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This review highlights the rational molecular structure design of mussel-inspired adhesive hydrogels and their applications in local immunomodulation.

Developing oral nanomedicines that suppress intestinal inflammation while modulating gut microbiota and brain interactions is essential for effectively treating inflammatory bowel disease. Here, we report an oral polyphenol-armored nanomedicine based on tumor necrosis factor–α (TNF-α)–small interfering RNA and gallic acid–mediated graphene quantum dot (GAGQD)–encapsulated bovine serum albumin nanoparticle, with a chitosan and tannin acid (CHI/TA) multilayer. Referred to “armor,” the CHI/TA multilayer resists the harsh environment of the gastrointestinal tract and adheres to inflamed colon sites in a targeted manner. TA provides antioxidative stress and prebiotic activities that modulate the diverse gut microbiota. Moreover, GAGQD protected TNF-α–siRNA delivery. Unexpectedly, the armored nanomedicine suppressed hyperactive immune responses and modulated bacterial gut microbiota homeostasis in a mouse model of acute colitis. Notably, the armored nanomedicine alleviated anxiety- and depression-like behaviors and cognitive impairment in mice with colitis. This armor strategy sheds light on the effect of oral nanomedicines on bacterial gut microbiome-brain interactions.

Core–shell PEDOT@PZIF-71 nanoparticles as conductive nanofillers were homogeneously incorporated into a hydrophilic network to form conductive hydrogels for bio-electronics and bio-capacitors.

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

Photodynamic bonds are stable in the dark and can reversibly dissociate/form under light irradiation. Photodynamic bonds are promising building blocks for responsive or healable materials, photoactivated drugs, nanocarriers, extracellular matrices, etc. However, reactive intermediates from photodynamic bonds usually lead to side reactions, which limit the use of photodynamic bonds. Here, we report that the Ru-Se coordination bond is a new photodynamic bond that reversibly dissociates under mild visible-light-irradiation conditions. We observed that Ru-Se bonds form via the coordination of a selenoether ligand with [Ru(tpy)(biq)(H2O)]Cl2 (tpy = 2,2':6',2″-terpyridine, biq = 2,2'-biquinoline) in the dark, while the Ru-Se bond reversibly dissociates under visible-light irradiation. No side reaction is detected in the formation and dissociation of Ru-Se bonds. To demonstrate that the Ru-Se bond is applicable to different operating environments, we prepared photoresponsive amphiphiles, surfaces, and polymer gels using Ru-Se bonds. The amphiphiles with Ru-Se bonds showed reversible morphological transitions between spherical micelles and bowl-shaped assemblies for dark/light irradiation cycles. The surfaces modified with Ru-Se-bond-containing compounds showed photoswitchable wettability. Polymer gels with Ru-Se cross-links underwent photoinduced reversible sol-gel transitions, which can be used for reshaping and healing. Our work demonstrates that the Ru-Se bond is a new type of dynamic bond, which can be used for constructing responsive, reprocessable, switchable, and healable materials that work in a variety of environments.

Metal‐organic frameworks (MOFs) refer to porous coordination materials that are formed from the assembly of metal ions and organic ligands. They have unique features, such as a large specific surface area, multiple active sites, easy functionalisation, and adjustable biocompatibility. MOFs have recently been widely used in the field of biomedical engineering owing to their unique structures and properties. This has enabled them to replace traditional materials and effectively address several problems. Through continuous development, MOF‐based biomaterials have been remarkably improved by clarifying the relationship between MOF structures and properties. As a result, they are being extensively studied in the fields of chemical and material science. MOF‐based biomaterials can meet the growing demands for efficient materials in biomedical applications. This review first discusses the basic structure of MOFs, followed by their preparation and functionalisation methods. The biomedical applications of MOF‐based biomaterials in the fields of antibacterial activity, tumour therapy, skin repair, and bone repair are then summarised. Finally, challenges and future perspectives in the biomedical applications of MOF‐based biomaterials are outlined.

Injectable hydrogels have become the material of choice for the treatment of solid tumours based on their advantages in loading anti-tumour materials. This study reviews the main scientific research achievements on anti-tumour injectable hydrogels in recent years. The gel-forming mechanism of anti-tumour injectable hydrogels was listed, and the advantages and difficulties of each gel-forming mechanism were summarised. In addition, several current anti-tumour methods based on injectable hydrogels were discussed, including chemotherapy, hyperthermia-based therapy, catalytic therapy and immune therapy, as well as the integration of diagnosis and treatment to monitor the progress of cancer treatment. The anti-tumour mechanism and the advantages and disadvantages of various tumour treatments were analysed. Finally, the future development trend of injectable hydrogels for anti-tumour therapy was discussed.

Biomaterial surfaces tend to adhere only under dry conditions, preventing them from being used in underwater environments such as body fluids. Therefore, biomaterial surfaces with underwater adhesion ability have received increasing attention. In nature, some organisms can adapt to different environments by evolving appendages with underwater adhesion capability and unique functions. Most of these outstanding functions are derived from special micro/nanostructures and/or chemical compositions of these organisms. Thus, modification of biomaterials surfaces with similar microstructures and chemical groups would help promote underwater adhesion. In this review, we discuss (1) the mechanisms of underwater adhesion; (2) surface modification strategies for underwater adhesion, including mussel-inspired, interlocking, bio-structured surface, and specific adhesion strategies; and (3) the challenges and potential of developing surface-modified, multiscale biomaterials with underwater adhesion.

Repairing osteochondral defects is a considerable challenge because it involves the breakdown of articular cartilage and underlying bone. Traditional hydrogels with a homogenized single-layer structure cannot fully restore the function of osteochondral cartilage tissue. In this study, a mussel-inspired hydrogel with a bilayer structure is developed to repair osteochondral defects. The hydrogel is synthesized by simultaneously polymerizing two layers using a one-pot method. The resulting upper and lower gelatin methacryloyl-polydopamine hydrogel layers are used as cartilage and subchondral bone repair layers, respectively. Polydopamine-induced hydroxyapatite in situ mineralization takes place in the lower layer to mimic the structure of subchondral bone. The bilayer hydrogel exhibits good mechanical properties for the synergistic effect of covalent and noncovalent bonds, as well as nanoreinforcement of mineralized hydroxyapatite. To improve the tissue-inducibility of hydrogels, transforming growth factor β3 is immobilized in the upper layer to induce cartilage regeneration, while bone morphogenetic protein 2 is immobilized in the lower layer to induce bone regeneration. Bone and cartilage repair performance of the hydrogel is examined by implantation into a full-thickness cartilage defect of a rabbit knee joint. The bilayer-structure hydrogel promotes regeneration of osteochondral tissue, thus providing a new option for repair of osteochondral defects.

Regenerating periodontal bone tissues in the aggravated inflammatory periodontal microenvironment under diabetic conditions is a great challenge. Here, a polydopamine-mediated graphene oxide (PGO) and hydroxyapatite nanoparticle (PHA)-incorporated conductive alginate/gelatin (AG) scaffold is developed to accelerate periodontal bone regeneration by modulating the diabetic inflammatory microenvironment. PHA confers the scaffold with osteoinductivity and PGO provides a conductive pathway for the scaffold. The conductive scaffold promotes bone regeneration by transferring endogenous electrical signals to cells and activating Ca

Hydrogels consisting of a three-dimensional hydrophilic network of biocompatible polymers have been widely used in tissue engineering. Owing to their tunable mechanical properties, hydrogels have been applied in both hard and soft tissues. However, most hydrogels lack self-adhesive properties that enable integration with surrounding tissues, which may result in suture or low repair efficacy. Self-adhesive hydrogels (SAHs), an emerging class of hydrogels based on a combination of three-dimensional hydrophilic networks and self-adhesive properties, continue to garner increased attention in recent years. SAHs exhibit reliable and suitable adherence to tissues, and easily integrate into tissues to promote repair efficiency. SAHs are designed either by mimicking the adhesion mechanism of natural organisms, such as mussels and sandcastle worms, or by using supramolecular strategies. This review summarizes the design and processing strategies of SAHs, clarifies underlying adhesive mechanisms, and discusses their applications in tissue engineering, as well as future challenges.

Immunotherapy is a powerful way to treat cancer, however, systemic treatment-associated adverse effects remain a major concern. In this study, a bioadhesive injectable hydrogel is developed to provide localized immune niches for tumor microenvironment immunomodulation and cancer catalytic immunotherapy. First, a phenolic single atom nanozyme (SAN) was developed by in situ synthesis of Pd single atom on catechol-grafted carbon-quantum-dot (DA-CQD@Pd) templates. Then, the bioadhesive injectable hydrogel consisting of DA-CQD@Pd SAN and immune adjuvant CpGODN was formed through SAN-catalyzed free-radical polymerization. The SAN exhibited peroxidase-like activity to generate ROS and kill tumor cells through catalytic therapy. The hydrogel locally released CpGODN in a sustained manner, which limited the risk of systemic exposure, reducing the impact of CpGODN toxicity, and protecting CpGODN from degradation. The bioadhesive hydrogel immobilized around solid tumor to provide an immune response site after injection. When combined it with the administration of immune checkpoint inhibitor anti-PD-L1, the hydrogel realized localized immunomodulation, maximized therapeutic efficacy and prevents tumor metastasis via a catalytic immunotherapy.

Graphene or graphene oxide reinforced chitosan composites were widely demonstrated to exhibits potential applications in bone tissue engineering for their excellent biocompatibility and osteoinductivity. Nevertheless, the poor mechanical properties that caused by the weak interfacial interactions between graphene or graphene oxide and chitosan limit their applications to a great extent. In the study, graphene oxide reinforced chitosan with chemical interfacial bonding ( CN bond) through the amide reaction significantly improved the interfacial interactions and then the mechanical properties of the composites. The compression testing demonstrated effects of the interfacial modification on the mechanical properties of composites. X-ray photoelectron spectroscopy (XPS) results indicated that the new formation of C N bond between graphene oxide and the chitosan matrix. ReaxFF molecular dynamics simulations were carried out to investigate the interactions between graphene oxide and chitosan at the atomistic scale. In vitro cytocompatibility testing demonstrated that the interfacial chemical modifications exhibit no effects on the biocompatibility of the composites. Thus, a meaningful way was proposed in this study to obtain the graphene oxide/chitosan biocomposites for tissue engineering with improved mechanical properties and excellent biocompatibility.

Tough and conductive hydrogels are the promising materials for various applications. However, fabrication of these hydrogels at room or low temperatures, without external stimuli, is a challenge. H...

Owing to highly tunable topology and functional groups, hyper-branched polymers are a potential candidate for toughening agents, for achieving supramolecular interactions with hydrogel networks. However, their toughening effects and mechanisms are not well understood. Here, by means of tensile and pure shear testings, we characterise the mechanics of a nanoparticle–hydrogel hybrid system that incorporates a hyper-branched polymer (HBP) with abundant hydroxyl end groups into the matrix of the polyacrylic acid (PAA) hydrogel. We found that the third and fourth generations of HBP are more effective than the second one in terms of strengthening and toughening effects. At a HBP content of 14 wt%, compared to that of the pure PAA hydrogel, strengths of the hybrid hydrogels with the third and fourth HBPs are 2.3 and 2.5 times, toughnesses are increased by 525% and 820%. However, for the second generation, strength is little improved, and toughness is increased by 225%. It was found that the stiffness of the hybrid hydrogel is almost unchanged relative to that of the PAA hydrogel, evidencing the weak characteristic of hydrogen bonds in this system. In addition, an outstanding self-healing feature was observed, confirming the fast reforming nature of broken hydrogen bonds. For the hybrid hydrogel, the critical size of failure zone around the crack tip, where serious viscous dissipation occurs, is related to a fractocohesive length, being about 0.62 mm, one order of magnitude less than that of other tough double-network hydrogels. This study can promote the application of hyper-branched polymers in the rapid evolving field of hydrogels for improved performance.

Polydopamine (PDA) is an important candidate material for the surface modification of biomedical devices because of its good adhesiveness and biocompatibility. However, PDA nanofilms lack osteoinductivity, limiting their applications in bone tissue engineering. Hydroxyapatite nanoparticles (HA-NPs) are the major component of natural bone, which can be used to effectively enhance the osteoinductivity of PDA nanofilms. Herein, we developed a pulse electrochemical driven layer-by-layer (PED-LbL) assembly process to rapidly deposit HA-NPs and PDA (HA-PDA) multilayer nanofilms. In this process, PDA and HA-NPs are

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., Graphical abstract A stable and efficient mussel-inspired nanozyme was developed by chelating ultrasmall Ag nanoparticles with tannic acid, and was employed to trigger hydrogel self-setting without external stimuli, and endow it with antibacterial, conductive, and adhesive properties in a facile manner for bioelectronics.Image 1, Highlights • The mussel-inspired nanozyme with ultrasmall size was developed by the in-situ reduction of Ag NP with TA. • The mussel-inspired nanozyme exhibited catalytic dynamic antibacterial activity. • The mussel-inspired nanozyme triggered self-gelation of hydrogel without external stimuli. • The mussel-inspired nanozyme endowed the hydrogel with adhesiveness. • The nanozyme enabled the hydrogel to be used as a multifunctional adhesive bioelectronic.

Graphene oxide (GO) attracts considerable attention for biomedical applications owing to its unique nanostructure and remarkable physicochemical characteristics. However, it is challenging to uniformly deposit GO on chemically inert Ti scaffolds, which have good biocompatibility and wide applications in bone engineering. In this study, a GO-functionalized Ti porous scaffold (GO/Ti scaffold) was prepared by depositing GO onto polydopamine (PDA) modified Ti scaffolds. The mussel-inspired PDA modification facilitated the interaction between GO and Ti surfaces, leading to a uniform coverage of GO on Ti scaffolds. BMP2 and vancomycin (Van) were separately encapsulated into gelatin microspheres (GelMS). Then, drug-containing GelMS were assembled on GO/Ti scaffolds and anchored by the functional groups of GO. The modified scaffold independently delivered multiple biomolecules with different physiochemical properties, without interfering with each other. Thus, the GO/Ti scaffold has the dual functions of inducing bone regeneration and preventing bacterial infection. In summary, this mussel-inspired GO/Ti hybrid scaffold combined the good mechanical properties of Ti scaffolds and the advantages of GO nanosheets. GO nanosheets with their unique nanostructure and functional groups, together with GelMS on Ti scaffolds, are suitable carriers for drug delivery and provide adhesive sites for cell adhesion and create nanostructured environments for bone regeneration.

Upconversion nanoparticles (UCNPs) sensitized photolytitic cleavage of the blue/UV photoinitiator bis(4-methoxybenzoyl) diethyl germanium (1). 1 initiated radical photopolymerization in combination with NaYF4:TmYb@NaYF4 UCNPs. A 974 nm NIR laser served as excitation source to generate blue and UV light. In addition, a metal free photo-ATRP system comprising (i-propyl) thioxanthone (ITX), N,N,N′,N′′,N′′-pentamethyldiethylenetriamine (PMDETA) and -bromo(i-butyl) ethylester (-BrBuEt)) was used instead of 1. This resulted in a significant smaller polydispersity compared to the UCNP/1 system. Control of polymerization was successfully proved by chain extension showing control of chain termination. For the first time, we demonstrated photolytic formation of acidic cations in such NIR UCNP-systems comprising an ITX/iodonium photoinitiator for sensitized generation of acidic cations. In addition, 1 also resulted in crosslinking of 1,6-hexanediol diacrylate (HDDA) in combination with UCNP and NIR-laser excitation. UV filter materials such as TiO2 do not significantly interfere crosslinking.

Graphene oxide (GO) is a carbon-based nanomaterial with high surface area and abundant functional groups, providing various sites for binding and immobilization of growth factor vehicles. This study used GO nanolayer as an anchor for the immobilization of bone morphogenetic protein-2 (BMP-2)-encapsulated bovine serum albumin nanoparticles (NPs) on the hydroxyapatite (HA) and tricalcium phosphate (TCP) scaffolds by electrostatic interaction between the positive charges of the NPs and negative charges of GO. GO nanolayers prevented the rapid degradation of TCP scaffolds. Moreover, GO nanolayers promoted NP adsorption on these scaffolds, and realized BMP-2 sustained release. NPs endowed the scaffold surfaces with a nanostructure similar to that of the extracellular matrix (ECM), improving bone marrow stromal cell (BMSC) attachment. Furthermore, the positive charged NPs and negative charged GO nanolayers constructed a charge-balanced surface on the scaffolds, enhancing BMSC proliferation. The nanostructure, charge balance and BMP-2 sustained release capability synergistically improved BMSC differentiation and bone regeneration. In summary, GO is a potential candidate to modify biomaterial surfaces as an anchor for efficient immobilization of growth factor vehicles. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1311-1323, 2017.

Conductive polymers are promising for bone regeneration because they can regulate cell behavior through electrical stimulation; moreover, they are antioxidative agents that can be used to protect cells and tissues from damage originating from reactive oxygen species (ROS). However, conductive polymers lack affinity to cells and osteoinductivity, which limits their application in tissue engineering. Herein, an electroactive, cell affinitive, persistent ROS-scavenging, and osteoinductive porous Ti scaffold is prepared by the on-surface in situ assembly of a polypyrrole-polydopamine-hydroxyapatite (PPy-PDA-HA) film through a layer-by-layer pulse electrodeposition (LBL-PED) method. During LBL-PED, the PPy-PDA nanoparticles (NPs) and HA NPs are in situ synthesized and uniformly coated on a porous scaffold from inside to outside. PDA is entangled with and doped into PPy to enhance the ROS scavenging rate of the scaffold and realize repeatable, efficient ROS scavenging over a long period of time. HA and electrical stimulation synergistically promote osteogenic cell differentiation on PPy-PDA-HA films. Ultimately, the PPy-PDA-HA porous scaffold provides excellent bone regeneration through the synergistic effects of electroactivity, cell affinity, and antioxidative activity of the PPy-PDA NPs and the osteoinductivity of HA NPs. This study provides a new strategy for functionalizing porous scaffolds that show great promise as implants for tissue regeneration.

Polydopamine (PDA) is an important candidate material for the surface modification of biomedical devices because of its good adhesiveness and biocompatibility. However, PDA nanofilms lack osteoinductivity, limiting their applications in bone tissue engineering. Hydroxyapatite nanoparticles (HA-NPs) are the major component of natural bone, which can be used to effectively enhance the osteoinductivity of PDA nanofilms. Herein, we developed a pulse electrochemical driven layer-by-layer (PED-LbL) assembly process to rapidly deposit HA-NPs and PDA (HA-PDA) multilayer nanofilms. In this process, PDA and HA-NPs are in situ synthesized in two sequential oxidative and reductive pulses in each electrochemical deposition cycle and alternately deposited on the substrate surfaces. PDA assists the in situ synthesis of HA-NPs by working as a template, which avoids the noncontrollable HA nucleation and aggregation. The HA-PDA multilayer nanofilms serve as a tunable reservoir to deliver bone morphogenetic protein-2 and ex...

Biomimetic calcium phosphate mineralized graphene oxide/chitosan (GO/CS) scaffolds with hierarchical structures were developed. First, GO/CS scaffolds with large micropores (∼300 μm) showed high mechanical strength due to the electrostatic interaction between the oxygen-containing functional groups of GO and the amine groups of CS. Second, octacalcuim phosphate (OCP) with porous structures (∼1 μm) was biomimetically mineralized on the surfaces of the GO/CS scaffolds (OCP-GO/CS). The hierarchical microporous structures of OCP-GO/CS scaffolds provide a suitable environment for cell adhesion and growth. The scaffolds have exceptional adsorbability of nanoparticles. Bone morphogenetic protein-2 (BMP-2)-encapsulated bovine serum albumin (BSA) nanoparticles and Ag nanoparticles (Ag-NPs) were adsorbed in the scaffolds for enhancement of osteoinductivity and antibacterial properties, respectively. Antibacterial tests showed that the scaffolds exhibited high antibacterial properties against both Escherichia coli and Staphylococcus epidermidis. In vitro and in vivo experiments revealed that the scaffolds have good biocompatibility, enhanced bone marrow stromal cells proliferation and differentiation, and induced bone tissue regeneration. Thus, the biomimetic OCP-GO/CS scaffolds with immobilized growth factors and antibacterial agents might be excellent candidates for bone tissue engineering.