This review summarizes recent progress of the robust and smart hydrogels prepared from natural polymers including polysaccharides, proteins, etc. These hydrogels exhibit outstanding mechanical properties due to their nanofibrous aggregated microstructures and special crosslinking networks. Furthermore, these hydrogels show some smart stimuliresponsive behaviors triggered by pH, temperature, light, electricity and magnetism. Hopefully, these hydrogels derived from natural polymers with inherent biodegradation and biocompatibility have great application potential in the fields of biomedicine, tissue engineering, soft robots and bio-machine.

Hydrogels have drawn considerable attention in the past two decades due to their excellent biocompatibility and multi-stimuli responsiveness. They have a wide range of applications in the fields related to tissue engineering, sensors and biomedicine. Their applications are strongly influenced by the surface properties of hydrogels and the interfacial interactions between hydrogels and other substrates. In particular, the surface wettability and adhesion of hydrogels decide their applications as drug carriers and wound dressing materials. Nevertheless, there is a lack of systematic discussion on the surface functionalization strategies of hydrogels. Therefore, this review aims at summarizing the strategies of functionalizing the surfaces of hydrogels and bonding hydrogels with other solid substrates. It also explores the challenges and future perspectives of interfacial engineering of hydrogels.

Small molecule peptides and their derivatives are an emerging class of supramolecular hydrogelators that have attracted rapidly growing interest in the fields of drug delivery and regenerative medicine due to their inherent biodegradability and biocompatibility, as well as versatility in molecular design and ease of synthesis. Built upon the directional, intermolecular interactions such as hydrogen bonding and π-π stacking, peptide-based molecular units can associate in aqueous solution into filamentous assemblies of various sizes and shapes. Under appropriate conditions, these filamentous assemblies can percolate into a 3D network with materials properties tailorable for specific biomedical applications. In this review, we survey the literature published over the past three years in the development of peptide-based hydrogelators for biomedical applications. We highlight several representative examples and center our discussion on the fundamentals of molecular design, assembly, and gelation conditions.

A strategy was developed for the synthesis of highly ordered 2D arrays of Ag-PNIPAM hybrid microgel. The highly ordered 2D arrays of PNIPAM microgel were prepared by dispersing PNIPAM microgel on a charge-reversible substrate. The microgel spheres self-assembled into a 3D colloidal crystal, and the first 111 plane was fixed in situ onto the substrate as a result of spontaneous charge reversal of the substrate, leaving a high-quality 2D array of PNIPAM microgel. Ag nanoparticles were then synthesized in situ inside the microgel spheres by introduction of Ag⁺ ions into the microgel spheres and reduction with sodium borohydride. The resulting 2D arrays are highly ordered. The inter-particle distance in the array can be tuned. In addition, the method allows the synthesis of large size arrays and the use of nonplanar substrate.

Over the past decades, the urgent need for high strength conductive hydrogels in diverse applications has motivated an unremitting effort to combine the improved mechanical properties of hydrogels with conductive performances. In this work, high strength conductive hydrogels intensified with intermolecular hydrogen bonding are fabricated by in situ mixing poly(2-vinyl-4, 6-diamino-1, 3, 5-triazine-co-polyethylene glycol diacrylates) (PVDT-PEGDA) hydrogels with poly(3, 4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT/PSS). The conductive hydrogels in deionized water exhibit high mechanical performances with compressive strength and tensile strength in the range of 7.58-9.52 MPa and 0.48-1.20 MPa respectively, which are ascribed to the intermolecular hydrogen bonding interactions of diaminotriazinediaminotriazine (DAT-DAT) in the network. Meanwhile, adding PEDOT/PSS can significantly increase both the specific conductivities and equilibrium water contents of the hydrogels. These cytocompatible conductive hydrogels may have a great potential to be used as electrical stimuli responsive soft biomaterials.

PEG-related adhesives are limited in clinical use because they are easy to swell and cannot support the cell growth. In this study, we produced a series of POSS-modified PEG adhesives with high adhesive strength. Introduction of inorganic hydrophobic POSS units decreased the swelling of the adhesives and enhanced cell adhesion and growth. The in vitro cytotoxicity and in vitro inflammatory response experiments clearly demonstrated that the adhesives were nontoxic and possessed excellent biocompatibility. Compared with the sutured wounds, the adhesive-treated wounds showed an accelerated healing process in wounded skin model of the Bama miniature pig, demonstrating that the POSS-modified PEG adhesive is a promising candidate for wound closure.

Smart hydrogels have received increasing attention for their great potential for the applications in many fields. Herein, we report a facile approach to prepare a class of dual-responsive hydrogels assembled from synthetic statistical/block thermal-responsive copoly(L-glutamate)s copolymerized with poly(ethylene glycol), which were prepared by ring-opening polymerization (ROP) and post-modification strategy. The incorporation of oligo(ethylene glycol) (OEG) and glutamic acid residues offers the gels with thermal- and pH-responsive properties simultaneously. We have systematically studied the influence of both temperature and pH on the gelation behaviors of these copolymers. It is found that the increase of glutamic acid content and solution pH values can significantly suppress the gelation ability of the samples. Circular dichroism (CD) results show that the α-helix conformation appears to be the dominant secondary conformation. More interestingly, the gelation property of the block copolymer with statistical thermal-responsive copoly(L-glutamate)s shows greater dependence on pH as compared to that with block segments due to the distinct morphology of the self-assemblies. The obtained hydrogels exhibit pH-dependent and thermal-responsive gelation behaviors, which enable them as an ideal smart hydrogel system for biomedical applications.

Multi-bond network (MBN) which contains a single network with hierarchical cross-links is a suggested way to fabricate robust hydrogels. In order to reveal the roles of different cross-links with hierarchical bond energy in the MBN, here we fabricate poly(acrylic acid) physical hydrogels with dual bond network composed of ionic cross-links between carboxyl-Fe³⁺ interactions and hydrogen bonds, and compare these dually cross-linked hydrogels with singly and ternarily cross-linked hydrogels. Simple models are employed to predict the tensile property, and the results confirm that the multi-bond network with hierarchical distribution in the bond energy of cross-links endows hydrogel with effective energy-dissipating mechanism. Moreover, the dually cross-linked MBN gels exhibit excellent mechanical properties (tensile strength up to 500 kPa, elongation at break~2400%) and complete self-healing after being kept at 50℃ for 48 h. The factors on promoting self-healing are deeply explored and the dynamic multi-bonds are regarded to trigger the self-healing along with the mutual diffusion of long polymer chains and ferric ions.

Simple preparation of stimuli-responsive hydrogels with good mechanical properties and mild stimuli-responsiveness is essential for their applications as smart soft robots. Mechanically strong Janus poly(N-isopropylacrylamide)/graphene oxide (PNIPAM/GO) nanocomposite hydrogels with stimuli-responsive bending behaviors are prepared through a simple one-step method by using molds made of a Teflon plate and a glass plate. Residual oxygen in the air bubbles on the Teflon plate surface affects the polymerization and hence the cross-linking density, leading to the different swelling/deswelling rates of the two sides of the gels. Therefore, the hydrogels exhibit bending/unbending behaviors upon heating/cooling in water. The incorporation of GO nanosheets dramatically enhances the mechanical properties of Janus hydrogels. Meanwhile, the photo-responsive property of the GO nanosheets also imparts the hydrogels with remote-controllable deformation under IR irradiation. The application of the Janus PNIPAM/GO hydrogels as thermo-responsive grippers is demonstrated.

The developments of tough hydrogels in recent years have greatly expanded the applications of hydrogels as structural materials. However, most of the tough hydrogels are made of synthetic polymers. To develop biopolymer-based tough hydrogels has both fundamental and practical significances. Here we report a series of polysaccharides-based tough hydrogel films prepared by polyion complexation and solvent evaporation of chondroitin sulfate (CS) and protonated chitosan (CHT) solutions with different weight ratios. The obtained CS/CHT gel films with thickness of 40-80 μm and water content of 66 wt%-81 wt% possess excellent mechanical properties, with tensile breaking stress and breaking strain being 0.4-3 MPa and 160%-320%, respectively. We found that in the mixture solutions there are large amounts of excess CHT in terms of charges; after swelling the films in water, the acetic acid, which is used to protonate the amino groups of CHT, diffuses out of the gel matrix, enhancing the intermolecular interactions between CHT molecules and thus improving the mechanical properties of gel films, besides the ionic bonds between CS and CHT. Antimicrobial tests also showed that the gel films with low weight ratio of CS to CHT, corresponding to the case with excess CHT, have evident antimicrobial effect. These CS/CHT gel films with good mechanical properties and antimicrobial effect should extend the applications of hydrogels in biomedical fields.

Novel hydrogels based on core-shell structured macro-crosslinkers were synthesized, which exhibited high toughness and multiple responsiveness. Sodium dodecyl sulfate (SDS) micelles mediated by NaCl were used to encapsulate hydrophobic stearyl methacrylate (C18) in the core, and hydrophilic 2-acrylamido-2-methyl-1-propanesulfonic (AMPS) monomers in the corona. Such core-shell micelles were simultaneously copolymerized with acrylamide monomers through free radical polymerization. As a result, hydrogels crosslinked by amphiphilic "poly(C18)-PAMPS" macro-crosslinkers were obtained. These hydrogels showed excellent tensile and compression strength and toughness. Cyclic compression loading-unloading tests demonstrated that the hydrogels were of outstanding fatigue resistance, and showed partial damage of energy dissipation mechanism. The damaged energy dissipation mechanism could be recovered at room temperature and the recovery could be accelerated at elevated temperatures. The hydrogels were sensitive to the change in pH and ion strength, showing reversible swelling/deswelling behaviors.

The dopamine containing hydrogels with rapid responsive shape memory capability were synthesized by a one-pot method. The temporary shape of hydrogel was fixed within 20 s in NaOH solution by the tris-complex crosslinking of metal-ligand complex between Fe³⁺ ions and catechol groups, while the permanent shape was recovered completely in HCl solution within 60 s upon the change from tris-complex to mono-complex. The hydrogel showed unique spontaneous actuation behavior. It could curl spontaneously without further external force deformation when immersed in NaOH solution again after the first shape recovery in HCl solution. This might be attributed to the competitive result of swelling and additional tris-complex crosslinking formation when immersed in NaOH solution. In addition, the hydrogels also had proper modulus, elongation ratio and tensile strength. Such hydrogel provides a new candidate material for designing soft actuators and robots modulated with spontaneous actuating.

In recent years, DNA supramolecular hydrogels have attracted much attention due to their injectability, biocompatibility, responsiveness and self-healing properties. In this work, we designed a linear DNA brick containing one duplex with two cytosine (C)-rich sequence on both ends. This brick can first assemble to form duplex under pH 8 condition. After adjusting the pH to 5, the C-rich sequence tends to form intermolecular i-motif structure, which joins the linear DNA molecules together to form interlocked cyclic structures and yield the DNA hydrogel. By adjusting the length and bending curvature of the duplex part of the molecule, one can change the basic unit of the hydrogel structure to tune the properties of the DNA hydrogel.