. Label-free quantitative proteomics analysis demonstrated that S100A8 and S100A9 expressions were associated with adhesion formation; the microgel-containing hydrogels inhibited these expressions. The microgel-containing hydrogels with multifunctionality decreased the formation of postoperative intra-abdominal adhesions in a murine model, demonstrating promise for clinical applications.

Traditional hydrogels often fail to match the dynamic interactions between mechanical and cellular behaviors exhibited by the natural cartilage extracellular matrix. In this research, we constructed a novel hybrid hydrogels system based on sodium alginate and polyglutamic acid. By controlling the grafting rate and concentration of polymer, the gelation time and mechanical strength can be adjusted between range of 8–28 s and 60–144 kPa. By adding microcrystalline cellulose into the system, so that the degradation time was prolonged (125%) and the swelling rate was reduced (470%). Additionally, the presence of hydrazone bonds gives the system some dynamic response characteristics, and the hydrogel exhibits excellent self healing and injectable ability. It was found that the system had positive cytocompatibility (80%), which accelerated regulatory gene expression in cartilage tissue. In conclusion, this injectable hydrogel with self-healing and customizable mechanical strength will have broad application prospects in future biomedical engineering. [Display omitted] • Adjustable the mechanical strength (60–144 kPa) and gelation time (8–28 s). • Micro-nano enhancement of hydrogel system using microcrystalline cellulose. • Simulating the construction chondrocytes of 3D dynamic microenvironment. • Promoting chondrogenic differentiation of stem cells. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is one of the most challenging clinical issues. It is characterized by the disruption of neural circuitry and connectivity, resulting in neurological disability. Adipose-derived stem cells (ADSCs) serve as a promising source of therapeutic cells for SCI treatment. However, the therapeutic outcomes of direct ADSCs transplantation are limited in the presence of an inflammatory microenvironment. Herein, a cell-adaptable neurogenic (CaNeu) hydrogel was developed as a delivery vehicle for ADSCs to promote neuronal regeneration after SCI. The dynamic network of CaNeu hydrogel loaded with ADSCs provides a cell-infiltratable matrix that enhances axonal growth and eventually leads to improved motor evoked potential, hindlimb strength, and coordination of complete spinal cord transection in rats. Furthermore, the CaNeu hydrogel also establishes an anti-inflammatory microenvironment by inducing a shift in the polarization of the recruited macrophages toward the pro-regeneration (M2) phenotype. Our study showed that the CaNeu-hydrogel‒mediated ADSCs delivery resulted in significantly suppressed neuroinflammation and apoptosis, and that this phenomenon involved the PI3K/Akt signaling pathway. Our findings indicate that the CaNeu hydrogel is a valuable delivery vehicle to assist stem cell therapy for SCI, providing a promising strategy for central nervous system diseases. [ABSTRACT FROM AUTHOR]

In the past decade, cartilage tissue engineering has arisen as a promising therapeutic option for degenerative joint diseases, such as osteoarthritis, in the hope of restoring the structure and physiological functions. Hydrogels are promising biomaterials for developing engineered scaffolds for cartilage regeneration. However, hydrogel-delivered mesenchymal stem cells or chondrocytes could be exposed to elevated levels of reactive oxygen species (ROS) in the inflammatory microenvironment after being implanted into injured joints, which may affect their phenotype and normal functions and thereby hinder the regeneration efficacy. To attenuate ROS induced side effects, a multifunctional hydrogel with an innate anti-oxidative ability was produced in this study. The hydrogel was rapidly formed through a dynamic covalent bond between phenylboronic acid grafted hyaluronic acid (HA-PBA) and poly(vinyl alcohol) and was further stabilized through a secondary crosslinking between the acrylate moiety on HA-PBA and the free thiol group from thiolated gelatin. The hydrogel is cyto-compatible and injectable and can be used as a bioink for 3D bioprinting. The viscoelastic properties of the hydrogels could be modulated through the hydrogel precursor concentration. The presence of dynamic covalent linkages contributed to its shear-thinning property and thus good printability of the hydrogel, resulting in the fabrication of a porous grid construct and a meniscus like scaffold at high structural fidelity. The bioprinted hydrogel promoted cell adhesion and chondrogenic differentiation of encapsulated rabbit adipose derived mesenchymal stem cells. Meanwhile, the hydrogel supported robust deposition of extracellular matrix components, including glycosaminoglycans and type II collagen, by embedded mouse chondrocytes in vitro . Most importantly, the hydrogel could protect encapsulated chondrocytes from ROS induced downregulation of cartilage-specific anabolic genes (ACAN and COL2) and upregulation of a catabolic gene (MMP13) after incubation with H 2 O 2 . Furthermore, intra-articular injection of the hydrogel in mice revealed adequate stability and good biocompatibility in vivo . These results demonstrate that this hydrogel can be used as a novel bioink for the generation of 3D bioprinted constructs with anti-ROS ability to potentially enhance cartilage tissue regeneration in a chronic inflammatory and elevated ROS microenvironment., (© 2021 IOP Publishing Ltd.)

Thymopentin (TP5) is widely used in the treatment of autoimmune diseases, but the short in vivo half-life of TP5 strongly restricts its clinical applications. A series of blank and TP5 loaded hydrogels were synthesized via reversible dual imine bonding by mixing water soluble O -carboxymethyl chitosan (CMCS) with a dynamer (Dy) prepared from Jeffamine and benzene-1,3,5-tricarbaldehyde. TP5 release from hydrogels was studied at 37 °C under in vitro conditions. The molar mass of CMCS, drug loading conditions and drug content were varied to elucidate their effects on hydrogel properties and drug release behaviors. Density functional theory was applied to theoretically confirm the chemical connections between TP5 or CMCS with Dy. All hydrogels exhibited interpenetrating porous architecture with average pore size from 59 to 83 μm, and pH-sensitive swelling up to 10,000% at pH 8. TP5 encapsulation affected the rheological properties of hydrogels as TP5 was partially attached to the network via imine bonding. Higher TP5 loading led to higher release rates. Faster release was observed at pH 5.5 than at pH 7.4 due to lower stability of imine bonds in acidic media. Fitting of release data using Higuchi model showed that initial TP5 release was essentially diffusion controlled. All these findings proved that the dynamic hydrogels are promising carriers for controlled delivery of hydrophilic drugs, and shed new light on the design of drug release systems by both physical mixing and reversible covalent bonding. Thymopentin was loaded in O -carboxymethyl chitosan-based hydrogels via physical mixing and imine bonding. In vitro release was investigated, and analyzed using Higuchi model and density functional theory computation. [Display omitted] • O -carboxymethyl chitosan-based dynamic hydrogels are synthesized by dual-imine bonding • Thymopentin-loaded dynamic hydrogels are fabricated by in-situ encapsulation • As-prepared hydrogels exhibit strongly pH-sensitive swelling behaviors • Thymopentin release rate can be tuned by varying parameters, including pH, drug load, and hydrogel preparation • Density functional theory theoretically confirms the chemical connections between thymopentin and hydrogel network [ABSTRACT FROM AUTHOR]

• Dynamic hydrogels are prepared from carboxymethyl chitosan and 3-D dynamer by imine bond formation. • The resulting hydrogels exhibit excellent pH-sensitive swelling properties. • The hydrogels present outstanding self-healing properties. • The hydrogels exhibit good cytocompatibility. • The hydrogels present great potential for applications in tissue engineering. Novel dynamic hydrogels were prepared from O-carboxymethyl chitosan (CMCS) and a water soluble dynamer Dy via crosslinking by imine bond formation using an environmentally friendly method. Dy was synthesized by reaction of Benzene-1,3,5-tricarbaldehyde with Jeffamine. The resulting soft hydrogels exhibit a porous and interconnected morphology, storage modulus up to 1400 Pa, and excellent pH-sensitive swelling properties. The swelling ratio is relatively low at acidic pH due to electrostatic attraction, and becomes exceptionally high up to 7000 % at pH 8 due to electrostatic repulsion. Moreover, hydrogels present outstanding self-healing properties as evidenced by closure of split pieces and rheological measurements. This study opens up a new horizon in the preparation of dynamic hydrogels with great potential for applications in drug delivery, wound dressing, and in particular in tissue engineering as the hydrogels present excellent cytocompatibility. [ABSTRACT FROM AUTHOR]

• HA hydrogels formed by boronic ester dynamic covalent bond were facilely prepared. • Dynamic HA hydrogels possess good injectability and self-healing properties. • Dynamic hydrogels can be used for reactive oxygen species responsive drug delivery. • Dynamic hydrogels were biocompatible and protected cells from ROS induced damage. • Hydrogels can be used for 3D printed cell-laden scaffolds and "direct-in-gel" printing. In this study, an injectable and self-healing hydrogel based on the boronic ester dynamic covalent bond between phenylboronic acid modified hyaluronic acid (HA-PBA) and the commercially available poly (vinyl alcohol) (PVA) is prepared and should have multi-functions for biomedical applications. The hydrogels were rapidly formed under mild conditions, and the rheological properties and in vitro degradation were systematically characterized. The HA-based hydrogels possessed good injectability and self-healing properties because of the dynamic bond. Moreover, due to the sensitivity of boronic ester to the biologically relevant concentration of hydrogen peroxide (H 2 O 2), a major reactive oxygen species (ROS), the injectable hydrogel could be used as a H 2 O 2 /ROS responsive drug delivery system. The hydrogels supported good viability of encapsulated neural progenitor cells (NPC) and protected NPC from ROS induced damage in vitro when H 2 O 2 was present in the media. The dynamic hydrogels were further applied as bio-inks for 3D printing/bioprinting. Overall, this facilely prepared dynamic hydrogel based on HA-PBA and PVA may have many potential biomedical applications, including drug delivery, 3D culture of cells, and 3D bioprinting. [ABSTRACT FROM AUTHOR]

Adhesive hydrogels are widely applied for biological and medical purposes; however, they are generally unable to adhere to tissues under wet/underwater conditions. Herein, described is a class of novel dynamic hydrogels that shows repeatable and long‐term stable underwater adhesion to various substrates including wet biological tissues. The hydrogels have Fe3+‐induced hydrophobic surfaces, which are dynamic and can undergo a self‐hydrophobization process to achieve strong underwater adhesion to a diverse range of dried/wet substrates without the need for additional processes or reagents. It is also demonstrated that the hydrogels can directly adhere to biological tissues in the presence of under sweat, blood, or body fluid exposure, and that the adhesion is compatible with in vivo dynamic movements. This study provides a novel strategy for fabricating underwater adhesive hydrogels for many applications, such as soft robots, wearable devices, tissue adhesives, and wound dressings. [ABSTRACT FROM AUTHOR]

Synthetic macroscopic materials transforming from bulk solid or semisolid to a closed structure with inner cavities and distinct outer and inner microstructures are rarely reported. Here, we report an in situ method for directing spatial surface-interior separation from bulk dynamic hydrogels to closed three-dimensional (3D) hydrogel containers with inner cavities via constructing a competitively cross-linking gradient within dynamic hydrogels. The initial cross-linking of phenylboronic acid/catechol complexes is disrupted by stronger ferric ions/catechol associations, generating gradually weakened cross-linking from the outside to the inside. Both stronger cross-linking in the outer shells and sequentially weaker cross-linked interior generated during swelling closed the hydrogel container with a tunable dense outer shell, fluffy inner layer, and cavities in the core. Cellulose nanocrystals could be used to significantly improve the spatial distinction of gradient cross-linking within hydrogels, leading to an even denser outer shell with tunable shell thickness. Moreover, cavitary hydrogel containers with diverse shapes can be programmed by designing the initial shapes of dynamic hydrogels and macroscopic assembly of individual dynamic hydrogels based on their self-healing capability after subsequent surface-interior separation. These cavitary hydrogel containers demonstrate thermal-responsive gate systems with unique sustained release at higher temperature and potential reaction containers for oxygen generation on demand. This facile spatial surface-interior separation strategy for fabricating closed cavity systems has great potential for various applications.

Dynamic G-quadruplex hydrogel is engineered by using guanosine, 2-formylphenylboronic acid, and 4-Arm PEG-NH 2 . The gelation conditions are optimized by varying concentrations of the gelators, pH, and different alkali metal ions. The formation of imino-boronate bonds during the gelation process is fully characterized with FT-IR, 1 H NMR, and 11 B NMR spectroscopy. The secondary supramolecular G-quadruplex structure and the formation of nanofibrillar morphology are well examined using several spectroscopic and microscopic techniques. The mechanical strength of the hydrogel is investigated by rheological experiments. The hydrogel is injectable and self-healable due to the dynamic nature of the imono-boronate bonds. The dynamic bonds provide distinct shear-thinning and thixotropic properties to the resulting hydrogel with almost 90% recovery of its mechanical strength after four cycles. The pH responsive behavior of the hydrogel is achieved by pH sensitive imino-boronate bonds, which are unstable at acidic pH. To investigate the biocompatibility of the hydrogel, a wide range of hydrogel concentrations are examined by in vitro cell culture experiments using the MCF-7 cell line. After a biocompatibility test of the hydrogel, the anticancer drug doxorubicin is incorporated inside the gel to analyze the drug release profile at different pHs. The release rate of the loaded drug is observed faster in lower pH (pH 4.8) than in physiological pH (pH 7.4). Different release rate of the drug from the drug loaded hydrogel in different pHs is driven by the pH sensitive imino-boronate bonds. The release profile of the drug is slow, sustain and steady.

Liquid-solid transition is a widely used strategy to shape polymeric materials and encode their microstructures. However, it is still challenging to fully exploit liquid behaviors of material precursors. In particular, the dynamic and static liquid behaviors naturally conflict with each other, which makes it difficult to integrate their advantages in the same materials. Here, by utilizing a shear-thinning phenomenon in the dynamic hybrid hydrogels, we achieve a hydrodynamic alignment of cellulose nanocrystals (CNC) and preserve it in the relaxed hydrogel networks due to the much faster relaxation of polymer networks (within 500 s) than CNC after the unloading of external force. During the following drying process, the surface tension of hydrogels further enhances the orientation index of CNC up to 0.872 in confined geometry, and these anisotropic microstructures demonstrate highly tunable birefringence (up to 0.004 14). Due to the presence of the boundaries of dynamic hydrogels, diverse xerogels including fibers, films, and even complex three-dimensional structures with variable anisotropic microstructures can be fabricated without any external molds.

Hydrogels with spatiotemporally tunable mechanical properties have been increasingly employed for studying the impact of tissue mechanics on cell fate processes. These dynamic hydrogels are particularly suitable for recapitulating the temporal stiffening of a tumor microenvironment. To this end, we have reported an enzyme-mediated stiffening hydrogel system where tyrosinase ( Tyr ase ) was used to stiffen orthogonally crosslinked cell-laden hydrogels. Herein, a mathematical model was proposed to describe enzyme diffusion and reaction within a highly swollen gel network, and to elucidate the critical factors affecting the degree of gel stiffening. Briefly, Fick's second law of diffusion was used to predict enzyme diffusion in a swollen poly(ethylene glycol) (PEG)-peptide hydrogel, whereas the Michaelis⁻Menten model was employed for estimating the extent of enzyme-mediated secondary crosslinking. To experimentally validate model predictions, we designed a hydrogel system composed of 8-arm PEG-norbornene (PEG8NB) and bis-cysteine containing peptide crosslinker. Hydrogel was crosslinked in a channel slide that permitted one-dimensional diffusion of Tyr ase . Model predictions and experimental results suggested that an increasing network crosslinking during stiffening process did not significantly affect enzyme diffusion. Rather, diffusion path length and the time of enzyme incubation were more critical in determining the distribution of Tyr ase and the formation of additional crosslinks in the hydrogel network. Finally, we demonstrated that the enzyme-stiffened hydrogels exhibited elastic properties similar to other chemically crosslinked hydrogels. This study provides a better mechanistic understanding regarding the process of enzyme-mediated dynamic stiffening of hydrogels.

Bioprinting techniques allow for the recreation of 3D tissue-like structures. By deposition of hydrogels combined with cells (bioinks) in a spatially controlled way, one can create complex and multiscale structures. Despite this promise, the ability to deposit customizable cell-laden structures for soft tissues is still limited. Traditionally, bioprinting relies on hydrogels comprised of covalent or mostly static crosslinks. Yet, soft tissues and the extracellular matrix (ECM) possess viscoelastic properties, which can be more appropriately mimicked with hydrogels containing reversible crosslinks. In this study, we have investigated aldehyde containing oxidized alginate (ox-alg), combined with different cross-linkers, to develop a small library of viscoelastic, self-healing, and bioprintable hydrogels. By using distinctly different imine-type dynamic covalent chemistries (DCvC), (oxime, semicarbazone, and hydrazone), rational tuning of rheological and mechanical properties was possible. While all materials showed biocompatibility, we observed that the nature of imine type crosslink had a marked influence on hydrogel stiffness, viscoelasticity, self-healing, cell morphology, and printability. The semicarbazone and hydrazone crosslinks were found to be viscoelastic, self-healing, and printable-without the need for additional Ca 2+ crosslinking-while also promoting the adhesion and spreading of fibroblasts. In contrast, the oxime cross-linked gels were found to be mostly elastic and showed neither self-healing, suitable printability, nor fibroblast spreading. The semicarbazone and hydrazone gels hold great potential as dynamic 3D cell culture systems, for therapeutics and cell delivery, and a newer generation of smart bioinks.