Strategy for Preparing Mechanically Strong Hyaluronic Acid–Silica Nanohybrid Hydrogels via In Situ Sol–Gel Process

A hybridization method to prepare a hyaluronic acid (HA)‐based nanohybrid hydrogel is proposed that introduces an additional inorganic silica network via an in situ sol–gel process. HA hydrogels have been extensively studied because of their excellent biocompatibility and biological functions; however, their poor mechanical strength hinders their use in tissue engineering applications. In the present work, the sol–gel technique is employed to achieve the formation of a structurally organized silica network in the HA hydrogel matrix rather than mixing of discrete particles with the HA polymer matrix. Importantly, the silica densification process results in significant enhancement of the mechanical properties. In addition, the nanohybrid hydrogels exhibit great degradation resistance and bioactivity on both fibroblast and pre‐osteoblast cells. Moreover, the physical characteristics and biological properties can be modulated by varying the silica content; these materials thus show great potential for a wide range of applications for soft and hard tissues.     

Mesoscale Characterization of Supramolecular Transient Networks Using SAXS and Rheology

Hydrogels and, in particular, supramolecular hydrogels show promising properties for application in regenerative medicine because of their ability to adapt to the natural environment these materials are brought into. However, only few studies focus on the structure-property relationships in supramolecular hydrogels. Here, we study in detail both the structure and the mechanical properties of such a network, composed of poly(ethylene glycol), end-functionalized with ureido-pyrimidinone fourfold hydrogen bonding units. This network is responsive to triggers such as concentration, temperature and pH. To obtain more insight into the sol-gel transition of the system, both rheology and small-angle X-ray scattering (SAXS) are used. We show that the sol-gel transitions based on these three triggers, as measured by rheology, coincide with the appearance of a structural feature in SAXS. We attribute this feature to the presence of hydrophobic domains where cross-links are formed. These results provide more insight into the mechanism of network formation in these materials, which can be exploited for tailoring their behavior for biomedical applications, where one of the triggers discussed might be used.     

Synthesis and Self-Assembly Properties of Bola-Amphiphilic Glycosylated Lipopeptide-Type Supramolecular Hydrogels Showing Colour Changes Along with Gel–Sol Transition

Supramolecular hydrogels formed by self-assembly of low-molecular-weight amphiphiles (hydrogelators) have attracted significant attention, as smart and soft materials. However, most of the observed stimuli-responsive behaviour of these supramolecular hydrogels are limited to gel–sol transitions. In this study, we present bola-amphiphilic glycosylated lipopeptide-type supramolecular hydrogelators that exhibit reversible thermochromism along with a gel–sol transition. The bola-amphiphiles have mono-, di-, tri- or tetra-phenylalanine (F) as a short peptide moiety. We investigate and discuss the effects of the number of F residues on the gelation ability and the morphology of the self-assembled nanostructures.     

Preparation,characterization, and release properties of hydrogels based on hyaluronan for pharmaceutical and biomedical use

Hyaluronic acid (HA) is a natural polysaccharide that is widely distributed in the human body. Its physicochemical properties and high biocompatibility make it a good candidate for biomedical and pharmaceutical uses. In the present work, we report HA‐based hydrogels that could be applied as drug delivery systems or as implants for the treatment of joint diseases. We use butanediol diglycidyl ether as a chemical crosslinker to obtain HA hydrogels. Using a new dissolution tester and ketoprofen (KP) as a model drug, we study the release properties of the hydrogels. We obtain homogeneous and transparent hydrogels with high strength and elasticity. The swelling ratio (SR) depends on the crosslinker concentration and pH of the medium. We also reveal differences between the release profile of KP from swollen and unswollen hydrogels. The characteristics and differences in KP release profiles depending on the SR suggest the possibility of obtaining controlled release from HA‐based hydrogels. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 130: 1377‐1382, 2013     

Biomineralized hyaluronic acid/poly(vinylphosphonic acid) hydrogel for bone tissue regeneration

Novel biomineralized hydrogels composed of hyaluronic acid (HA) and vinyl phosphonic acid (VPAc) were designed with the aim of developing a biomimetic hydrogel system to improve bone regeneration by local delivery of a protein drug including bone morphogenetic proteins. We synthesized crosslinked hydrogels composed of methacrylated HA and poly(VPAc) [P(VPAc)], which serves as a binding site for calcium ions during the mineralization process. The HA/P(VPAc) hydrogels were biomineralized by a urea‐mediation method to create functional polymer hydrogels that can deliver the protein drug and mimic the bone extracellular matrix. The water content of the hydrogels was influenced by the HA/P(VPAc) composition, crosslinking density, biomineralization, and ionic strength of the swelling media. All HA/P(VPAc) hydrogels maintained more than 84% water content. Enzymatic degradation of HA/P(VPAc) hydrogels was dependent on the concentration of hyaluronidase and the crosslinking density of the polymer network within the hydrogel. In addition, the release behavior of bovine serum albumin from the HA/PVPAc hydrogels was mainly influenced by the drug loading content, water content, and biomineralization of the hydrogels. In a cytotoxicity study, the HA/P(VPAc) and biomineralized HA/P(VPAc) hydrogels did not significantly affect cell viability. These results suggest that biomineralized HA/P(VPAc) hydrogels can be tailored to create a biomimetic hydrogel system that promotes bone tissue repair and regeneration by local delivery of protein drugs. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 41194.     

Synthesis and evaluation of hyaluronic acid hydrogels modified with various crosslinkers as biodegradable polymers

Hyaluronic acid (HA), a high‐molecular‐weight natural polysaccharide, is often used in medical devices for regenerative medicine as it can undergo biodegradation via enzymatic action in the human body. HA exhibits both viscoelasticity and high biocompatibility and has therefore been used for ocular surgery. In particular, HA‐based hydrogels have been utilized as cell scaffold materials and devices in ophthalmological treatments. In this study, four hydrogels have been synthesized from HA derivatives with methacrylate groups and modified with crosslinkers such as adipic acid dihydrazide, divinyl sulfone, and dithiothreitol. Each of the synthesized hydrogels exhibits high transparency and strength as well as biodegradability in vitro. Hence, these HA‐based hydrogels demonstrate potential for applications as drug delivery systems and implants. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 45453.     

Dynamic–Mechanical Properties of Bioartificial Polymeric Materials

Bioartificial polymeric materials represent a new class of polymeric materials based on blends of synthetic and natural polymers, designed with the purpose of producing new materials with enhanced properties with respect to the single components. The mechanical properties of bioartificial materials prepared using poly(vinyl alcohol) (PVA), poly(acrylic acid) (PAA) and poly(methacrylic acid) (PMAA) as synthetic components, and collagen (SC), gelatin, starch, hyaluronic acid (HA) and dextran as biological components, were investigated by dynamic mechanical thermal analysis. The materials were prepared in the form of films or hydrogels and treated by glutaraldehyde (GTA) vapour or thermal dehydration in order to reduce their solubility in water. The results indicate that SC/PVA, gelatin/PVA and starch/PVA films behave as biphasic systems, showing good mechanical properties over a wide range of temperature. It was observed that the GTA procedure affects only the biological component of the SC/PVA and gelatin/PVA blends, whilst the thermal treatment influences mainly the synthetic polymer. In the case of HA/PVA hydrogels, a modulus variation was found with the HA content related to the organization degree and perfection of the PVA network structure. It seems evident that, in the experimental conditions used, dextran/PAA mixtures behave as miscible blends showing a glass transition intermediate between those of the pure components. With both untreated and GTA-treated gelatin/PMAA blends, it was not possible to evaluate the miscibility of the systems; it could only be affirmed that these materials show good mechanical properties over a wide range of temperature. © 1997 SCI.     

Carbon nanotube‐hybridized supramolecular hydrogel based on PEO‐b‐PPO‐b‐PEO/α‐cyclodextrin as a potential biomaterial

In virtue of the potential biomedical application of carbon nanotube (CNT), the CNT was hybridized into a supramolecular hydrogel based on the selective inclusion of α‐cyclodextrin (α‐CD) onto poly(ethylene oxide) (PEO) segments of a triblock copolymer, i.e., PEO‐block‐poly(propylene oxide)‐block‐PEO. Different from the previous report, the content of α‐CD, in contrast to that of ethylene oxide unit, was decreased to decrease the network density in hydrogel and hence improve the diffusion of encapsulated substances. As a result, the modulus of the hydrogels climbed slightly after introducing CNT. Furthermore, as the essential properties for wound dressing, the antimicrobial activity, the skin‐adhesion, and water‐retention of such supramolecular hybrid hydrogels were also verified. On the other hand, the supramolecular hybrid hydrogels inherited the shear‐thinning property and are suitable as an injectable biomaterial. The cell viability assay confirmed the equivalent cytotoxicity of the supramolecular hybrid hydrogels to that of the native hydrogels without CNT. Consequently, such CNT‐hybridized supramolecular hydrogel shows a great potential in the biomedical application. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Preparation and Properties of Double-Crosslinked Hydroxyapatite Composite Hydrogels

Natural polymer hydrogels have good mechanical properties and biocompatibility. This study designed hydroxyapatite-enhanced photo-oxidized double-crosslinked hydrogels. Hyaluronic acid (HA) and gelatin (Gel) were modified with methacrylate anhydride. The catechin group was further introduced into the HA chain inspired by the adhesion chemistry of marine mussels. Hence, the double-crosslinked hydrogel (HG) was formed by the photo-crosslinking of double bonds and the oxidative-crosslinking of catechins. Moreover, hydroxyapatite was introduced into HG to form hydroxyapatite-enhanced hydrogels (HGH). The results indicate that, with an increase in crosslinking network density, the stiffness of hydrogels became higher; these hydrogels have more of a compact pore structure, their anti-degradation property is improved, and swelling property is reduced. The introduction of hydroxyapatite greatly improved the mechanical properties of hydrogels, but there is no change in the stability and crosslinking network structure of hydrogels. These inorganic phase-enhanced hydrogels were expected to be applied to tissue engineering scaffolds.     

Modulating properties of chemically crosslinked PEG hydrogels via physical entrapment of silk fibroin

A variety of polymers of synthetic origins (e.g., poly(ethylene glycol) or PEG) and macromolecules derived from natural resources (e.g., silk fibroin or SF) have been explored as the backbone materials for hydrogel crosslinking. Purely synthetic PEG‐based hydrogels are often chemically crosslinked to possess limited degradability, unless labile motifs are designed and integrated into the otherwise non‐degradable macromers. On the other hand, SF produced by Bombyx mori silkworm can be easily formulated into physical hydrogels. These physical gels, however, are less stable than the chemically crosslinked gels. Here, we present a simple strategy to prepare hybrid PEG‐SF hydrogels with chemically crosslinked PEG network and physically entrapped SF. Visible light irradiation initiated rapid thiol‐acrylate gelation to produce a network composed of non‐degradable poly(acrylate‐co‐NVP) chains, hydrolytically labile thioether ester bonds, and interpenetrating SF fibrils. We evaluated the effect of SF entrapment on the crosslinking efficiency and hydrolytic degradation of thiol‐acrylate PEG hydrogels. We further examined the effect of adding soluble SF or sonicated SF (S‐SF) on physical gelation of the hybrid materials. The impacts of SF or S‐SF inclusion on the properties of chemically crosslinked hybrid hydrogels were also studied, including gel points, gel fraction, equilibrium swelling ratio, and mesh size. We also quantified the fraction of SF retention in PEG hydrogels, as well as the influence of remaining SF on moduli and degradation of chemically crosslinked thiol‐acrylate PEG hydrogels. This simple hybrid hydrogel fabrication strategy should be highly useful in future drug delivery and tissue engineering applications. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43075.     

Enhancing mechanical strength of hydrogels via IPN structure

In this investigation, polyacrylamide (PAAm) as the flexible network is introduced to enhance the mechanical strength of hyaluronic acid–gelatin (HA–Gel) hydrogels by interpenetrating polymer network (IPN). The structure, mechanical property, and rheology property of the IPN hydrogels are investigated. It is found that the compressive strength of the HA–Gel/PAAm IPN hydrogels has increased five times higher than that of HA–Gel hydrogels. Rheological test demonstrates that elastic moduli (G′) and viscous moduli (G″) of HA–Gel/PAAm IPN hydrogels increase 100 times higher than those of HA–Gel hydrogels. Moreover, the HA–Gel hydrogels are fractured under the low compressive stress, whereas HA–Gel/PAAm IPN hydrogels are not broken under the high compressive stress. It is envisioned that the IPN hydrogels will be an effective approach to enhance the mechanical strength and broaden the range of hydrogels' applications. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 44503.     

Supramolecular hydrogels of polyaniline-poly(styrene sulfonate) prepared in concentrated solutions

Polyaniline-poly(styrene sulfonate) (PAn-PSS) hydrogels have been synthesized via supramolecular self-assembly between positively-charged PAn chains and negatively-charged PSS chains. Phase diagram is plotted to systematically investigate the gelation conditions for the PAn-PSS system. A hierarchical porous microstructure consisting of oriented 1D nanofibers is observed in the hydrogels, and the phase structure, molecular structure and crystal structure are also characterized. Based on the investigation of a unique transformation of the hydrogels to colloidal particles in alkaline solutions, the electrostatic interaction is proposed to be the origin force for the gelation of the materials. Additionally, in comparison with conventional PAn-PSS colloids, as-prepared PAn-PSS hydrogels are demonstrated to possess improved capacitance performance, such as higher energy density, higher power density and better electrochemical stability. The present study gives valuable hints for achieving controlled fabrication of supramolecular materials with designed structures and outstanding properties.     

Photopolymerized hydrogel composites from poly(ethylene glycol) and hydroxyapatite for controlled protein delivery in vitro

The incorporation of hard particles into soft hydrogels can improve the mechanical properties and provide necessary bioactivity to the hydrogels for desired biomedical applications. Hydrogel composites containing hydroxyapatite (HA) are promising materials for orthopedic applications. In this study, injectable poly(ethylene glycol) (PEG) hydrogel precursor solutions containing HA particles and model protein bovine serum albumin (BSA) were synthesized in situ by photopolymerization. In vitro BSA release properties from the hydrogel composites containing various amounts of HA were investigated and discussed. Fourier transform infrared spectroscopy and scanning electron microscopy were employed to investigate the interaction between HA and the hydrogel network and the morphology of the hydrogel composites. It is found that PEG hydrogel composites containing HA sustained the release of BSA for at least 5 days and the presence of HA slowed down BSA release. Photopolymerized hydrogel composites containing HA may find potential use as a drug delivery matrix for orthopedic tissue engineering. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

89Sr-doped hydroxyapatite nanoparticles as a potential therapeutic agent for bone tumors

Hydroxyapatite (HA) nanoparticles have been studied due to their high biocompatibility, similarity with bone tissue, and their capacity for bone regeneration since these nanoparticles can easily adhere on osteosarcoma and osteoblast cells, promoting osteoblast growth and osteosarcoma cell uptake. These materials may still accumulate spontaneously and selectively in regions of bone tumors through the enhanced permeability and retention effect. HA also allows the incorporation of strontium in your network. Strontium as a biochemical analog of calcium can maintain the osteogenesis characteristics of HA allowing the production of the radioactive isotopes strontium-89 and phosphorus-32 through neutron irradiation. These radioisotopes are beta emitters that enable the treatment of bone tumors, while the affected region is regenerated. In this work, we investigated the synthesis of strontium-doped HA nanorods through the hydrothermal coprecipitation method as a potential therapeutic agent for bone tumors. All materials were successfully obtained and demonstrated high cell viability, maintaining the osteogenic capacity, making these materials promising agents for the specific treatment of bone tumors. The results indicate that the Sr provides an increase in therapeutic potential due to its beta emission.     

Antiswelling and robust supramolecular polyurea hydrogels induced by the synergy of hydrogen bond and hydrophobic interaction for constructing durable underwater anti-oil-fouling coatings

Hydrogels are attractive materials for constructing underwater antifouling coatings on solid substrates. However, the application of hydrogel coatings usually faces the obstacles of complex preparation process and poor durability. Herein, we present a facile method to prepare durable hydrogel coatings on metal foils based on rationally designed supramolecular polyurea (PU) hydrogels. PU hydrogels are designed to be cross-linked with hydrogen bonds (H-bonds) and hydrophobic interactions in the hard segment domains by using dihydrazides with different alkyl spacer lengths ( (CH₂)_m ) as chain extender. The synergy of H-bond and hydrophobic interaction can stabilize H-bonds in water, as confirmed by Raman spectroscopy. As a result, PU hydrogels exhibit antiswelling capacity and robustness in both deionized water and seawater. Subsequently, PU hydrogel coatings on Cu/Al foils are prepared by convenient brush coating and subsequent swelling. The resulting hydrogel coatings exhibit excellent underwater anti-oil-adhesion and self-cleaning property, and are durable enough to withstand various static and dynamic damaging tests. The good durability of PU hydrogel coatings should be ascribed to the robust adhesion interface and excellent antiswelling capacity of PU hydrogels. The combination of facile preparation and good durability makes PU hydrogel coatings promising candidates for reliable underwater antifouling.     

Supramolecularly Mediated Robust,Anti‐Fatigue,and Strain‐Sensitive Macromolecular Microsphere Composite Hydrogels

Hydrogels are increasingly investigated and applied in flexible electronic devices, but their practical applications are often restricted by the poor mechanical and limited anti‐fatigue properties. This works reports an approach to robust, anti‐fatigue, and strain‐sensitive hydrogels by introducing macromolecular microsphere and mediating their supramolecular cross‐linking points. A model network composed of sulfonated polystyrene (SPS) microspheres and poly(acrylamide‐co‐acrylic acid)/Fe³⁺ (poly(Am‐co‐AA)/Fe³⁺) is investigated. The resulting composite hydrogels have high tensile strength (4.29 MPa) and anti‐fatigue property. More interestingly, such composite hydrogels have strain‐dependent conductivity and can be applied in robust flexible strain sensors for monitoring various human motions. Overall, the hydrogels developed herein not only help to understand the enhancing mechanism of composite hydrogels, but also offer alternative materials for fabricating robust electronic devices.     

Synthesis of poly(acrylic acid)–Fe3+/gelatin/poly(vinyl alcohol) triple‐network supramolecular hydrogels with high toughness,high strength and self‐healing properties

Hydrogels with good mechanical and self‐healing properties are of great importance for various applications. Poly(acrylic acid)–Fe³⁺/gelatin/poly(vinyl alcohol) (PAA‐Fe³⁺/Gelatin/PVA) triple‐network supramolecular hydrogels were synthesized by a simple one‐pot method of copolymerization, cooling and freezing/thawing. The PAA‐Fe³⁺/Gelatin/PVA triple‐network hydrogels exhibit superior toughness, strength and recovery capacity compared to single‐ and double‐network hydrogels. The mechanical properties of the synthesized hydrogels could be tailored by adjusting the compositions. The PAA‐Fe³⁺/Gelatin/PVA triple‐network hydrogel with 0.20 mmol Fe³⁺, 3% gelatin and 15% PVA could achieve good mechanical properties, the tensile strength and elongation at break being 239.6 kPa and 12.8 mm mm^?1, respectively, and the compression strength reaching 16.7 MPa under a deformation of about 91.5%. The synthesized PAA‐Fe³⁺/Gelatin/PVA triple‐network hydrogels have good self‐healing properties owing to metal coordination between Fe³⁺ and carboxylic groups, hydrogen bonding between the gelatin chains and hydrogen bonding between the PVA chains. Healed PAA‐Fe³⁺(0.20)/Gelatin3%/PVA15% triple‐network hydrogels sustain a tensile strength of up to 231.4 kPa, which is around 96.6% of the tensile strength of the original samples. Therefore, the synthesized triple‐network supramolecular hydrogels would provide a new strategy for gel research and expand the potential for their application. © 2019 Society of Chemical Industry     

Terminally cross-linking polyrotaxane hydrogels applicable for cellular microenvironments

Polyrotaxanes, composed of multiple cyclic molecules threaded onto a polymer chain axis capped with bulky molecules, exhibit unique structural features wherein cyclic molecules can move along a chain. We have previously constructed biointerfaces that utilize the molecular mobility of polyrotaxanes for controlling cellular responses. To implement the features in a three-dimensionally engineered cellular microenvironment, this study developed supramolecular hydrogels using polyrotaxane cross-linkers capped with 4-vinylbenzyl groups at the terminals of a polymer chain axis, where the 4-vinylbenzyl groups in the polyrotaxane allow polymerization with other polyrotaxanes to form polyrotaxane networks. Polyrotaxane hydrogels are successfully prepared without any additional monomers via redox polymerization. The dynamic viscoelasticity and swellability of the hydrogels can be varied depending on the concentration of the polyrotaxanes. When fibroblasts are cultured on hydrogels, sufficient adhesion for cultivation is observed. Therefore, polyrotaxane hydrogels demonstrate suitable potential as new supramolecular biomaterials with dynamic structural features.     

Advanced Functional Materials Constructed from Pillar[n]arenes

Pillar[n]arenes are new generation of supramolecular macrocyclic host, which exhibit excellent host−guest recognition properties. In the last decade, functional materials constructed from pillar[n]arenes have been attracted more and more attention and displayed outstanding characteristics, such as stimuli-responsiveness, self-healing and adaptability. In this mini-review, we provide a survey of the pillar[n]arene-based literatures covering light-harvesting systems, functional hydrogels, and solid materials. It is anticipated that more and more pillar[n]arenes-based advanced materials with multi-functional properties will appear in the near future.     

Engineering Hyaluronic Acid for the Development of New Treatment Strategies for Osteoarthritis

Osteoarthritis (OA) is a degenerative joint disease that is characterized by inflammation of the joints, degradation of cartilage, and the remodeling of other joint tissues. Due to the absence of disease-modifying drugs for OA, current clinical treatment options are often only effective at slowing down disease progression and focus mainly on pain management. The field of tissue engineering has therefore been focusing on developing strategies that could be used not only to alleviate symptoms of OA but also to regenerate the damaged tissue. Hyaluronic acid (HA), an integral component of both the synovial fluid and articular cartilage, has gained widespread usage in developing hydrogels that deliver cells and biomolecules to the OA joint thanks to its biocompatibility and ability to support cell growth and the chondrogenic differentiation of encapsulated stem cells, providing binding sites for growth factors. Tissue-engineering strategies have further attempted to improve the role of HA as an OA therapeutic by developing diverse modified HA delivery platforms for enhanced joint retention and controlled drug release. This review summarizes recent advances in developing HA-based hydrogels for OA treatment and provides additional insights into how HA-based therapeutics could be further improved to maximize their potential as a viable treatment option for OA.