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Supermacroporous hydrogels, possessing sponge-like structure and permeability, have drawn significant atten-tion for their bioengineering and biomedical applications. However, their mechanical weakness due to their low-density structure is one of their biggest limitations. This work reports a multi-step cryogelation technique, which does not require special equipment, for preparing tough supermacroporous hydrogels on the basis of the double-network (DN) strategy. The produced supermacroporous DN gels possess interconnected pores with pore sizes of 50–230 μm. They also show a com-pressive modulus of up to ~100 kPa, which is 2- to 4-times higher than that of the corresponding supermacroporous single-network (SN) gels, and compressive strength of up to 1 MPa at 80% compression. The supermacroporous DN cryogels are also stretchable with a work of extension of up to 38 kJ m-3, which is 1 to 2 orders larger than that of the SN cryogels. The high stiffness and stretchability distinguish them from other types of cryogels. Supermacroporous triple-network (TN) gels and DN gels composed of different polymer combinations are also prepared. The technique presented herein is suitable for pre-paring supermacroporous DN gels from various polymers; hence, it is promising in meeting bioengineering and biomedical demands.

Inspired by bone tissues, we mineralized low crystalline hydroxyapatite (HAp) particles in double network (DN) hydrogels, and we observed that the HAp minerals toughen the gels. The contribution of dissipated energy from HAp minerals was over 500% higher than that from the polymer during tensile deformation. We elucidated that the amorphous parts in the HAp minerals break at deformation, acting as energy-dissipative sacrificial bonds. This result implies that not only brittle polymer networks but also minerals can provide sacrificial bonds to toughen soft materials.

Due to the soft and wet characteristics of hydrogels that acquire high mechanical strength by toughening strategies, tough and robust hydrogels are attractive as next-generation structural biomaterials, especially for the substitution of soft connective tissues such as cartilage, tendons, and ligaments. Firm fixation of the gels to bone in vivo is an indispensable technology in clinical applications. However, since the surface of the hydrogel is very watery, current medical adhesives cannot fix the gels at all. In this review, first, the double network (DN) strategy, a universal method to toughen hydrogels, is presented. Second, by combining hydroxyapatite (HAp) of a main bony inorganic component with a high-strength DN gel, a biocompatible adhesion method accompanied by spontaneous osteogenesis penetration into the gel matrix is introduced. In addition, the HAp-gel composite can be used as a simplified model of bone tissues because of their similarity in terms of components. Third, HAp formation spatially confined by the polymer network of gel is shown as a model of the earliest stage of biomineralization in vivo. These studies on biomineral–hydrogel composites have great potential to contribute not only basic research on osteogenesis mechanisms but also clinical applications of tough hydrogels. Double network (DN) gel - hydroxyapatite (HAp) composite achieves robust fixation to bone tissue accompanied by spontaneous osteogenesis penetration into the gel matrix. In addition, the HAp-DN gel composite can be used as a simplified model of bone tissues because of their similarity in terms of components. The HAp orientation is regulated by the anisotropy of the polymer network of gel, implying that the collagen matrix is oriented in the earliest stage of biomineralization in vivo.

Recently, we have developed a hydroxyapatite (HAp)-hybridized double-network (DN) hydrogel (HAp/DN gel), which can robustly bond to the bone tissue in the living body. The purpose of this study is to clarify whether the HAp/DN gel surface can differentiate the bone marrow-derived mesenchymal stem cells (MSCs) to osteogenic cells. We used the MSCs which were harvested from the rabbit bone marrow and cultured on the polystyrene (PS) dish using the autogenous serum-supplemented medium. First, we confirmed the properties of MSCs by evaluating colony forming unit capacity, expression of MSC markers using flow cytometry, and multidifferential capacity. Secondly, polymerase chain reaction analysis demonstrated that the HAp/DN gel surface significantly enhanced mRNA expression of the eight osteogenic markers (TGF-β1, BMP-2, Runx2, Col-1, ALP, OPN, BSP, and OCN) in the cultured MSCs at 7 days than the PS surfaces (p < 0.0001), while the DN gel and HAp surfaces provided no or only a slight effect on the expression of these markers except for Runx2. Additionally, the alkaline phosphatase activity was significantly higher in the cells cultured on the HAp/DN gel surface than in the other three material surfaces (p < 0.0001). Thirdly, when the HAp/DN gel plug was implanted into the rabbit bone marrow, MSC marker-positive cells were recruited in the tissue generated around the plug at 3 days, and Runx2 and OCN were highly expressed in these cells. In conclusion, this study demonstrated that the HAp/DN gel surface can differentiate the MSCs into osteogenic cells.

Hydrogels are promising materials for several applications, including cell scaffolds and artificial load-bearing substitutes (cartilages, ligaments, tendons, etc.). Direct observation of the nanoscale polymer network of hydrogels is essential in understanding its properties. However, imaging of individual network strands at the molecular level is not achieved yet due to the lack of suitable methods. Herein, for the first time, we developed a novel mineral-staining method and network fixation method for transmission electron microscopy observation to visualize the hydrogel network in its unperturbed conformation with nanometer resolution. Surface network observation indicates that the length of surface dangling chains, which play a major role in friction and wetting, can be estimated from the gel mesh size. Moreover, bulk observations reveals a hierarchical formation mechanism of gel heterogeneity. These observations have the great potential to advance gel science by providing comprehensive perspective that link bulk gel properties with nanoscale.

Soft tissue engineering requires antifouling materials that are biocompatible and mechanically flexible. Conventional hydrogels containing more than 70 wt% water are thus promising antifouling material candidates. However, some hydrogels are difficult to apply in internal body organs because of undesirable protein absorption on their surfaces. Due to the lack of an effective method for observing the true charge densities of hydrogels, the reason why electrostatic interactions dominate protein absorption behavior remains unclear. In this work, we adopt the microelectrode technique (MET) to study the electrical potentials of hydrogels with negative, positive, and neutral potentials and demonstrate the protein absorption behaviors on those hydrogels. The results show that MET is an effective method to obtain the surface charge densities of various hydrogels. Furthermore, the amounts of absorbed proteins on the gels were quantified with respect to the charge densities of the hydrogels. The results indicate that electrostatic absorption is quantitatively dominated by a combination of hydrogel charge density and overall protein charge. Based on the knowledge obtained in this work, the effects of hydrogel surface charges on protein absorption can be better understood. Thus, the results are expected to promote the application of hydrogels in tissue engineering.

Double network hydrogels (DN gels) exhibit extraordinarily high strength and toughness by interplay of the two contrasting networks: the rigid, brittle network serves as a sacrificial bond that fractures at a relatively low strain, while the soft, stretchable network serves as hidden length that sustains stress by large extension afterward. The internal fracture process of the brittle network strongly depends on the relative strength of the two networks. In this study, we study the internal fracturing process of typical DN gels that show yielding or necking under uniaxial stretching using in situ small-angle X-ray scattering. Two samples consisting of the same brittle first network from poly(2-acrylamido-2-methylpropanesulfonic acid) but stretchable second network from poly(N,N-dimethylacrylamide) of different concentrations were adopted. We found that (1) the brittle network shows nonaffine deformation even far below the yield strain by local fracture; (2) for the sample of low second network concentration, significant strain amplification occurs around the submicrometer-scale voids (defects) preexisting in the brittle network, which induces the fracture percolation of brittle network from voids to show the necking phenomenon; and (3) the strain amplification at voids is suppressed in the sample of high second network concentration, and fracture of brittle network occurs dispersedly, showing yielding without necking.

Recent studies reported a multiscale structure in tough and self-healing hydrogels containing physical associations. For example, a type of tough and self-healing hydrogel from charge-balanced polyampholytes (PA) has a mesoscale bicontinuous double network structure with structural length around 400 nm. This mesoscale network structure plays an essential role in the multistep rupture process, which leads to the high toughness of PA hydrogels. In this work, by using an osmotic stress method, we symmetrically studied how the relative strength of soft and hard networks and the strength of ionic bonds influence the property of PA gels. We found that increasing osmotic stress of the bath solution triggers the structure transition from bicontinuous double network structure to a homogeneous structure, which drives the concurrently opaque−transparent transition in optical property and viscoelastic−glassy transition in mechanical behavior. The gels around the structural transition point were found to possess both high toughness (fracture energy of 7200 J m−2) and high stiffness (Young’s modulus of 12.9 MPa), which is a synergy of soft network and hard network of the bicontinuous structure. Our work not only provides an approach to tune the structure and property of physical hydrogels through tuning physical association but also gives a demo to investigate their relationships, yet another step forward gives inspiration to design a new type of tough and self-healing materials around the structural transition point.

Tough triblock copolymer hydrogels with microstructures of sphere, cylinder, and laminae were constructed using a newly developed “drying and swelling” method without changing the chemical structures of their monomeric units. These tough triblock copolymer hydrogels commonly showed high fracture stress of ∼10 MPa but exhibited varied elastic moduli depending on their microstructures. Furthermore, the constructed laminar gel formed pH-sensitive photonic gel at the base conditions, providing the gel application with potential as a sensor. Given their high toughness, biocompatibility, and tunable modulus, this study helps expand the potential application of amphiphilic block copolymer hydrogels for medical and industrial use.

Soft and wet hydrogels have many similarities to biological tissues, though their mechanical fragility had been one of the biggest obstacles in biomedical applications. Studies and developments in double network (DN) hydrogels have elucidated how to create tough gels universally based on sacrificial bond principles and opened a path for biomedical application of hydrogels in regenerative medicine and artificial soft connective tissues, such as cartilage, tendon, and ligament, which endure high tension and compression. This review explores a universal toughening mechanism for and biomedical studies of DN hydrogels. Moreover, because the term sacrificial bonds has been mentioned often in studies of bone tissues, consisting of biomacromolecules and biominerals, recent studies of gel–biomineral composites to understand early-stage osteogenesis and to simulate bony sacrificial bonds are also summarized.

The double network (DN) gel is a rigid, tough, and safe hydrogel; however, like all hydrogels and existing particle embolization materials composed of a polymer, they lack X-ray visibility. Thus, it is not possible to locate the embolization material in the body. In this study, we successfully developed an X-ray-visible embolization material, a tough DN gel incorporated with biocompatible heavy metal powder. The DN gel particles, composed of poly(N,N'-dimethylacrylamide) and poly(2-acrylamido-2-methylpropanesulfonic acid) with tantalum powder, were synthesized via two-step suspension radical polymerization. The characteristics of the DN particles were evaluated by comparing them with Embosphere®, an existing embolization material. Furthermore, we used a rat carotid artery embolic model to evaluate the material’s X-ray computed tomography visibility in vivo. The developed embolization material was visible in X-ray computed tomography scans and safe for use in the body. Moreover, as it remained in the vessels for a long time, it is expected to be more effective than Embosphere®. Thus, the developed material is a promising DN particle embolization material with X-ray computed tomography visibility.

One-dimensional photonic crystals or multilayer films produce colors that change depending on viewing and light illumination angles because of the periodic refractive index variation in alternating layers that satisfy Bragg's law. Recently, we have developed multilayered photonic hydrogels of two distinct bulk geometries that possess an alternating structure of a rigid polymeric lamellar bilayer and a ductile polyacrylamide (PAAm) matrix. In this paper, we focus on fabrication of composite gels with variable photonic band gaps by controlling the PAAm layer thickness. We report programmable angle-dependent and angle-independent structural colors produced by composite hydrogels, which is achieved by varying bulk and internal geometries. In the sheet geometry, where the lamellae are aligned parallel to the sheet surface, the photonic gel sheet exhibits strong angle-dependent colors. On the other hand, when lamellae are coaxially aligned in a cylindrical geometry, the gel rod exhibits an angle-independent color, in sharp contrast with the gel sheet. Rocking curves have been constructed to justify the diverse angle-dependent behavior of various geometries. Despite varying the bulk geometry, the tunable photonic gels exhibit strong mechanical performances and toughness. The distinct angle dependence of these tough photonic materials with variable band gaps could benefit light modulation in displays and sensor technologies.

We study the effect of dehydration on the structure and mechanical properties of anisotropic lamellar hydrogels, consisting of alternative stacking of several thousands of nanoscale rigid bilayers from amphiphilic poly(dodecyl glyceryl itaconate) (PDGI) and submicroscale soft hydrogel layers from hydrophilic polyacrylamide (PAAm) networks. We found that the layered microstructure is well preserved with dehydration, and a ductile–brittle transition occurs at the critical water content. This transition is related to the rubbery–glassy transition of the PAAm layers, which occurs at 58 wt % water content and is much higher than 26 wt % of bulk PAAm hydrogels. Such specific behavior of the lamellar hydrogels indicates that the dynamics of the submicroscale PAAm hydrated layer intercalated between the rigid bilayers are very different from its bulk state.

Novel, supramolecular, anisotropic hydrogels (called MC-PDGI gels) are presented in this study. These MC-PDGI gels consist of multi-cylindrical lipid bilayers aligned in a uniaxial manner and embedded in a soft hydrogel matrix. The bilayers and the hydrogel interact weakly due to hydrogen bonding. These MC-PDGI gels swell after exposure to water, which causes their volume and diameter to increase while simultaneously causing their length to decrease. This anisotropic swelling-induced contraction behavior is the result of competition between the isotropic elasticity of the hydrogel matrix and the interfacial tension of the lipid bilayers. Moreover, the MC-PDGI gels exhibit unique quasi one-dimensional diffusion behavior owing to the difficulty of molecular penetration through the multi-layered lipid bilayers. These materials would be useful for prolonged drug release or as an actuator.

We have developed a novel hydroxyapatite (HAp)-coated double-network (DN) hydrogel (HAp/DN gel). The purpose of this study was to determine details of the cell and tissue responses around the implanted HAp/DN gel and to determine how quickly and strongly the HAp/DN gel bonds to the bone in a rabbit osteochondral defect model. Immature osteoid tissue was formed in the space between the HAp/DN gel and the bone at 2 weeks, and the osteoid tissue was mineralized at 4 weeks. The push-out load of the HAp/DN gel averaged 37.54 N and 42.15 N at 4 and 12 weeks, respectively, while the push-out load of the DN gel averaged less than 5 N. The bonding area of the HAp/DN gel to the bone was above 80% by 4 weeks, and above 90% at 12 weeks. This study demonstrated that the HAp/DN gel enhanced osseointegration at an early stage after implantation. The presence of nanoscale structures in addition to osseointegration of HAp promoted osteoblast adhesion onto the surface of the HAp/DN gel. The HAp/DN gel has the potential to improve the implant-tissue interface in next-generation orthopaedic implants such as artificial cartilage. Statement of Significance Recent studies have reported the development of various hydrogels that are sufficiently tough for application as soft supporting tissues. However, fixation of hydrogels on bone surfaces with appropriate strength is a great challenge. We have developed a novel, tough hydrogel hybridizing hydroxyapatite (HAp/DN gel), which is directly bondable to the bone. The present study demonstrated that the HAp/DN gel enhanced osseointegration in the early stage after implantation. The presence of nanoscale structures in addition to the osseointegration ability of hydroxyapatite promoted osteoblast adhesion onto the surface of the HAp/DN gel. The HAp/DN gel has the potential to improve the implant-tissue interface in next-generation orthopaedic implants such as artificial cartilage.

The purpose of this study was to clarify fundamental mechanical properties and biological responses of the sodium hyaluronate-containing double network (HA-DN) gel and chondroitin sulfate-containing double network (CS-DN) gel, which were newly developed using the molecular stent method. This study discovered the following facts. First, these hydrogels had high mechanical performance comparable to the native cartilage tissue, and the mechanical properties were not affected by immersion in the saline solution for 12 weeks. Secondly, the mechanical properties of the CS-DN gel were not significantly reduced at 12 weeks in vivo, while the mechanical properties of the HA-DN gel were significantly deteriorated at 6 weeks. Thirdly, the degree of inflammation around the HA-DN gel was the same as that around the negative control. The CS-DN gel showed a mild but significant foreign body reaction, which was significantly greater than the negative control and less than the positive control at 1 week, while the inflammation was reduced to the same level as the negative control at 4 and 6 weeks. Fourthly, these gels induced differentiation of the ATDC5 cells into chondrocytes in the culture with the insulin-free maintenance medium. These findings suggest that these tough hydrogels are potential biomaterials for future application to therapeutic implants such as artificial cartilage. Statement of Significance The present study reported fundamental biomaterial properties of the sodium hyaluronate-containing double network (HA-DN) gel and chondroitin sulfate-containing double network (CS-DN) gel, which were newly developed using the molecular stent method. Both the HA- and CS-DN gels had high mechanical properties comparable to the cartilage tissue and showed the ability to induce chondrogenic differentiation of ATDC5 cells in vitro. They are potential biomaterials that may meet the requirements of artificial cartilage concerning the material properties. Further, these DN gels can be also applied to the implantable inducer for cell-free cartilage regeneration therapy.

Polyampholyte (PA) hydrogels are a new class of tough and selfhealing supramolecular hydrogels that have a potential as load-bearing soft materials. Studying on the creep behavior of these hydrogels and understanding the molecular mechanism are important for prediction of lifetime of the materials. In the present work, we study the creep rupture dynamics of the PA hydrogels with and without chemical cross-linking, in a certain observation time window. We have found that above some critical loading stress both physical and lightly chemically cross-linked hydrogels undergo creep rupture while moderately chemically cross-linked hydrogel resists creep flow. To elucidate the molecular mechanism, we have further compared the creep behaviors of the physical and lightly chemically cross-linked samples. The creep rate of the samples decreases with the creep time, following a power law relation, regardless of the loading stress variation. The fracture time of both of these hydrogels exponentially decreases with the increase of the loading stress, following the same master curve at high loading stress region, while the behavior of the two samples becomes different in the low loading stress region. We have explained the delayed fracture dynamics at high loading stress region in terms of a relatively weak strong bond rupture mechanism.

In this study, controlled amount of dangling ends is introduced to the two series of poly(ethylene glycol)-based hydrogel networks with three and four crosslinking functionality by using click chemistry. The structure of the gels with regulated defect percentage is confirmed by comparing the results of low-field NMR characterization and Monte Carlo simulation. The mechanical properties of these gels were characterized by tensile stress–strain behaviors of the gels, and the results are analyzed by Gent model and Mooney–Rivlin model. The shear modulus of the swollen gels is found to be dependent on the functionality of the network, and decreases with the defect percentage. Furthermore, the value of shear modulus well obeys the Phantom model for all the gels with varied percentage of the defects. The maximum extension ratio, obtained from the fitting of Gent model, is also found to be dependent on the functionality of the network, and does not change with the defect percentage, except at very high defect percentage. The value of the maximum extension ratio is between that predicted from Phantom model and the Affine model. This indicates that at the large deformation, the fluctuation of the crosslinking points is suppressed for some extend but still exists. Polymer volume fractions at various defect percentages obtained from prediction of Flory–Rehner model are found to be in well agreement with the swelling experiment. All these results indicate that click chemistry is a powerful method to regulate the network structure and mechanical properties of the gels. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2016

A series of physical double-network hydrogels is synthesized based on an amphiphilic triblock copolymer. The gel, which contains strong hydrophobic domains and sacrificial dynamic bonds of hydrogen bonds, is stiff and tough, and even stiffens in concentrated saline solution. Furthermore, due to its supramolecular structure, the gel features improved self-healing and self-recovery abilities.

Most studies on hydrogel swelling instability have been focused on a constrained boundary condition. In this paper, we studied the mechanical instability of a piece of disc-shaped hydrogel during free swelling. The fast swelling of the gel induces two swelling mismatches; a surface-inner layer mismatch and an annulus-disc mismatch, which lead to the formation of a surface crease pattern and a saddle-like bulk bending, respectively. For the first time, a stripe-like surface crease that is at a right angle on the two surfaces of the gel was observed. This stripe pattern is related to the mechanical coupling of surface instability and bulk bending, which is justified by investigating the swelling-induced surface pattern on thin hydrogel sheets fixed onto a saddle-shaped substrate prior to swelling. A theoretical mechanism based on an energy model was developed to show an anisotropic stripe-like surface crease pattern on a saddle-shaped surface. These results might be helpful to develop novel strategies for controlling crease patterns on soft and wet materials by changing their three-dimensional shape.

On implanting hydroxyapatite-mineralized tough hydrogel into osteochondral defects of rabbits, osteogenesis spontaneously penetrates into the gel matrix owing to the semi-permeablility of the hydrogel. The gradient layer (around 40 μm thick) contributes quite strong bonding of the gel to bone. This is the first success in realizing the robust osteointegration of tough hydrogels, and the method is simple and feasible for practical use.

We report, for the first time, the quantitative measurement of the local electric potential of brittle polyelectrolyte hydrogels using the microelectrode technique (MET). Given the solid-like nature of the hydrogels, the difficulty of applying MET is how to make a good contact of the microelectrode to the hydrogel. Poor local contact substantial underestimates the potential. We observed that, the potential measured decays exponentially with the increase of capillary diameter of the microelectrode. This behavior is related to the capillary wall thickness that determines the contact distance of the electrode probe to the hydrogel. The characteristic decay length in respective to the wall thickness is very close to the local Debye length around the capillary. The latter is much larger than that of the bath solution due to the reverse osmosis effect. By using microelectrodes with a tip wall thickness less than the local Debye length, the Donnan potential of polyelectrolyte gel could be accurately measured. Us...

Mechanically robust hydrogels are promising biomaterials as artificial supportive tissue. These applications require selective and robust bonding of the hydrogels to living tissue. Recently, we achieved strong in vivo bone bonding of a tough double network (DN) hydrogel, a potential material for use as artificial cartilage and tendon, by hybridizing osteoconductive hydroxyapatite (HAp) in the gel surface layer. In this work, we report micro patterning of HAp at the surface of the DN hydrogel for selective osteoconduction. Utilizing the dissolution of HAp in an acidic environment, the soft lithography technique using an acid gel stamp was adopted to form a high-resolution HAp pattern on the gel. The HAp-patterned gel showed well-regulated migration and adhesion of cells in vitro. Moreover, the HAp-patterned gel showed selective and robust bonding to the rabbit bone tissue in vivo. This HAp soft lithography technique allows for simple and quick preparation of tailor-made osteoconductive hydrogels and can be applied to other hydrogels for selective bone bonding. STATEMENT OF SIGNIFICANCE: Hydrogels, preserving large amount of water, have been studied for next-generation artificial soft tissues. However, fixation of hydrogels to living tissue was unsolved issue for clinical application. Recently, we achieved robust bonding of a tough double network gel to bone in vivo by coating of osteoconductive hydroxyapatite in the gel surface layer. For further progress for practical use, we report the micro patterning of HAp at the surface of the DN hydrogel by using soft lithography technique, to perform selective bonding to only objective area without unnecessary coalescence. The HAp lithography technique is simple, quick and non-toxic method to prepare tailor-made osteoconductive hydrogels and has universality of species of hydrogels.

Developing nonspecific, fast, and strong adhesives that can glue hydrogels and biotissues substantially promotes the application of hydrogels as biomaterials. Inspired by the ubiquitous adhesiveness of bacteria, it is reported that neutral polyampholyte hydrogels, through their self-adjustable surface, can show rapid, strong, and reversible adhesion to charged hydrogels and biological tissues through the Coulombic interaction.

Double-network hydrogels are one of the most promising candidates as artificial soft supporting tissues owing to their excellent mechanical performance, water storage capability, and biocompatibility. A double-network hydrogel consists of two contrasting polymer networks: rigid and brittle first network and soft and ductile second network. To satisfy this double-network requirement, polyelectrolyte and neutral polymer are suitable as the first and the second networks, respectively. Combination of these two networks gives rise to extraordinarily tough double-network hydrogel as a result of substantial internal fracture of the brittle first network at large deformation, which contributes to the energy dissipation. Therefore, the first network serves as the sacrificial bonds to toughen the material. The double-network principle is universal and many kinds of double-network hydrogels composed of various chemical species have been developed. Moreover, a molecular stent technology has been developed to synthesize the double-network hydrogels using neutral polymer network as the brittle first network. The sulfonic double-network hydrogel was found to induce spontaneous hyaline cartilage regeneration in vivo.

Novel, tough, strong, and self-healable polyacrylamide (PAAm) gels are fabricated by inducing an appropriate phase-separation structure using a poor solvent. The phase separation induces a gel-glass-like transition of the PAAm gels, providing the gels an anomalously high modulus (211 MPa), fracture stress (7.13 MPa), and fracture energy (4.16 x 10(4) J m(-2)), while keeping a high solvent content (approximate to 60 vol%).

Marine collagen has been attracting attention as a medical material in recent times due to the low risk of pathogen infection compared to animal collagen. Type I collagen extracted from the swim bladder of Bester sturgeon fish has excellent characteristics such as high denaturation temperature, high solubility, low viscosity and an extremely fast rate to form large bundle of fibers under certain conditions. These specific characteristics of swim bladder collagen (SBC) permit us to create stable, disk shaped hydrogels with concentric orientation of collagen fibers by the controlled diffusion of neutral buffer through collagen solution at room temperature. However, traditionally used animal collagens, e.g. calf skin collagen (CSC) and porcine skin collagen (PSC), could not form any stable and oriented structure by this method. The mechanism of the superstructure formation of SBC by a diffusion induced gelation process has been explored. The fast fibrillogenesis rate of SBC causes a quick squeezing out of the solvent from the gel phase to the sol phase during gelation, which builds an internal stress at the gel-sol interface. The tensile stress induces the collagen molecules of the gel phase to align along the gel-sol interface direction to give this concentric ring-shaped orientation pattern. On the other hand, the slow fibrillogenesis rate of animal collagens due to the high viscosity of the solution does not favor the ordered structure formation. The denaturation temperature of SBC increases significantly from 31 degrees C to 43 degrees C after gelation, whereas that of CSC and PSC were found to increase a little. Rheology experiment shows that the SBC gel has storage modulus larger than 15 kPa. The SBC hydrogels with thermal and mechanical stability have potential as bio-materials for tissue engineering applications.

A simplified model describing the sliding friction of hydrogel on solid surface by dynamic adsorption of the polymer chains is proposed on the basis of polymer adsorption-repulsion theory. This dynamic adsorption model is used to analyze the friction results of zwitterionic hydrogels sliding over glass substrates with different substrate wettability, hydrogel swelling degree, ionic strength, and pH of bath solution. The adsorption time tau(b) of polymer strands is found to decrease with the increase in sliding velocity or the Weissenberg number as a result of stretching. The adsorption time tau(0)(b), and the adsorption energy U-ads at stress-free condition, which are characteristic for each friction system, are also estimated. Roughly, a master curve is observed for the normalized adsorption lifetime tau(b)/tau(0)(b) and the Weissenberg number, with less dependence on the adsorption energy and the bulk properties of the gels in the observed experimental conditions. Thus, the dynamic adsorption model successfully correlates the frictional behavior of hydrogels with the adsorption dynamics of polymer strands, which gives insight into the molecular design of hydrogels with predefined frictional properties for biomedical applications.

Ligaments are unique wet biological tissues with high tensile modulus and fracture stress, combined with high bending flexibility. Developing synthetic materials with these properties is a significant challenge. Hydrogel composites made from high stiffness fabrics is a strategy to develop such unique materials; however, the ability to produce these materials has proven difficult, since common hydrogels swell in water and interact poorly with solid components, limiting the transfer of force from the fabric to the hydrogel matrix. In this work, for the first time, we successfully produce extraordinarily tough hydrogel composites by strategically selecting a recently developed tough hydrogel that de-swells in water. The new composites, consisting of polyampholyte hydrogels and glass fiber woven fabrics, exhibit extremely high effective toughness (250 000 J m(-2)), high tear strength (similar to 65 N mm(-1)), high tensile modulus (606 MPa), and low bending modulus (4.7 MPa). Even though these composites are composed of water-containing, biocompatible materials, their mechanical properties are comparable to high toughness Kevlar/polyurethane blends and fiber-reinforced polymers. Importantly, the mechanical properties of these composites greatly outperform the properties of either individual component. A mechanism is proposed based on established fabric tearing theory, which will enable the development of a new generation of mechanically robust composites based on fabrics. These results will be important towards developing soft biological prosthetics, and more generally for commercial applications such as tear-resistant gloves and bulletproof vests.

Bone tissues possess excellent mechanical properties such as compatibility between strength and flexibility and load bearing owing to the hybridization of organic/inorganic matters with anisotropic structure. To synthetically mimic such an anisotropic structure of natural organic/inorganic hybrid materials, we carried out hydroxyapatite (HAp) mineralization in stretched tough double network (DN) hydrogels. Anisotropic mineralization of HAp took place in stretched hydrogels, as revealed by high brightness synchrotron X-ray scattering and transmission electron microscopic observation. The c-axis of mineralized HAp aligned along the stretching direction, and the orientation degree S calculated from scattering profiles increased with increasing in the elongation ratio λ of the DN gel, and S at λ = 4 became comparable to that of rabbit tibial bones. The morphology of HAp polycrystal gradually changed from spherical to unidirectional rod-like shape with increased elongation ratio. A possible mechanism for the anisotropic mineralization is proposed, which would be one of the keys to develop mechanically anisotropic organic/inorganic hybrid materials.

Proteins of thermophiles are thermally stable in a high-temperature environment, adopting a strategy of enhancing the electrostatic interaction in hydrophobic media at high temperature. Herein, inspired by the molecular mechanism of thermally stable proteins, the synthesis of novel polymer materials that undergo ultrarapid, isochoric, and reversible switching from soft hydrogels to rigid plastics at elevated temperature is reported. The materials are developed from versatile, inexpensive, and nontoxic poly(acrylic acid) hydrogels containing calcium acetate. By the cooperative effects of hydrophobic interaction and ionic interaction, the hydrogels undergo significant spinodal decomposition and subsequent rubbery-to-glassy transition when heated to an elevated temperature. As a result, the gels exhibit super-rapid and significant hikes in stiffness, strength, and toughness by up to 1800-, 80-, and 20-folds, respectively, when the temperature is raised from 25 to 70 degrees C, while the volumes of the gels are almost unchanged. As a potential application, the performance of the materials as athletic protective gear is demonstrated. This work provides a pathway for developing thermally stiffened materials and may significantly broaden the scope of polymer applications.

Amorphous cellulose-based tough double-network (DN) elastomers were successfully fabricated. These elastomers comprise interpenetrated poly(ethyl acrylate) (PEA) network as the soft matrix and the amorphous cellulose network as the brittle component. Unlike carbon-black-filled conventional rubbers, the obtained cellulose/PEA DN elastomers are transparent and can be dyed without any color limitation. Although the cellulose network in the DN elastomer comprises only 2.55 wt%, such cellulose network efficiently reinforces in toughness (10 times), stiffness (28 times), strength (8 times), and durability of the DN elastomer compared to the PEA elastomer. The structure and toughening mechanism of the cellulose/PEA DN elastomers are different from previously reported cellulose composites, in which cellulose nanocrystals were used simply as fillers. Upon deformation, the brittle cellulose network in the DN elastomer is ruptured sacrificially to dissipate energy, which effectively prevents crack propagation. The damaged cellulose network recovers its original structure to show recoverable mechanical properties by thermal annealing.

Recently, we have developed a series of charge balanced polyampholyte (PA) physical hydrogels by random copolymerization in water, which show extraordinarily high toughness, self-healing ability and viscoelasticity. The excellent performance of PA hydrogels is ascribed to dynamic ionic bond formation through inter- and intra-chain interactions. The randomness results in ionic bonds of wide strength distribution, the strong bonds, which serve as permanent crosslinking, imparting the elasticity, while the weak bonds reversibly break and re-form, dissipating energy. In this work, we developed a simple physical method, called a pre-stretching method, to promote the performance of PA hydrogels. By imposing a pre-stretching on the sample in the as-prepared state, ion complexation during dialysis is prominently accelerated and the final performance is largely promoted. Further analysis suggests that the strong bond formation induced by pre-stretching is responsible for the change in final performance. Pre-stretching decreases the entropy of the system and increases the chain alignment, resulting in an increased possibility for strong bond formation.

Soft supporting tissues in the human body, such as cartilages and ligaments, are tough materials and firmly fixed to bones. These soft tissues, once injured, cannot regenerate spontaneously in vivo . Developing tough and biocompatible hydrogels as artificial soft supporting tissues would substantially improve outcomes after soft tissue injury. Collagen is the main rigid component in soft connective tissues which is organized in various hierarchical arrays. We have successfully developed a novel class of collagen fibril-based tough hydrogels based on the double network (DN) concept using swim bladder collagen (SBC) extracted from Bester sturgeon fish. The DN hydrogels, SBC/PDMAAm, are composed of physically/chemically crosslinked anisotropic SBC fibril as the first network and neutral, biocompatible poly(N,N′-dimethylacrylamide) (PDMAAm) as the second network. The anisotropic structure of SBC fibril network, which is well retained in the DN hydrogels, is formed by free injection method, taking advantage of the excellent fibrillogenesis capacity of SBC. The denaturation temperature of collagen is improved in the DN hydrogels. These DN gels possess anisotropic swelling behavior, exhibit excellent mechanical properties comparable to natural cartilage. The 4 weeks implantation of the gels in the osteochondral defect of rabbit knee also shows excellent biomechanical performance in vivo . Furthermore, the hydroxyapatite (HAp) coated DN gels, HAp/SBC/PDMAAm gels, strongly bond to bone after 4 weeks. This new class of collagen-based hybrid DN gels, as soft and elastic ceramics, having good biomechanical performance and strong bonding ability with bone would expand the choice for designing next-generation orthopedic implants such as artificial cartilage, bone defect repair material in the load-bearing region of the body.

We demonstrate arrangement techniques of proteins and cells using an amorphous calcium phosphate (ACP) nanofiber scaffold. It is well known that protein andosteoblastic cell are preferably adsorbed onto ACP surface. The ACP nanofiber scaffold was prepared by calcium phosphate mineralization on a polypeptide monolayer-coated mica substrate, and ACP nanofibers were oriented unidirectionaly. In a protein system, the ACP nanofiber scaffold was soaked in a fluorescein isothiocyanate conjugated immunoglobulin G (IgG-FITC) aqueous solution. From fluorescence microscopic measurement, the adsorbed IgG-FITC was highly confined and arranged on the ACP nanofiber. In a cell system, a mouse osteoblast-like cell (MC3T3-E1) behavior on the ACP nanofiber scaffold was observed. The cell was elongated unidirectionaly, and its cytoskeletal shape showed high aspect ratio. These results are clearly different from an ACP bulk template or bare mica substrate, and the arrangement technique enable to fabricate a fine-tuned biomaterial template.

We have demonstrated a unique method for rational arrangement of gold (Au) nanoparticles on a β-sheet peptide template through nucleobase pairing. For the template, the 16-mer peptide 1 was synthesized, which is based on an alternating amphiphilic sequence of Asp-Leu. Here Leu at the sixth position is replaced by thymine-modified Lys, and a polyethylene glycol chain is introduced to the C-terminus. The surface of Au nanoparticles was modified with the complementary adenyl group. Peptide 1 formed a stable β-sheet monolayer at the air/water interface under an appropriate surface pressure. The monolayer film transferred onto a mica surface by the Langmuir-Blodgett method showed a linearly striped pattern with 6.1 nm average stripe width and 6 nm average interval between stripes, derived from β-sheet assembly. The adenine-bound Au nanoparticles were successfully immobilized on the thymine-bound template through a complementary adenine-thymine hydrogen bonding pair. Interestingly, linear assembly structures of the Au nanoparticles were observed, thus being successfully reproduced by the original striped pattern of the template of 1. Our method might readily fabricate Au materials with our desirable 2D pattern through fine-tuning of β-sheet sequence and nucleobase position.

Tough and self‐recoverable hydrogel membranes with micrometer‐scale thickness are promising for biomedical applications, which, however, rarely be realized due to the intrinsic brittleness of hydrogels. In this work, for the first time, by combing noncovalent DN strategy and spin‐coating method, we successfully fabricated thin (thickness: 5–100 µm), yet tough (work of extension at fracture: 105–107 J m−3) and 100% self‐recoverable hydrogel membranes with high water content (62–97 wt%) in large size (≈100 cm2). Amphiphilic triblock copolymers, which form physical gels by self‐assembly, were used for the first network. Linear polymers that physically associate with the hydrophilic midblocks of the first network, were chosen for the second network. The inter‐network associations serve as reversible sacrificial bonds that impart toughness and self‐recovery properties on the hydrogel membranes. The excellent mechanical properties of these obtained tough and thin gel membranes are comparable, or even superior to many biological membranes. The in vitro and in vivo tests show that these hydrogel membranes are biocompatible, and postoperative nonadhesive to neighboring organs. The excellent mechanical and biocompatible properties make these thin hydrogel membranes potentially suitable for use as biological or postoperative antiadhesive membranes.

Natural structural materials (such as tendons and ligaments) are comprised of multiscale hierarchical architectures, with dimensions ranging from nano- to macroscale, which are difficult to mimic synthetically. Here a bioinspired, facile method to fabricate anisotropic hydrogels with perfectly aligned multiscale hierarchical fibrous structures similar to those of tendons and ligaments is reported. The method includes drying a diluted physical hydrogel in air by confining its length direction. During this process, sufficiently high tensile stress is built along the length direction to align the polymer chains and multiscale fibrous structures (from nano- to submicro- to microscale) are spontaneously formed in the bulk material, which are well-retained in the reswollen gel. The method is useful for relatively rigid polymers (such as alginate and cellulose), which are susceptible to mechanical signal. By controlling the drying with or without prestretching, the degree of alignment, size of superstructures, and the strength of supramolecular interactions can be tuned, which sensitively influence the strength and toughness of the hydrogels. The mechanical properties are comparable with those of natural ligaments. This study provides a general strategy for designing hydrogels with highly ordered hierarchical structures, which opens routes for the development of many functional biomimetic materials for biomedical applications.

Tough hydrogels have shown strong potential as structural biomaterials. These hydrogels alone, however, possess limited mechanical properties (such as low modulus) when compared to some load-bearing tissues, e.g., ligaments and tendons. Developing both strong and tough soft materials is still a challenge. To overcome this obstacle, a new material design strategy has been recently introduced by combining tough hydrogels with woven fiber fabric to create fiber reinforced soft composites (FRSCs). The new FRSCs exhibit extremely high toughness and tensile properties, far superior to those of the neat components, indicating a synergistic effect. Here, focus is on understanding the role of energy dissipation of the soft matrix in the synergistic toughening of FRSCs. By selecting a range of soft matrix materials, from tough hydrogels to weak hydrogels and even a commercially available elastomer, the toughness of the matrix is determined to play a critical role in achieving extremely tough FRSCs. This work provides a good guide toward the universal design of soft composites with extraordinary fracture resistance capacity.

Biomacromolecules usually form complex superstructures in natural biotissues, such as different alignments of collagen fibres in articular cartilages, for multifunctionalities. Inspired by nature, there are efforts towards developing multiscale ordered structures in hydrogels (recognized as one of the best candidates of soft biotissues). However, creating complex superstructures in gels are hardly realized because of the absence of effective approaches to control the localized molecular orientation. Here we introduce a method to create various superstructures of rigid polyanions in polycationic hydrogels. The control of localized orientation of rigid molecules, which are sensitive to the internal stress field of the gel, is achieved by tuning the swelling mismatch between masked and unmasked regions of the photolithographic patterned gel. Furthermore, we develop a double network structure to toughen the hydrogels with programmed superstructures, which deform reversibly under large strain. This work presents a promising pathway to develop superstructures in hydrogels and should shed light on designing biomimetic materials with intricate molecular alignments.

Photonic crystals with tunability in the visible region are of great interest for controlling light diffraction. Mechanochromic photonic materials are periodically structured soft materials designed with a photonic stop-band that can be tuned by mechanical forces to reflect specific colours. Soft photonic materials with broad colour tunability and fast colour switching are invaluable for application. Here we report a novel mechano-actuated, soft photonic hydrogel that has an ultrafast-response time, full-colour tunable range, high spatial resolution and can be actuated by a very small compressive stress. In addition, the material has excellent mechanical stability and the colour can be reversibly switched at high frequency more than 10,000 times without degradation. This material can be used in optical devices, such as full-colour display and sensors to visualize the time evolution of complicated stress/strain fields, for example, generated during the motion of biological cells.

Polyzwitterionic materials, which have both cationic and anionic groups in the polymeric repeat unit, show excellent anti-biofouling properties and are drawing more attention in the biomedical field. In this study, we have successfully synthesized novel single network hydrogels and double network (DN) hydrogels from the zwitterionic monomer, N-(carboxymethyl)-N,N-dimethyl-2-(methacryloyloxy) ethanaminium, inner salt (CDME). The polyCDME (PCDME) single network hydrogel behaves like a hydrophilic neutral hydrogel and its properties are not sensitive to temperature, pH, or ionic strength over a wide range. DN hydrogels using the poly(2-acrylamido-2-methylpropanesulfonic) (PAMPS) as the first network and PCDME as the second network, having a Young's modulus of 0.2-0.9 MPa, possess excellent mechanical strength (fracture stress: 1.2-1.4 MPa, fracture strain: 2.2-6.0 mm/mm) and toughness (work of extension at fracture: 0.9-2.4 MJ m(-3)) depending on the composition ratio of PCDME to PAMPS. The strength and toughness of the optimized PAMPS/PCDME DN is comparable to the normal PAMPS/PAAm DN hydrogels that use poly(acrylamide) (PAAm) as the second network. By macrophage adhesion test, both the PCDME hydrogels and the PAMPS/PCDME DN hydrogels have shown excellent anti-biofouling properties. These results demonstrate that the PCDME-based DN hydrogels have high potential as a novel soft and wet biomaterial.