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The heterogeneous structure that exists in virtually all hydrogels has a significant influence on the resulting strength and toughness. While the internal structure has been observed with electron microscopy, it is difficult to measure the in situ local polymer concentration in the native swollen state. In this study, a modified microelectrode technique (MET) was employed to measure the Donnan potential of a heterogeneous hydrogel with a phase-separated structure. With this method, we succeeded in observing quantitative in situ polymer concentrations ranging from 10.2 mu mol/L to several hundred mmol/L. From the obtained concentration profiles, we could successfully evaluate the internal phase-separated structure with a resolution of less than 0.8 mu m. Using MET, we could estimate the average activity coefficient of the hydrogel, and we found a difference in concentration between the dense and sparse phases. We demonstrate that MET is a powerful method that can locally and quantitatively measure the polyelectrolyte concentration distribution within hydrogels. Furthermore, this method can be applied to cells and organs in vivo due to their similarities with polyelectrolytes. Enabling the in situ determination of the internal structures of biomaterials could have important implications toward the characterization of damaged and diseased tissues on the local scale.

Summary The toughness of composite materials is size dependent below a critical load transfer length (lT). Fiber-reinforced viscoelastic polymers are uniquely suited to study the size-limited regime because the lT of these soft composites can be as high as several centimeters, in contrast to traditional composites where lT is extremely small, allowing a large window for macroscale characterization. In this work, we elucidate the parameters that influence the toughness of soft composites when failure is governed by a fiber pullout-induced matrix-fracture mechanism. We ultimately demonstrate three important points: (1) fiber-reinforced viscoelastic polymers can possess high toughness, even at dimensions well below lT, (2) significant toughness amplification occurs due to the presence of fibers, even when the fracture process consists solely of matrix rupture, and (3) the composite toughness in the fiber pullout region can be predicted from easily attainable component parameters.

Longer and stronger; stiff but not brittle Hydrogels are highly water-swollen, cross-linked polymers. Although they can be highly deformed, they tend to be weak, and methods to strengthen or toughen them tend to reduce stretchability. Two papers now report strategies to create tough but deformable hydrogels (see the Perspective by Bosnjak and Silberstein). Wang et al . introduced a toughening mechanism by storing releasable extra chain length in the stiff part of a double-network hydrogel. A high applied force triggered the opening of cycling strands that were only activated at high chain extension. Kim et al . synthesized acrylamide gels in which dense entanglements could be achieved by using unusually low amounts of water, cross-linker, and initiator during the synthesis. This approach improves the mechanical strength in solid form while also improving the wear resistance once swollen as a hydrogel. —MSL

In this account, we provide an overview of unique anisotropic hydrogels comprising uniaxially aligned lamellar bilayers embedded in amorphous gel matrix. Owing to their unique structures, the lamel...

Copolymer hydrogels formed from cationic and aromatic monomers with identical monomer compositions but different average sequences were synthesized by free-radical copolymerization in various solvents. We found that hydrogels with one-component-rich segments are mechanically stronger than those with adjacent-rich monomer sequences in water, while hydrogels with a rich cation-π adjacent sequence showed excellent mechanical strength and underwater adhesion in saltwater (0.7 M NaCl). The molecular mechanisms for these behaviors are discussed in terms of polymer structures. This work reveals the importance of monomeric sequences in determining hydrogel properties and provides a facile approach to develop hydrogels with different properties but the same monomer composition.

Cancer recurrence can arise owing to rare circulating cancer stem cells (CSCs) that are resistant to chemotherapies and radiotherapies. Here, we show that a double-network hydrogel can rapidly reprogramme differentiated cancer cells into CSCs. Spheroids expressing elevated levels of the stemness genes Sox2, Oct3/4 and Nanog formed within 24 h of seeding the gel with cells from any of six human cancer cell lines or with brain cancer cells resected from patients with glioblastoma. Human brain cancer cells cultured on the double-network hydrogel and intracranially injected in immunodeficient mice led to higher tumorigenicity than brain cancer cells cultured on single-network gels. We also show that the double-network gel induced the phosphorylation of tyrosine kinases, that gel-induced CSCs from primary brain cancer cells were eradicated by an inhibitor of the platelet-derived growth factor receptor, and that calcium channel receptors and the protein osteopontin were essential for the regulation of gel-mediated induction of stemness in brain cancer cells. A double-network hydrogel can rapidly reprogramme differentiated tumour cells into cancer stem cells that display elevated tumorigenicity in vivo.

Applying the double network principle to develop tough hydrogels with different polymer chemistries is important for the potential application of hydrogel materials. Synthesis of the two interpenetrated networks with contrasting structure and properties required for double networks usually involves a two-step polymerization process. In this work, we present a new method to synthesize tough double network hydrogels by post-physical crosslinking of linear semi-rigid polyelectrolytes entrapped in a chemically crosslinked neutral network. Owing to their semi-rigid structure, the linear polyelectrolytes form a brittle physical network above their overlap concentration in multi-valent ZrCl2O ion solutions without macroscopic phase separation within the flexible neutral network. The double network hydrogels thus prepared exhibit high modulus (∼1.7 MPa), strength (∼1.3 MPa), fracture strain (∼7.3), and strain energy density (∼5.9 MJ m-3), while containing over 80% water. These materials also exhibit modest self-healing ability (∼51% after 30 minutes), demonstrating an additional benefit of a physical sacrificial network. This method is simpler than the conventional two-step polymerization and could be applied to develop tough hydrogels from rigid polyelectrolytes, including biopolymers such as DNA, HA, and chondroitin sulfate.

The high water content of hydrogels makes them important as synthetic biomaterials, and tuning the mechanical properties of hydrogels to match those of natural tissues without changing chemistry is usually difficult. In this study, we have developed a series of hydrogels with varied stiffness, strength, and toughness based on a combination of poly(2-acrylamido-2-methylpropane sulfonic acid) (PAMPS), a strong acidic polyelectrolyte, and poly-N-(carboxymethyl)-N,N-dimethyl-2-(methacryloyloxy) ethanaminium) (PCDME), a polyzwitterion with a weak acidic moiety. We demonstrate that modifying the true molar ratio, R, of PCDME to PAMPS results in four unique categories of hydrogels with different swelling ratios and Young's moduli. When R 6.5, a tough and stiff double-network gel (DN) is formed. Both the PEC and DN gels exhibit high toughness and fracture stress, up to 1.8 and 1.5 MPa, respectively. Importantly, the PEC gels exhibit strong recovery properties along with high toughness, distinguishing them from DN gels. Without requiring a change in chemistry, we can tune the mechanical response of hydrogels over a wide spectrum, making this a useful system of soft and hydrated biomaterials.

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.

Polyelectrolyte gels exhibit intrinsic salt-sensitive swelling behaviour, which causes size instability in ionic environments. Thus, polyelectrolyte gels that show salt-insensitive swelling have been anticipated for applications in ionic environments, such as medical materials used in vivo. We found that double-network (DN) gels consisting of both a polyelectrolyte network and a non-ionic network are resistant to salt-sensitive swelling. This resistance is attributed to their lower osmotic pressure originating from mobile ions relative to the osmotic pressure of mixing at swelling equilibrium. Our investigation indicated that the two contrasting network structures within the DN gels are vital for achieving these properties, where the structures include a highly prestretched and sparse polyelectrolyte network and a coiled and dense non-ionic network. The salt-insensitivity of the DN gels will lead to their unique applications in ionic environments.

A tough and ductile, ultrathin film, double-network (DN), biopolymer-based hydrogel displaying the yielding phenomenon was synthesized from methacrylated chondroitin sulfate (MCS) and polyacrylamide (PAAm). The DN of MCS/PAAm exhibited a failure stress more than 20 times greater than the single network (SN) of either MCS or PAAm and exhibited yielding stresses over 1500 kPa. In addition, the stress–strain behavior with a yielding region was also seen in a hydrogel of MCS and poly(N,N-dimethyl acrylamide) (PDMAAm). By replacing PAAm with PDMAAm, interactions known to toughen networks are removed. This demonstration supports the idea that the brittle/ductile combination is key to the DN effect over specific interactions between the networks. The MCS/PAAm and MCS/PDMAAm DN hydrogels had comparable mechanical properties to the archtypal DN hydrogels of poly(2-acrylamido-2-methylpropanesulfonic acid) (PAMPS)/PAAm. In addition, these tough and ductile, biopolymer-based, double-network hydrogels demonstrated a s...

The utility and lifetime of materials made from polymer networks, including hydrogels, depend on their capacity to stretch and resist tearing. In gels and elastomers, those mechanical properties are often limited by the covalent chemical structure of the polymer strands between cross-links, which is typically fixed during the material synthesis. Here, we report polymer networks in which the constituent strands lengthen through force-coupled reactions that are triggered as the strands reach their nominal breaking point. Reactive strand extensions of up to 40% lead to hydrogels that stretch 40-50% further than, and exhibit tear energies twice that of, networks made from analogous control strands. The enhancements are synergistic with those provided by double network architectures, and complement other existing toughening strategies.

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.

Chitin is a biopolymer, which has been proven to be a biomedical material candidate, yet the weak mechanical properties seriously limit their potentials. In this work, a chitin-based double-network (DN) hydrogel has been designed as a potential superficial repairing material. The hydrogel was synthesized through a double-network (DN) strategy composing hybrid regenerated chitin nanofiber (RCN)-poly (ethylene glycol diglycidyl ether) (PEGDE) as the first network and polyacrylamide (PAAm) as the second network. The hybrid RCN-PEGDE/PAAm DN hydrogel was strong and tough, possessing Young’s modulus (elasticity) E 0.097 ± 0.020 MPa, fracture stress σf 0.449 ± 0.025 MPa, and work of fracture Wf 5.75 ± 0.35 MJ·m–3. The obtained DN hydrogel was strong enough for surgical requirements in the usage of soft tissue scaffolds. In addition, chitin endowed the DN hydrogel with good bacterial resistance and accelerated fibroblast proliferation, which increased the NIH3T3 cell number by nearly five times within 3 days. Subcutaneous implantation studies showed that the DN hydrogel did not induce inflammation after 4 weeks, suggesting a good biosafety in vivo. These results indicated that the hybrid RCN-PEGDE/PAAm DN hydrogel had great prospect as a rapid soft-tissue-repairing material.

In this paper, the frictional behavior of a neutral hydrogel, polyvinyl alcohol (PVA), on smooth solid substrates with various levels of hydrophobicity have been investigated in water using a strain-controlled parallel-plate rheometer. For the sliding velocity dependence of friction, we detected a distinct friction transition on hydrophobic substrates that are strongly adhesive to the gel, while no clear transition was observed on hydrophilic substrates that are weakly adhesive to the gel. Even on the most hydrophobic substrate, the maximum frictional stress is approximately 1/10–1/5 of the gel’s elastic modulus under a large normal strain of 26%. Furthermore, the frictional stress on hydrophobic substrates in the high velocity region, larger than the transition, is much lower than that on hydrophilic ones. We attempted to explain these phenomena with the help of two models: a molecular model based on the thermal fluctuations occurring during adsorption–desorption of polymers and a continuum mechanics model based on elastic dewetting and forced wetting.

Polyampholyte (PA) hydrogels are a fascinating class of soft materials that can exhibit high toughness while retaining self-healing characteristics. This behavior results from the random distribution of oppositely charged monomers along the polymer chains that form transient bonds with a range of bond strengths. PAs can be dissolved in aqueous salt solutions and then recast via immersion precipitation, making them particularly useful as surface coatings in biomedical applications. Moreover, this immersion precipitation technique allows these PA hydrogels to be fabricated into films less than 100 nm. One critical challenge to this aqueous processing method is the recrystallization of the salt upon water evaporation. Such recrystallization can disrupt the hydrogel morphology especially in thin films. In this study, a deep eutectic solvent (DES) formed from urea and choline chloride was used to dissolve PAs made from p-styrenesulfonic acid sodium salt and 3-(methacryloylamino)propyl trimethylammonium chloride. This DES has a freezing point of 12 degrees C, allowing it to remain stable and liquid-like at room temperatures. Thus, these PAs can be processed in DES solutions, without this issue of recrystallization and with simple methods such as spin coating and dip coating. These methods allow these hydrogels to be used in thin (

Biological connective tissues, such as cartilage and corneal stroma, are essentially hydrogels consisting of fibrous collagen and proteoglycans. Little is known of the surface properties of the hydrogel, although we observe fascinating tribological behavior in biological soft tissues, such as extremely low friction between animal cartilages. We consider that the role of the solvated polymer network existing in the extracellular matrix as a gel state is critically important in the specific frictional behavior of cartilages. In order to elucidate the general tribological features of a solvated polymer matrix, the friction of various kinds of hydrogels has been investigated, and very rich and complex frictional behaviors are observed. The friction force and its dependence on the load differ with the chemical structure of the gels, surface properties of the opposing substrates, and the measurement conditions, which are totally different from those of solids. Most importantly, the coefficient of friction of gels, μ, varies over a wide range and exhibits very low values (μ ≈ 10−3–10−4), which cannot be obtained from the friction between two solid materials. A repulsion–adsorption model has been proposed to explain the gel friction, which says that the friction is due to lubrication of a hydrated layer of polymer chains when the polymer chain of the gel is non-adhesive (repulsive) to the substrate, and the friction is due to elastic deformation of the adsorbed polymer chain when it is adhesive to the substrate.

BackgroundCurrently, although Inula nervosa Wall is substantially investigated, little is understood about blossoms of Inula nervosa Wall (BINW).ObjectiveIn this work, we systematically investigated the antioxidant activity of the extract from BINW by various standard assays including 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical ability, 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) di-ammonium salt radical cation (ABTS), and ferric reducing antioxidant potential (FRAP).MethodsChemical compounds were tentatively identified through an UHPLC-QTOF-MS system. Furthermore, the contents of nine compounds were detected with UHPLC method coupled with photodiode array (PDA) detector. By carefully analyzing the quantitative data via clusters analysis and principal component analysis (PCA).ResultsForty-six compounds were tentatively identified, and our results showed that nine compound samples in 21 batches of BINW collected from different areas could be differentiated and analyzed by a heatmap visualization. In addition, the contents of nine compounds (flavonoids, phenolic acids) exhibited a total of higher amounts and better antioxidant activities from Yunnan than those from the other three origins.ConclusionsOur study not only developed a powerful platform to explain the difference between traditional Chinese medicines species that are closely related through the chemometric and chemical profiling, but also presented a useful method to establish quality criteria of BINW with multiple origins.HighlightsTo characterize the BINW in detail, we not only performed DPPH, FRAP, and ABTS assays to investigate its antioxidant activity, but also established UHPLC-QTOF-MS/MS- and UHPLC-PDA-based methods to comprehensively identify and qualitatively analyze its components.

Quantitative characterization of the energy dissipative zone around the crack tip is the central issue in fracture mechanics of soft materials. In this research, we present a mechanochemical technique to visualize the bond scission of the first network in the damage zone of tough double-network hydrogels. The mechanoradicals generated by polymer chain scission are employed to initiate polymerization of a thermoresponsive polymer, which is visualized by a fluorophore. This technique records the spatial distribution of internal fracturing from the fractured surface to the bulk, which provides the spatial profiles of stress, strain, and energy dissipation around the crack-tip. The characterized results suggest that, in addition to the dissipation in relatively narrow yielded zone which is mostly focused in the previous works, the dissipation in wide pre-yielding zone and the intrinsic fracture energy have also significant contribution to the fracture energy of a DN gel.

Nonalcoholic fatty liver disease (NAFLD) is the second major chronic liver disease world-wide and growing. Current medical treatment of NAFLD is not effective, and there is an urgent need to find new effective drugs. Liraglutide is now the first-line treatment for type 2 diabetes mellitus (T2DM) with promise, according to recent reports, to mitigate the fatty degeneration of the liver. The investigators of the current study discern if liraglutide reduces non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet using mice via modulating Kupffer cells M2 polarization in the liver. The mice underwent four weeks of intraperitoneal injections of liraglutide (0.6 mg/kg body weight). In the NAFLD model used in this study, the liver index, the body weight, and the serum levels of ALT, AST, total cholesterol, and triglycerides were meaningfully improved. In sections using H&E and Oil Red O staining, hepatic steatosis was significantly improved. Liraglutide decreased liver inflammation and the inflammatory properties of Kupffer cells in the NAFLD mouse model and there was a higher ratio of M2/M1 Kupffer cells. In vitro studies found that Liraglutide treatment modulates Kupffer cells to M2-like activation via the cAMP-PKA-STAT3 signaling pathway. The perilous effects of a high-fat diet were alleviated by liraglutide, including hepatic steatosis, by modulating Kupffer cells M2 polarization via the cAMP-PKA-STAT3 signaling pathway. Liraglutide can indeed reverse the negative effects of NAFLD.

Polyelectrolyte complexation between oppositely charged polyelectrolytes forms coacervates in dilute solutions and thin films in concentrated solutions. It is difficult to obtain macroscopically uniform bulk polyelectrolyte complex (PEC) materials, since the two polymers form insoluble complexes quickly at the contact interface during mixing, resulting in heterogeneous aggregates. Here, we succeeded in preparing bulk PEC materials based on desalting-induced polyelectrolyte complexation via viscoelastic phase separation. With a high ionic strength aqueous medium, a homogeneous and concentrated solution containing oppositely charged polyelectrolytes is prepared. Desalting of the counter-ions and co-ions of the solution through semi-permeable membranes induces viscoelastic phase separation of the solution to form a physical hydrogel with open pore structure. Regulating the charge ratio of the two oppositely charged polymers results in significant changes in the porous morphology and mechanical properties. The charge-balanced PEC hydrogels show unique properties including high toughness and self-recovery due to the reversible ionic associations. The porous yet tough properties of bulk PEC hydrogels makes them potential candidates for applications such as cell scaffolds.

Negatively charged synthetic hydrogels have been known to facilitate various cellular responses including cell adhesion, proliferation, and differentiation; however, the molecular mechanism of hydrogel-dependent control of cell behavior remains unclear. Recently, we reported that negatively charged poly(2-acrylamido-2-methylpropanesulfonic acid) (PAMPS) gel induces chondrogenic differentiation of ATDC5 cells via novel protein reservoir function. In this study, we identified the cell adhesion molecules binding to PAMPS gels that act as mechanoreceptors. First, we performed a pull-down assay by particle gels using cell membrane proteins of ATDC5, and found that multiple membrane proteins bound to the PAMPS gel, whereas the uncharged poly(N,N'-dimethylacrylamide) gel as control did not bind to any membrane proteins. Western blot analysis indicated differential binding of integrin (ITG) isoforms to the PAMPS gel, in which the α4 isoform, but not α5 and αv, efficiently bound to the PAMPS gel. ITG α4 knockdown decreased cell spreading of ATDC5 on PAMPS gels, whereas the enhanced expression increased the behavior. Furthermore, ITG α4 depletion suppressed PAMPS gel-induced expression of bone morphogenic protein (BMP) 4 contributing to chondrogenic differentiation, in concordance with the reduction of ERK activation. These results demonstrated that membrane protein binding to PAMPS gels occurred in a charge-dependent manner, and that ITG α4 plays a crucial role in cell spreading on PAMPS gels and acts as a mechanoreceptor triggering cellular signaling leads to chondrogenic differentiation.

Although cation−π interactions play a critical role in biological systems, experimental studies in aqueous environments are limited due to a lack of suitable systems and methods. The recent success in synthesizing water-soluble poly(cation−π) bearing adjacent cationic/aromatic residues provides excellent systems for studying cation−π interactions in aqueous environments. In this study, we investigated competitive cation−π interactions between small cations and macrocations with phenyl groups in hydrogels consisting of various poly(cation−π)s. By measuring the Donnan potential of the hydrogels equilibrated in NaCl solutions of different ionic strengths using the microelectrode technique, the binding ratios of small cations (Na+) to the phenyl residues of polymer networks were determined. It was found that when NaCl concentration was lower than the macrocation concentration, the activity coefficient of the counterions (Cl–) in the hydrogels was very high (~2), indicating that a large amount of excess Cl– was trapped in the hydrogels due to Na+ adsorption on the phenyl groups of the polymer chains via cation−π interactions. Further calculations showed that each phenyl group can adsorb a maximum of 1.5 Na+ despite the presence of adjacent macrocations. Additionally, we discuss the mechanism by which small cations compete with adjacent macrocations in poly(cation−π) hydrogels.

The extreme mechanical strength of fibrous connective tissues in the human body, such as ligaments and tendons, has always been challenging for hydrogel scientists. Here, we created extremely strong, purely cellulose-based hydrogels (DCC-E gels). The fracture stress and Young’s modulus of the gels were improved to the level of an Achilles tendon even at their equilibrium swollen state. To make DCC-E gels, regenerated cellulose gels were first prepared with ethanol as the anti-solvent. DCC-E gels were then prepared by applying Drying in Confined Condition method, where regenerated cellulose gels were prestretched and dried while their length was fixed. Although strength improvement of materials is typically only achieved at the expense of toughness, a significant increase in strength was achieved while maintaining high levels of toughness. The high strength and toughness of the DCC-E gels were realized by optimizing the cellulose fibril arrangement from nanoscale to macroscale, which was done by selection of an appropriate solvent used for cellulose regeneration. Parallel aggregated fibrous structures observed in the DCC-E gels are thought to play a central role in the enhancement of both toughness and strength. This study can assist in expanding the application of biopolymer-based hydrogels in tissue engineering and soft electronics.

Double-network gels are a class of tough soft materials comprising two elastic networks with contrasting structures. The formation of a large internal damage zone ahead of the crack tip by the rupturing of the brittle network accounts for the large crack resistance of the materials. Understanding what determines the damage zone is the central question of the fracture mechanics of double-network gels. In this work, we found that at the onset of crack propagation, the size of necking zone, in which the brittle network breaks into fragments and the stretchable network is highly stretched, distinctly decreases with the increase of the solvent viscosity, resulting in a reduction in the fracture toughness of the material. This is in sharp contrast to the tensile behavior of the material that does not change with the solvent viscosity. This result suggests that the dynamics of stretchable network strands, triggered by the rupture of the brittle network, plays a role. To account for this solvent viscosity effect on the crack initiation, a delayed blunting mechanism regarding the polymer dynamics effect is proposed. The discovery on the role of the polymer dynamic adds an important missing piece to the fracture mechanism of this unique material.

In this work, we intended to investigate the relationship between the swelling ratio Q and Young's modulus E of hydrogels from their contracted state to extreme swelling state and elucidate the underlining molecular mechanism. For this purpose, we used tetra-poly(ethylene glycol) (tetra-PEG) gel, whose network parameters are well known, as the polymer backbone, and we succeeded in tuning the swelling of the gel by a factor of 1500 times while maintaining the topological structure of the network unchanged, using an approach combining a molecular stent method and a PEG dehydration method. A master curve of Q-E, independent of the method of obtaining Q, was obtained. Using the worm-like chain model, the experimentally determined master curve can be well reproduced. We also observed that the uniaxial stress-strain curve of the hydrogel can be well predicted by the worm-like chain model using the structure parameters determined from the fitting of the Q-E experimental curve.

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.

This article reviews the recently developed tough, self-recovery, and self-healing polyampholyte hydrogels. Polyampholyte hydrogels are synthesized using one-step radical copolymerization of cationic and anionic monomers with equal charges at high monomer concentration. The random copolymerization process makes the ionic monomers randomly distributing along the backbones, resulting in the formation of ionic bonds with a wide strength distribution via inter and intra chain complexation in the polymer network, weak bond and strong bonds. The strong bonds serve as permanent cross-linking, integrating the hydrogels to impart the elastic behavior, while the weak bonds can break upon the loading, dissipating energy to give the toughness, and re-form again after unloading to enable the self-recovery behavior. Accordingly, polyampholyte hydrogels have condensed polymers in water (ca 40−50 wt %). They are strongly viscoelastic and have a high toughness (fracture energy of 4000 J/m2), a wide range of tuning modulus (0.01 to 8 MPa), 100% self-recovery, and a high self-healing efficiency after cutting.

The ability to determine that successful transfer and equal loading occur prior to using primary antibodies is important. And total protein staining is commonly used to check transfer efficiency and normalization, which play a crucial role in western blotting. Ponceau S and coomassie blue are commonly used, but there are disadvantages reported in recent years. Therefore, we are interested in finding another method, which is cheap, easy and fast. As we know, protein binding region of PVDF membrane is still hydrophilic when carbinol volatilizes, however, the non-protein binding region of PVDF membrane became hydrophobic again. And this different wettability between non-protein binding region and protein binding region of Polyvinylidene difluoride membrane may be used to check transfer efficiency and equal loading in western blotting. Based on the principle above, we describe an optical approach where an experimenter can observe that the proteins have been transferred to the membrane without any staining within minutes.

Tough hydrogels with adjustable stiffness are expected for adapting application as various biomaterials. Oppositely charged polyelectrolytes form tough and self-healing physical polyion-complex (PIC) hydrogels via formation of inter-chain ionic bonds with a wide distribution in bond strength. The strong bonds serve as permanent crosslinking to impart elasticity and the weak bonds as reversible sacrificial bonds to dissipate energy and to self-heal. In this work, we fabricate four PIC hydrogels using four positively charged trimethyl-ammonium monomers with slightly different chemical moieties and a same negatively charged polymer. The obtained PIC hydrogels all show high toughness but large difference in stiffness, extensibility, and self-recovery kinetics. With slight difference in the monomer structure of the polycations, the modulus of the hydrogels varies over two orders in magnitude, from 0.36 to 56 MPa, and the difference in elongation at break is up to five times. The presence of acryloyl moiety and methyl moiety increase the stiffness of the hydrogels. In the temperature range studied, all the four PIC hydrogels exhibit the rheological simple behaviours, following the time-temperature superposition principle. The four samples show quite different dynamic relaxation spectra over wide frequency range, revealing large difference in the strength distribution of dynamic ionic bonds. SEM observation reveals quite different phase separation structure for the four samples, in which the polymer chain stiffness should play an important role. This understanding of structure-properties of the PIC hydrogels will merit the designing of various supramolecular tough hydrogels and therefore broaden the scope of hydrogels for the applications as biomaterials.

We report a novel thermally responsive system from poly(butyl methacrylate)-b-poly(methacrylic acid)-b-poly(butyl methacrylate) (PBMA-b-PMAA-b-PBMA) triblock copolymer in dimethylformamide (DMF) solvent. This system shows a sol–gel transition by cooling below a critical temperature Tc. The network relaxation times of these gels rightly fall in the typical rheological experiment window, permitting us to investigate the relaxation dynamics and underlying mechanism, with a combination of linear rheology, time-resolved small-angle X-ray scattering (SAXS), and temperature-elevated nuclear magnetic resonance (NMR) measurements. Both time–temperature superposition (TTS) and time–concentration superposition (TCS) are well held in this system. The relaxation dynamics at temperatures below and above Tc are quite different, giving two different activation energies E1a and E2a, respectively. The E1a, being polymer concentration independent, is related to micelle formation of end-blocks, while the concentration dependent E2a is related to the chain friction of entangled polymer solution. By coupling linear rheology, SAXS, and NMR, we quantitatively estimated the fraction of bridge, loop, and dangling chains. The longest relaxation time of the gel, τL, strongly depends on polymer concentration, which is attributed to the increased connectivity of the micellar network. By combining the shift factors aT and aC determined from TTS and TCS, respectively, we can obtain the τL at any given temperature and concentration from that at reference temperature and concentration.

Inspired by the toughening mechanism of double-network (DN) gels, tough hydrogel composites with a sandwich structure were fabricated from photoresponsive polymers. By copolymerization of hydrophilic monomers, 2-ureidoethyl methacrylate (UM), and photoresponsive hydrophobic monomers, (2-nitrobenzyloxycarbonylaminoethyl methacrylate (NBOC)) at high concentrations, physical hydrogels that are soft and highly stretchable are formed due to the hydrophobic associations of NBOC, serving as dynamic crosslinkers. By UV irradiation, the physical crosslinking switches into chemical crosslinking, and the soft physical hydrogels transform into rigid and less stretchable chemical hydrogels. By UV curing the surface layers of the physical hydrogels, we prepared hydrogel composites having a sandwiched structure with two rigid outer layers and a soft inner layer. The molecular-level continuous interfaces and matched swelling ratios between the layers ensure the macroscale hydrogel composites’ high strength and toughness with a DN gel effect. The outer layers fracture preferentially at deformation, playing a role like the first network of a DN gel, while the inner layer maintains the integrity, playing a role resembling the second network. The evolution of the fracture morphology of the rigid layers gives useful insight into the internal fracture process of DN gels.

Blossoms of Inula nervosa Wall. (BINW) are traditionally used as an analgesic and antitussive in China. In this study, in vitro anticomplementary activities of crude extract from BINW in 21 batches and of extracts of four monomeric compounds were evaluated by the classical pathway. The effect of the region of origin on the quality of BINW was evaluated by fingerprint analysis for the first time. Furthermore, chemometric methods including similarity analysis and principal component analysis were employed to evaluate the quality of BINW. The nine major monomeric compounds were quantitated by ultra-high-performance liquid chromatography. All nine analytes demonstrated excellent linearity with recoveries ranging from 97.25% to 102.76%. The limits of detection and quantification were 0.07-12.20 μg/mL and 0.22-40.27 μg/mL, respectively. Results indicate that different regions of origin have a significant effect on the quality of BINW. Fingerprint analysis in combination with chemometrics and multi-ingredient determination is an efficient and reliable approach for quality evaluation. The BINW samples from Yunnan had the highest ratio of 1,5-dicaffeoylquinic acid and thymol; they also exhibited significantly higher anticomplementary activity than those from three other areas. This study successfully established a rapid and efficient method to evaluate the quality and biological activity of BINW.

International audience; experiencing solvent exchange from good to poor, a gel usually exhibits a monotonous deswelling with time if the good and poor solvents are miscible. [7-11] During this process, the good solvent easily escapes from gels driven by osmotic pressure of solvent-solvent mixing, while the poor solvent hardly enters the gel due to the demixing of polymer and poor solvent (Figure 1a). Here, we report an abnormal swelling of hydrophobic gels in water to form "hydrophobic hydrogels." We discovered that when hydrophobic gels swollen with omniphilic organic solvents are immersed in water or aqueous solutions, instead of shrinkage, the hydrophobic gels substantially swell to reach a water content as high as 99.6 wt% at most. The significant swelling of hydrophobic gels in water leads to the formation of a novel class of "hydro-phobic hydrogels" that have a unique fruit-like structure and show unique functions such as selective water absorption. To our knowledge, such abnormal swelling phenomenon of hydrophobic gels in water has never been reported before. This abnormal swelling is attributed to the rapid formation of a semipermeable skin layer on the surface of the gel by the phase separation of the hydrophobic polymer in water, which brings about a strongly asymmetrical diffusion for the organic solvent and water. The impermeable organic solvent is effectively trapped inside the gel, and thus generates a high osmotic pressure which drives the permeable Normally, a polymer network swells in a good solvent to form a gel but the gel shrinks in a poor solvent. Here, an abnormal phenomenon is reported: some hydrophobic gels significantly swell in water, reaching water content as high as 99.6 wt%. Such abnormal swelling behaviors in the nonsolvent water are observed universally for various hydrophobic organogels containing omniphilic organic solvents that have a higher affinity to water than to the hydrophobic polymers. The formation of a semipermeable skin layer due to rapid phase separation, and the asymmetric diffusion of water molecules into the gel driven by the high osmotic pressure of the organic solvent-water mixing, are found to be the reasons. As a result, the hydrophobic hydrogels have a fruit-like structure, consisting of hydrophobic skin and water-trapped micropores, to display various unique properties, such as significantly enhanced strength, surface hydrophobicity, and antidrying, despite their extremely high water content. Furthermore, the hydrophobic hydrogels exhibit selective water absorption from concentrated saline solutions and rapid water release at a small pressure like squeezing juices from fruits. These novel functions of hydrophobic hydrogels will find promising applications, e.g., as materials that can automatically take the fresh water from seawater. Polymer gels are defined as crosslinked polymer networks that are swollen in solvents. Since the last three decades, gels, especially water-based hydrogels, have embraced increasing interest for the numerous engineering and biological applications, including bioengineering, [1,2] adhesion, [3,4] soft robotics, [5] and 3D printing. [6] Ordinarily, a polymer network swells in a good solvent having a high affinity to polymer, forming a gel. When

Hydrogels formed by polyelectrolyte complexation (PEC) of oppositely charged biopolymers, free of any chemical additives, are promising biomaterials. In this work, the mechanical behavior of hydrogels consisting of positively charged chitosan and negatively charged sodium hyaluronate (HA) at balanced charge composition is investigated. These hydrogels exhibit strong tensile strain and strain rate dependence. They are elastic-like, independent of the strain rate at small strain, but exhibit plastic-like behavior above the yield point by showing a monotonous decrease of the stress. The cyclic tensile test demonstrates that these hydrogels exhibit small and quickly recoverable hysteresis in the elastic-like region, but large and partially recoverable hysteresis above the yield point. The stress relaxation experiment shows a plateau in the reduced stress followed by an abrupt fracture, and the time-to-failure decreases exponentially with increasing applied step-strain. Such elastic-to-plastic-like transformation of the biopolymer PEC gels is quite different from the behaviors of PEC hydrogels formed by oppositely charged vinyl-type synthetic polyelectrolytes due to the difference in flexibility, charge density, and ionic bond strength of these polymers.

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.

Paclitaxel has been widely used in the treatment of breast cancer. However, the development of drug resistance often increases the failure of chemotherapy. Growing evidence has reported the significant role of microRNAs (miRs) in drug resistance. The present study identified that miR-24 was significantly downregulated in paclitaxel-resistant (PR) breast cancer patients and in MCF-7/PR human breast carcinoma cells, and that overexpression of miR-24 could increase the effect of paclitaxel on drug-resistant breast carcinoma cells. Furthermore, miR-24 could directly bind to the 3'-untranslated region of ATP binding cassette B9 to downregulate its expression, thereby reducing drug transportation and improving the anti-tumor effect of paclitaxel on breast cancer cells. In vivo experiments also demonstrated that overexpression of miR-24 could increase the sensitivity of drug-resistant MCF-7 cells to paclitaxel. In conclusion, the present results suggested a novel function for miR-24 in reducing paclitaxel resistance in breast cancer, which may be of important clinical significance.

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

This work developed a photonic hydrogel that is responsive to, and can distinguish between two stimuli of stress and pH. Patterning is used to locally change the chemistry of a one-dimensional (1D) photonic gel, such that the native region is responsive to mechanical stress while the chemically modified region is responsive to both mechanical stress and pH. By combining the optical signals in the native region and the modified region, one can distinguish the stimuli between pH and stress. Specifically, the native 1D photonic gel is composed of periodically aligned polymeric bilayers in a soft polyacrylamide (PAAm) network. The chemical modification is done by partially hydrolyzing PAAm into sodium polyacrylic acid in some patterned regions, which imparts pH sensitivity, in addition to the stress sensitivity, to these regions.

Oppositely charged homopolyelectrolytes were found to form strong, tough, and self-healing polyion-complex (PIC) hydrogels, similar to polyampholytes (PA) which have opposite charges randomly distributed on the same polymer chains. The excellent mechanical performances of these two novel hydrogels are the results of dynamic ionic bonds formation between entangled polymer chains. For the PIC system, only interchain bonding occurs, while for the PA system both inter- and intrachain bonding exist. In addition, the ion pairs are expected to form stronger bonding in the PIC system than those in the PA system. In this work, we performed a comparative study of PIC hydrogels with the PA hydrogels. The PIC hydrogels are synthesized by sequential homopolymerization of cationic and anionic monomers at varied formulation, and their swelling and mechanical properties are systematically studied in comparison to the PA hydrogels that were synthesized from random copolymerization of anionic monomers and cationic monomers of the similar formulation. Different from the PA system which only forms tough hydrogels around zero net charge composition without chemical cross-linking, the PIC system forms tough physical hydrogels even at weakly offbalanced charge composition. At the charge-balanced composition, the low entanglement concentration of homocharged polyelectrolyte chains leads to tough PIC hydrogels formation at much lower concentrations than that of PA hydrogels. As a result, the PIC hydrogels are much tougher than the PA hydrogels prepared at the same monomer composition. In similar to PA hydrogels, the PIC hydrogels also exhibit broad dynamic mechanical spectra, indicating the formation of ion complexes with widely ranged bond strength. The PIC hydrogels have strong viscoelasticity in comparison with PA hydrogels. However, the two systems show the similar activation energies of the dynamic mechanical spectra. The SEM microstructural observation shows that the PIC hydrogels have segregated structure while PA hydrogels are more homogeneous.

Tough double network (DN) hydrogels are promising substitutes of soft supporting tissues such as cartilage and ligaments. For such applications, it is indispensable to robustly fix the hydrogels to bones with medically feasible methods. Recently, robustly bonding the DN hydrogels to defected bones of rabbits in vivo has been proved successful. The low crystalline hydroxyapatite (HAp) of calcium-phosphate-hydroxide salt coated on the surface layer of the DN hydrogels induced spontaneous osteogenesis penetrating into the semi-permeable hydrogels to form a gel/bone composite layer. In this work, the 44 Ca isotope-doped HAp/DN hydrogel is implanted in a defect of rabbit femoral bone and the dynamic osteogenesis process at the gel/bone interface is analyzed by tracing the calcium isotope ratio using isotope microscopy. The synthetic HAp hybridized on the surface layer of DN gel dissolves rapidly in the first two weeks by inflammation, and then the immature bone with a gradient structure starts to form in the gel region, reutilizing the dissolved Ca ions. These results reveal, for the first time, that synthetic HAp is reutilized for osteogenesis. These facts help to understand the lifetime of bone absorbable materials and to elucidate the mechanism of spontaneous, non-toxic, but strong fixation of hydrogels to bones.

International audience; The contact of a hydrogel during the rotational shearing on glass surface in concentrated polymer solution was observed in situ. Dynamic contact patterns that rotate in-phase with the rotational shearing of the gel were observed for the first time. The contact patterns with a periodicity in the circumferential direction appeared and became fine with the shearing time. The patterns appeared more quickly at elevated sliding velocity, polymer concentration, and normal pressure. Furthermore, the softness of the gel also substantially influenced the character of the patterns. The pattern formation was discussed in terms of the non-linear rheology of the polymer solution at the rotational soft interface.

Recently, charge balanced polyampholytes (PA) have been found to form tough and self-healing hydrogels. This class of physical hydrogels have a very high equilibrated polymer concentration in water (ca. 40-50 wt%), and are strongly viscoelastic. They are synthesized by random copolymerization of equal amounts of oppositely charged monomers at a high concentration, followed by a dialysis process of the small counter-ions and co-ions in water. The randomly distributed, opposite charges of the polymer form multiple ionic bonds of intra- and inter-chains with strength distribution. The strong inter-chain bonds, stabilized by topological entanglement, serve as quasi-permanent crosslinks, imparting the elasticity, while the weak bonds, both inter- and intra-chains, reversibly break and re-form to dissipate energy to toughen the materials. In this work, we intend to clarify the structure of the physical PA hydrogels from the tensile behaviors of the PA hydrogels. To clarify the structure and its formation mechanism, we analysed the tensile behaviors of the samples before and after the dialysis. We separated the quasi-permanent crosslinking of strong inter-chain bonds and the dynamic crosslinking of weak inter-chain bonds by using a combined model that consists of the Upper Convected Maxwell model and the Gent strain hardening model. The model fitting of the tensile behaviors extracts quantitative structural parameters, including the densities of weak and strong inter-chain bonds and the theoretical finite extensibility of polymer chains. Based on the fitting results of the combined model, the structural parameters of partial chains at a fixed observation time, including the Kuhn number, Kuhn length, and chain conformation, are determined using the scaling theory. The effects of monomer concentration at preparation, the effect of dialysis and the initial strain rate on the dynamic structure of PA gels, are discussed based on these analyses.

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%).

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.