Preparation and characterization of composite hydrogels based on crosslinked hyaluronic acid and sodium alginate

In this study, a novel composite hydrogel with improved cellular structure and mechanical properties was prepared by the crosslinking of hyaluronic acid (HA) and sodium alginate (SAL). The amide linkages (covalent bonds) in the hydrogel that we expected to form were confirmed by Fourier transform infrared spectroscopy. The hydrogels had a pore size larger than 100 μm and were observed by scanning electron microscopy. Texture profile analysis indicated that the hardness of the hydrogels was enhanced by an increase in the polymer's concentration, but it declined with an increase in the HA/SAL molar ratio. The swelling capacity was reduced with increases in the polymer's concentration and the 1‐ethyl‐3‐(3‐dimethyl aminopropyl)‐1‐carbodiimide hydrochloride (EDC)/HA molar ratio, and it was enhanced by an increase in the HA/SAL molar ratio. The resistance against hyaluronidase was negatively correlated with the proportion of HA in the hydrogels and positively correlated with the EDC/HA molar ratio. Given the improved physicochemical properties that we produced, these novel hydrogels may have the potential to be applied in tissue engineering scaffolding. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41898.     

Morphology of crosslinked hyaluronic acid porous hydrogels

Hydrogels, based on hyaluronic acid or hyaluronan (HA), are gaining attention as possible cell‐scaffolding materials for the regeneration of a variety of tissues. This article describes how HA, a naturally occurring polymer, has been crosslinked to reduce its degradation rate and freeze dried to produce porous materials suitable for tissue engineering. The resulting pore architecture has been assessed as a function of freezing temperature and freezing rate, type of crosslinkers, and methods used in the crosslinking process. On comparing the average densities of crosslinked and uncrosslinked scaffolds, it is apparent that the chemical modification increases sponge density and wall thickness of the pores while decreasing the pore size. The mechanical response of the modified materials has been investigated by equilibrium‐swelling measurements and compression tests. These materials have an average pore size ranging from 167 to 215 μm, which suggests that they would be a suitable temporary site for cell proliferation. The materials exhibit moderate mechanical integrity and are expected to be capable of withstanding physiological stresses in vivo. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Swelling and mechanical properties of crosslinked hydrogels containing N-vinylpyrrolidone

Copolymers of 2-hydroxyethyl methacrylate/N-vinyl-2-pyrrolidone (HEMA/NVP) and methyl methacrylate (MMA)/NVP were prepared in the presence of varying amounts of ethylene glycol dimethacrylate (EGDMA) and methylene diacrylamide (MDA) as crosslinkers by photopolymerisation. The resultant solid polymers were swollen to equilibrium in water at 293 K to produce hydrogels. These hydrogels were characterised by soluble fraction and equilibrium water content. The gels were also characterised by compression—strain measurements, which enabled the calculation of Young's modulus and effective crosslink density. The differences in these properties of HEMA/NVP and MMA/NVP polymer series and the effects of MDA versus EGDMA as a crosslinker were explained in terms of compositional drift of polymerisation, heterogeneous crosslinking and hydrophilicity/hydrophobicity of the components involved. In comparison with EGDMA, MDA was found to be more effective in reducing the soluble fraction of the polymers studied and to produce less rigid networks when swollen.     

Control of swelling properties of polyvinyl alcohol/hyaluronic acid hydrogels for the encapsulation of chondrocyte cells

Hydrogel scaffolds for tissue engineering are important biomaterials. The target in this study was to prepare polyvinyl alcohol/hyaluronic acid hydrogels for the encapsulation of chondrocyte cells by a simple cross‐linking reaction. Control of the swelling properties and morphology of the hydrogels for cultivation of chondrocytes was studied. The hydrogels were prepared from polyvinyl alcohol and hyaluronic acid derivatives bearing primary amine and aldehyde functionalities, respectively. The formation of the hydrogel upon mixing the aqueous solutions of the polymer derivatives took place at room temperature in a few seconds. The swelling properties of the hydrogels were found to depend on the polymer concentration and degree of substitution of the modified polymers. Scanning electron microscopy studies showed that the hydrogels had a suitable porous morphology for cell encapsulation. Furthermore, in vitro cell viability tests with the hydrogels showed no cytotoxicity for chondrocytes and that the cells grew well in the hydrogel scaffolds. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42272.     

Enzymatic and ionic crosslinked gelatin/K‐carrageenan IPN hydrogels as potential biomaterials

Hydrogels of a natural origin have attracted considerable attention in the field of tissue engineering due to their resemblance to ECM, defined degradability and compatibility with biological systems. In this study, we introduced carrageenan into a gelatin network, creating IPN hydrogels through biological methods of enzymatic and ionic crosslinking. Their gelation processes were monitored and confirmed by rheology analysis. The combination of biochemical and physical crosslinking processes enables the formation of biohydrogels with tunable mechanical properties, swelling ratios and degradation behaviors while maintaining the biocompatibilities of natural materials. The mechanical strength increased with an increase in carrageenan content while swelling ratio and degradability decreased correspondingly. In addition, the IPN hydrogels were shown to support adhesion and proliferation of L929 cell line. All the results highlighted the use of biological crosslinked gelatin‐carrageenan IPN hydrogels in the context of tissue engineering. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 10.1002/app.40975.     

Physico‐optical properties of a crosslinked hyaluronic acid scaffold for biomedical applications

Optical techniques are increasingly employed for monitoring cell–matrix interactions in suitably prepared 3D scaffolds. The ability of designing and realizing synthetic extracellular matrix with well‐controlled optical properties is a crucial need in this field. For this purpose, a crosslinked hyaluronic acid (HA) scaffold is prepared. Fourier transform infrared and ultraviolet–visible spectroscopies enable to monitor the scaffold preparation process and to evidence scaffold high transparency and low fluorescence in the visible range. 3D optical characteristics of the HA scaffold are tested by two‐photon microscopy (TPM) imaging of embedded fluorescent microbeads and alive keratinocytes labeled with vital PKH67 dye at different depths from the scaffold surface. Some useful indications about the potentiality of TPM measurements for the determination of attenuation coefficient of turbid media are also reported. Moreover, the use of the presented HA scaffold for preparing tissue phantoms for fluorescence imaging or diffuse imaging is proposed. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 45243.     

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.     

Vinyl carbonate photopolymers with improved mechanical properties for biomedical applications

Recently, vinyl carbonates have been demonstrated to be a versatile alternative to acrylates and methacrylates in biomedical applications as they exhibit photoreactivity and mechanical properties on a level or even above (meth)acrylates. Furthermore, much lower cytotoxicity as well as degradation via a surface erosion mechanism qualify them for medical use. However, it is highly desirable to improve the mechanical properties of vinyl carbonates to reach the performance of PLA. Thus, the main focus of this study lies on designing vinyl carbonates with suitable functional groups that are capable of augmenting mechanical properties of vinyl carbonates, e.g. cyclic structures or urethane groups, and implementing them into the vinyl carbonate structures. Resulting monomers were tested regarding their photoreactivity and cytotoxicity. Furthermore, cured specimens were investigated concerning their mechanical properties. In addition, the thiol-ene reaction was utilized to further improve photoreactivity. The new vinyl carbonates exhibit excellent biocompatibility and photoreactivity that can be significantly enhanced through the addition of thiols onto the level of highly photoreactive acrylates. Most importantly, results showed that the mechanical properties could be improved onto the level of PLA and above.     

Crosslinking structures of gelatin hydrogels crosslinked with genipin or a water‐soluble carbodiimide

It was suggested in our previous studies that carbodiimide‐ and genipin‐crosslinked gelatin hydrogels could be used as bioadhesives to overcome the cytotoxicity problem associated with formaldehyde‐crosslinked gelatin hydrogels. In this study, we investigated the crosslinking structures of carbodiimide‐ and genipin‐crosslinked gelatin hydrogels. We found that crosslinking gelatin hydrogels with carbodiimide or genipin could produce distinct crosslinking structures because of the differences in their crosslinking types. Carbodiimide could form intramolecular crosslinks within a gelatin molecule or short‐range intermolecular crosslinks between two adjacent gelatin molecules. On the basis of gel permeation chromatography, we found that the polymerization of genipin molecules could occur under the conditions used in crosslinking gelatin hydrogels via a possible aldol condensation. Therefore, besides intramolecular and short‐range intermolecular crosslinks, additional long‐range intermolecular crosslinks could be introduced into genipin‐crosslinked gelatin hydrogels. Crosslinking a gelatin hydrogel with carbodiimide was more rapid than crosslinking with genipin. Therefore, the gelation time for the carbodiimide‐crosslinked gelatin hydrogels was significantly shorter than that of the genipin‐crosslinked gelatin hydrogels. However, the cohesive (interconnected) structure of the carbodiimide‐crosslinked gelatin hydrogels was readily broken because, unlike the genipin‐crosslinked gelatin hydrogels, there were simply intramolecular and short‐range intermolecular crosslinks present in the carbodiimide‐crosslinked hydrogel. In the cytotoxicity study, the carbodiimide‐crosslinked gelatin hydrogels were dissolved into small fragments in the cultural medium within 10 min. In contrast, the genipin‐crosslinked gelatin hydrogels remained intact in the medium throughout the entire course of the study. Again, this may be attributed to the differences in their crosslinking structures. The genipin‐crosslinked gelatin hydrogels were less cytotoxic than the carbodiimide‐crosslinked gelatin hydrogels. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 91: 4017–4026, 2004     

Engineering hydrophobically associated hydrogels with rapid self-recovery and tunable mechanical properties using metal-ligand interactions

In this contribution, hydrophobic association and metal-ligand coordination have been employed in a dual physical crosslinking strategy to access hydrogels based on micellar copolymerization of acrylamide and a hydrophobic acrylic monomer (containing terpyridine (terpy) for metal-ligand interaction). The mechanical properties of these hydrogels are strongly influenced by the thermodynamic stability and kinetic lability of the metal-terpy crosslinks present in these materials. While the hydrogel tensile strength and stability on water exposure are enhanced by choosing stronger Fe²⁺-terpy crosslinks, the weaker and more kinetically labile Zn²⁺-terpy coordination bonds enable significantly higher energy dissipation under tensile loading and self-healing in the resultant hydrogels.     

Laboratory scale study on rheological behavior,morphological and structural properties of crosslinked polyacrylamide composite hydrogels embedded with date seed powder

Incorporation of biofillers in polymeric hydrogels has continued to receive great attention in recent times because of their excellent properties. In this study, polyacrylamide (PAM) and polyethyleneimine (PEI) were used to develop novel composite hydrogels filled with date seed powder (DSP) via chemical crosslinking technique. Pristine PAM/PEI hydrogel and PAM/PEI‐DSP hydrogels at various DSP loadings were fabricated and subjected to gelation at 40°C for 24 h. The impact of various DSP loadings on the hydrogel samples developed was investigated using hybrid rheometer, SEM, XRD, and FTIR instruments, respectively. Rheological measurements confirmed the viscoelastic responses of the neat PAM/PEI hydrogel and the PAM/PEI‐DSP hydrogels reinforced with various DSP contents (0.8, 2.4, and 4 wt %). The dynamic strain, dynamic frequency and time sweep tests demonstrated that PAM/PEI‐DSP hydrogels were slightly more elastic than the virgin PAM/PEI hydrogel. The SEM characterization revealed the surface micrographs of the neat PAM/PEI hydrogel and the PAM/PEI‐DSP hydrogels at different DSP loadings to be smooth, homogeneous, and dense. Besides, the SEM micrographs supported the incorporation of DSP in the PAM/PEI‐DSP hydrogel samples. XRD analysis showed that the structures of neat PAM/PEI hydrogel and PAM/PEI‐DSP hydrogels filled with various DSP contents were predominantly amorphous while FTIR results confirmed the functional groups and evidence of crosslinking in the neat PAM/PEI hydrogel and the PAM/PEI‐DSP hydrogels embedded with different DSP contents. It is believed that these new hydrogels have huge development potentials and promising future in wastewater treatment and removal of heavy metal ions in aqueous solutions. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42110.     

Regimes of microstructural evolution as observed from rheology and surface morphology of crosslinked poly(vinyl alcohol) and hyaluronic acid blends during gelation

Hyaluronic acid (HA)‐based materials are being investigated because of their role in biological fluids and tissues. Poly(vinyl alcohol) (PVA) when blended with HA at different compositions leads to superior mechanical properties compared to pure HA. The PVAHA blend hydrogels are potential candidates for pharmaceutical, biomedical, and cosmetic applications. It is essential to understand the structure, gelation time, and morphological properties of these hydrogels. In this work, a blend system of PVA crosslinked with glutaraldehyde in the presence of HA is studied. Semidilute solutions of PVA and HA are blended, followed by gelation due to crosslinking. The crosslinked gels as well as the gel cast membranes were examined. The effect of HA on the gelation process is investigated using rheological characterization. It is shown that kinetics of gelation is influenced by HA content, though storage modulus of the gels is influenced marginally. The structural features of PVAHA gels were also probed with scanning electron microscopy and dynamic light scattering. It is argued that there is a complex interplay between intra‐ and intermolecular crosslinking of PVA and PVA–HA interactions during the gel formation. Based on the insights obtained from various probing techniques for PVAHA gels with different HA content, three broad structural features were identified. It is shown that the hydrogel is semi‐interpenetrating network at lower HA content (<10% HA), cocontinuous morphology at moderate HA content and with domains at high HA content (>20% HA). © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 41081.     

Synthesis and properties of novel hydrogels from oxidized pectin crosslinked gelatin for biomedical applications

Gelatin (G) edible films with a new kind of dialdehyde polysaccharide, oxidized pectin (OP) as crosslinking agent are successfully prepared using casting techniques. FTIR and X-ray diffraction studies demonstrate that crosslinking is achieved through the reaction of aldehyde groups of oxidized pectin with the free amino groups in gelatin with a small affectation of the triple helix of gelatin. The qualitative and quantitative data about structures of films were determined by atomic force microscopy. Thermogravimetric analysis reveals that G/OP film has improved thermal stability in comparison with pure gelatin. Examination of the hemolytic potential showed that the obtained hydrogels are non-hemolytic in nature. These hydrogels are also nontoxic and blood-compatible. This kind of hydrogel is expected to be useful in the biomedical field, e.g., as wound dressing.     

Environmentally friendly synthesis and photopolymerization of acrylated methyl ricinoleate for biomedical applications

In this study, we aimed to develop an efficient synthesis and photopolymerization of acrylated methyl ricinoleate (AMR) for biomedical applications. During the first step of the synthesis, methyl ricinoleate (MR) and boric acid were esterified via azeotropic distillation in toluene. Afterward, MR–boric acid ester was acrylated with acrylic acid at 165 °C via a boric acid ester acidolysis reaction. The bulk photopolymerization of AMR was performed in the presence of the photoinitiator 2,2-dimethoxy-2-phenyl acetophenone (DMPA) under 365 nm UV irradiation. Even with the use of 0.4% DMPA, a 35% monomer conversion was achieved within 30 min. Moreover, AMR, the plant-oil-based monomer, was also copolymerized with N-isopropyl acrylamide to obtain thermoresponsive hydrogels on the glass surface for biomedical applications. The synthesized materials were characterized by Fourier transform infrared (FTIR) spectroscopy, ¹H-NMR spectroscopy, and thermal characterization via thermogravimetric analysis (TGA) and differential scanning calorimetry techniques. The surfaces were characterized by FTIR and Energy Dispersive X-ray (EDS) spectroscopy. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47969.     

Synthesis and swelling properties of new crosslinked polyorthocarbonates

Crosslinked polyorthocarbonates were synthesized by the condensation of tetraethyl orthocarbonate and hydroxyl functional monomers. The main goal of this study was to produce a solvent‐absorbent polymer with a high absorption capacity and to use these polymers for the removal of organic solvents from the environment and the recovery of these solvents. The synthesized polymers were characterized by Fourier transform infrared spectroscopy, solid‐state ¹³C‐NMR spectroscopy, thermogravimetric analysis, and differential scanning calorimetry. All of the polymers (except Poly 1 and Poly 2 ) had a high and fast uptake ability for organic solvents, such as tetrahydrofuran, dichloromethane, benzene, and acetone. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Ultraviolet‐crosslinked hydrogel sustained‐release hydrophobic antibiotics with long‐term antibacterial activity and limited cytotoxicity

To prolong erythromycin (EM) release and prevent the side effects of EM, a Pluronic F‐127 diacrylate macromer (PF127) was synthesized and then self‐assembled into micelles with their hydrophobic cores loaded with EM. The EM‐loaded micelles were mixed with a photoinitiator to form the EM/PF127 hydrogels rapidly under a low‐intensity UV light. Afterward, the hydrogel properties, antibacterial performance, and cytotoxicity of this novel hybrid hydrogel were investigated. The results show that the EM/PF127 hydrogel had a rapid gelation time. The sustained release of EM reduced its side effects. With controlled antibacterial activity, the use of EM would be safer and more efficient. What is more, the EM/PF127 hydrogel showed a slight cytotoxicity, and this suggests great potential application as antibacterial hydrogels in the prevention of postoperative infection. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40438.     

Thiol–norbornene photoclick hydrogels for tissue engineering applications

Thiol–norbornene (thiol–ene) photoclick hydrogels have emerged as a diverse material system for tissue engineering applications. These hydrogels are crosslinked through light‐mediated orthogonal reactions between multifunctional norbornene‐modified macromers [e.g., poly(ethylene glycol) (PEG), hyaluronic acid, gelatin] and sulfhydryl‐containing linkers (e.g., dithiothreitol, PEG–dithiol, biscysteine peptides) with a low concentration of photoinitiator. The gelation of thiol–norbornene hydrogels can be initiated by long‐wave UV light or visible light without an additional coinitiator or comonomer. The crosslinking and degradation behaviors of thiol–norbornene hydrogels are controlled through material selections, whereas the biophysical and biochemical properties of the gels are easily and independently tuned because of the orthogonal reactivity between norbornene and the thiol moieties. Uniquely, the crosslinking of step‐growth thiol–norbornene hydrogels is not oxygen‐inhibited; therefore, gelation is much faster and highly cytocompatible compared with chain‐growth polymerized hydrogels with similar gelation conditions. These hydrogels have been prepared as tunable substrates for two‐dimensional cell cultures as microgels and bulk gels for affinity‐based or protease‐sensitive drug delivery, and as scaffolds for three‐dimensional cell encapsulation. Reports from different laboratories have demonstrated the broad utility of thiol–norbornene hydrogels in tissue engineering and regenerative medicine applications, including valvular and vascular tissue engineering, liver and pancreas‐related tissue engineering, neural regeneration, musculoskeletal (bone and cartilage) tissue regeneration, stem cell culture and differentiation, and cancer cell biology. This article provides an up‐to‐date overview on thiol–norbornene hydrogel crosslinking and degradation mechanisms, tunable material properties, and the use of thiol–norbornene hydrogels in drug‐delivery and tissue engineering applications. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41563.     

Design and study of the potential of crosslinked cationic polymers as drug delivery systems for dermal application

Crosslinked carriers based on cationic monomer [2‐(acryloyloxy)ethyl]trimethylammonium chloride or 2‐(dimethylamino)ethyl methacrylate were developed and investigated as new platform for ibuprofen transdermal delivery. Series of networks of varied composition and structure were synthesized and characterized by FTIR spectroscopy and following swelling kinetics in different solvents. Dermal safety tests to examine the skin irritation and sensitization potential of the network films were performed in vivo. Chosen network compositions were loaded with ibuprofen by swelling in its ethanol solution. The structures of the drug carriers were investigated by scanning electron microscopy. Ibuprofen release from the developed drug delivery systems was followed in phosphate buffer solution at 37 °C. The investigation proved the feasibility of the developed cationic copolymer networks as effective platforms with modified ibuprofen release for potential dermal application. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46420.     

Characterization and gas‐permeation properties of crosslinked diacetylene‐containing polymer membranes from ferulic acid

Thermally and UV crosslinked poly[propargyl(3‐methoxy‐4‐propargyloxy) cinnamate] (PPOF) were investigated in terms of their physical, thermal, optical, and gas‐permeation properties. The crosslinked membranes had high gel contents because of the formation of a diacetylene network. The wide‐angle X‐ray diffraction patterns showed that all of the membranes were amorphous in structure, regardless of the type of crosslinking reaction. The membrane density increased after the crosslinking reaction; this suggested that the free volume of the crosslinked membrane was lower than that of the untreated membranes. Drastic color changes in the membranes were also observed because of the highly conjugated crosslinked network of diacetylene. In addition, the conjugation caused by diacetylene crosslinking led to visible absorption within the range 400–600 nm. The gas permeation of the crosslinked membrane was reduced compared with that of the untreated membranes. In particular, the gas permeability of the thermally crosslinked membrane was lower than that of UV‐irradiated membrane. On the basis of this result, the degree of crosslinking by thermal treatment was higher than that of UV irradiation. Hence, the crosslinked PPOF membranes showed improved gas‐barrier properties due to the high conjugation of the crosslinked diacetylene network induced by thermal treatment and UV irradiation. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013