Newly designed hydrogel with both sensitive thermoresponse and biodegradability

The synthesis and characterization of thermoresponsive hydrogels on the basis of N‐isopropylacrylamide (IPAAm) copolymers crosslinked with biodegradable poly(amino acids) are described. This hydrogel was prepared with two kinds of reactive IPAAm‐based copolymers containing poly(amino acids) as the side‐chain groups and activated ester groups. We introduced the graft chains by decarboxylation polymerization of amino acid N‐carboxyanhydrides initiated from lateral amino groups in the PIPAAm copolymer. The hydrogels easily crosslinked with degradable poly(amino acid) chains by only mixing the copolymer aqueous solutions. The gelling method in this study would provide some of the following innovative features: (1) no necessary removal of unreacted monomers and so forth, (2) simpler loading of drugs into the hydrogels (only mixing when gelling), and (3) easier insertion into the body. On the basis of the swelling ratio measurement of the hydrogel, large volume changes dependent on temperature changes were observed. Moreover, the enzymatic temperature‐dependent degradation was confirmed. The results suggested that these hydrogels could be used for an injectable or implantable matrix of temperature‐modulated drug release. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 779–787, 2003     

3‐D Interdigitated electrodes for uniform stimulation of electro‐responsive hydrogels for biomedical applications

Stimuli‐responsive hydrogels are continuing to increase in demand in biomedical applications. Occluding a blood vessel is one possible application which is ideal for a hydrogel because of their ability to expand in a fluid environment. However, typically stimuli‐responsive hydrogels focus on bending instead of radial uniform expansion, which is required for an occlusion application. This article focuses on using an interdigitated electrode device to stimulate an electro‐responsive hydrogel in order to demonstrate a uniform swelling/deswelling of the hydrogel. A Pluronic‐bismethacrylate (PF127‐BMA) hydrogel modified with hydrolyzed methacrylic acid, in order to make it electrically responsive, is used in this article. An interdigitated electrode device was manufactured containing Platinum electrodes. The results in this paper show that the electrically biased hydrogels deswelled 230% more than the non‐biased samples on average. The hydrogels deswelled uniformly and showed no visual deformations due to the electrical bias. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2013 , 51, 1523–1528     

Ru(II)(tpy)2‐functionalized hydrogels: Synthesis,reversible responsiveness,and coupling with the belousov‐zhabotinsky reaction

This work aims at developing an approach to Ru(II)(Tpy)₂‐functionalized hydrogels and exploring the coupling of the hydrogels with the Belousov‐Zhabotinsky (BZ) reaction. Based on free radical polymerization, two synthetic routes are developed. The first one is the direct gelation by copolymerization of acrylamide as hydrophilic component and Ru(II)(Tpy)₂ as the functional group. The second one is carried out through a combined approach. A terpyridine‐containing hydrogel is first prepared and then post‐functionalized by coordination between Ru(III)(Tpy)Cl₃ and terpyridine groups in the hydrogel network. Utilizing the synthetic hydrogels, the reversible redox responsiveness, the coupling with the BZ reaction, the occurrence and the self‐oscillating properties of the BZ reaction in the hydrogel networks are studied. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 2214–2222     

Accelerated iterative strategy for the divergent synthesis of dendritic macromolecules using a combination of living radical polymerization and an irreversible terminator multifunctional initiator

Our laboratory has reported the elaboration of an iterative strategy for the synthesis of dendritic macromolecules from conventional monomers. This synthetic method involves a combination of self‐regulated metal‐catalyzed living radical polymerization initiated from arenesulfonyl chlorides and an irreversible terminator multifunctional initiator (TERMINI). The previous TERMINI, (1,1‐dimethylethyl)[[1‐[3,5‐bis(S‐phenyl‐4‐N,N′ diethylthiocarbamate)phenyl]ethenyl]oxy]dimethylsilane, was prepared in nine reaction steps. The replacement of the previous TERMINI with one that requires only three steps for its synthesis, diethylthiocarbamic acid S‐{3‐[1‐(tert‐butyl‐dimethyl‐silanyloxy)‐vinyl]‐5‐diethylcarbamoylsulfanyl‐phenyl} ester, and the use of the more reactive Cu₂S/2,2′‐bipyridine rather than the Cu₂O/2,2′‐bipyridine self‐regulated catalyst have generated an accelerated method for the synthesis of dendritic macromolecules. This method provides rational design strategies for the synthesis of dendritic macromolecules with different compaction by the use of a single monomer. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 4894–4906, 2005     

Lactose‐containing hydrogels for enzyme stabilization

A lactose‐containing monomer, N‐(2‐lactosylethyl)acrylamide, was synthesized and polymerized with N‐hydroxyethyl acrylamide and 1 wt % of N, N'‐methylenebis(acrylamide) and potassium persulfate as the initiator to produce hydrogels. The weight percent of N‐(2‐lactosylethyl)acrylamide were increased from 0 to 100% in increments of 10%. Hydrogels were successfully produced with up to 90 wt % of N‐(2‐lactosylethyl)acrylamide. Gelation was confirmed by inverted vial tests and rheology measurements. The as‐prepared hydrogels were used for papain stabilization against heat burden and papain that was loaded into hydrogels showed 45% more activity after heating as compared to papain that was heated without hydrogel stabilization. This hydrogel stabilization technique has potential applications in preserving enzyme activity. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 2507–2514     

Injectable supramolecular hybrid hydrogels formed by MWNT‐grafted‐poly(ethylene glycol) and α‐cyclodextrin

Poly(ethylene glycol)‐grafted‐multiwalled carbon nanotube (MWNT‐g‐PEG) was synthesized by a coupling reaction and formed inclusion complexes (ICs) after selective threading of the PEG segment of the MWNT‐g‐PEG through the cavities of α‐cyclodextrins (α‐CDs) units. The polypseudorotaxane structures of the as‐obtained hydrogels were confirmed by ¹H NMR, X‐ray diffraction and DSC analyses. The complexation of the PEG segments with α‐CDs and the hydrophobic interaction between the MWNT resulted in the formation of supramolecular hybrid hydrogels with a strong network. Thermal analysis showed that the thermal stability of the hydrogel was substantially improved by up to 100 °C higher than that of native hydrogel. The resultant hybrid hydrogels were found to be thixotropic and reversible, and could be applied as a promising injectable drug delivery system. The mechanical strength of the hybrid hydrogels was greatly improved in comparison with that of the corresponding native hydrogels. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 3145–3151, 2010     

Double‐crosslinked reversible redox‐responsive hydrogels based on disulfide–thiol interchange

We present novel redox‐responsive hydrogels based on poly(N‐isopropylacrylamide) or poly(acrylamide), consisting of a reversible disulfide crosslinking agent N,N′‐bis(acryloyl)cystamine and a permanent crosslinking agent N,N′‐methylenebisacrylamide for microfluidic applications. The mechanism of swelling/deswelling behavior starts with the cleavage and reformation of disulfide bonds, leading to a change of crosslinking density and crosslinking points. Raman and ultraviolet‐visible spectroscopy confirm that conversion efficiency of thiol–disulfide interchange up to 99%. Rheological analysis reveals that the E modulus of hydrogel is dependent on the crosslinking density and can be repeatedly manipulated between high‐ and low‐stiffness states over at least 5 cycles without significant decrease. Kinetic studies showed that the mechanical strength of the gels changes as the redox reaction proceeds. This process is much faster than the autonomous diffusion in the hydrogel. Moreover, cooperative diffusion coefficient (D_coop) indicates that the swelling process of the hydrogel is affected by the reduction reaction. Finally, this reversibly switchable redox behavior of bulky hydrogel could be proven in microstructured hydrogel dots through short‐term photopatterning process. These hydrogel dots on glass substrates also showed the desired short response time on cyclic swelling and shrinking processes known from downsized hydrogel shapes. Such stimuli‐responsive hydrogels with redox‐sensitive crosslinkers open a new pathway in exchanging analytes for sensing and separating in microfluidics applications. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019 , 57, 2590–2601     

Strong and tough hydrogels crosslinked by multi-functional polymer colloids

Tough polymer hydrogels have great potential applications in soft actuators, artificial muscles, tissue engineering, and so forth. To improve the strength and toughness of hydrogels, numerous strategies have been developed to integrate efficient energy dissipation mechanisms into the hydrophilic networks. Among them, the use of macro-crosslinkers to replace conventional chemical ones has become promising to develop tough hydrogels. Polymer colloids—including nano-/microparticles, nano-/microgels, hydrophobic associates, and block copolymer assemblies—have been employed in literature as multi-functional macro-crosslinkers that link polymer chains through covalent bonds or noncovalent interactions. The dislocation, deformation, desociation, and rupture of polymer colloids upon loadings are the major mechanisms to dissipate energy. This article provides a comprehensive account of most recent progresses on tough hydrogels crosslinked by polymer colloids, and explores the toughening mechanisms. It aims to inspire novel designs of tough hydrogels with multi-functionalities. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2018 , 56, 1336–1350     

Injectable hydrogels

Hydrogels are promising for a variety of medical applications due to their high water content and mechanical similarity to natural tissues. When made injectable, hydrogels can reduce the invasiveness of application, which in turn reduces surgical and recovery costs. Key schemes used to make hydrogels injectable include in situ formation due to physical and/or chemical cross‐linking. Advances in polymer science have provided new injectable hydrogels for applications in drug delivery and tissue engineering. A number of these injectable hydrogel systems have reached the clinic and impact the health care of many patients. However, a significant remaining challenge is translating the ever‐growing family of injectable hydrogels developed in laboratories around the world to the clinic. © 2012 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2012     

Synthesis and swelling behavior of comb‐type grafted hydrogels by reversible addition–fragmentation chain transfer polymerization

The comb‐type grafted hydrogels poly(N‐isopropylacrylamide)‐g‐poly(N‐isopropylacrylamide) (PNIPAM‐g‐PNIPAM) and poly(acrylic acid)‐g‐poly(N‐isopropylacrylamide) (PAAc‐g‐PNIPAM) were prepared by reversible addition–fragmentation chain transfer polymerization. A macromolecular chain‐transfer agent was prepared first. Then, hydrogels were obtained by a reaction with a comonomer (N‐isopropylacrylamide or acrylic acid) in the presence of N,N‐methylenebisacrylamide as a crosslinker. The equilibrium swelling ratios and the swelling and deswelling kinetics of PNIPAM‐g‐PNIPAM were measured. The effects of the chain length and amount on the swelling behavior were investigated. The deswelling mechanism was illustrated. Meanwhile, the PAAc‐g‐PNIPAM hydrogel was used to confirm the versatility of this novel method. It was prepared in an alcoholic medium, whereas hydrogen‐bonding complexes formed in 1,4‐dioxane, which was chosen as the reaction medium for the PNIPAM‐g‐PNIPAM hydrogel. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 2615–2624, 2005     

Synthesis and characterization of thermoresponsive poly(ethylene glycol)‐based hydrogels and their magnetic nanocomposites

Temperature‐responsive hydrogels are one of the most widely studied types of stimuli‐responsive hydrogel systems. Their ability to transition between their swollen and collapsed states makes them attractive for controlled drug delivery, microfluidic devices, and biosensor applications. Recent work has shown that poly(ethylene glycol) (PEG) methacrylate polymers are temperature‐responsive and exhibit a wide range of lower critical solution temperatures based on the length of ethylene glycol units in the macromer chain. The addition of iron oxide nanoparticles into the hydrogel matrix can provide the ability to remotely heat the gels upon exposure to an alternating magnetic field (AMF). In this work, diethylene glycol (n = 2) methyl ether methacrylate and PEG (n = 4.5) methyl ether methacrylate copolymers were polymerized into hydrogels with 5 mol % PEG 600 (n = 13.6) dimethacrylate as the crosslinker along with 5 wt % iron oxide nanoparticles. Volumetric swelling studies were completed from 22 to 80 °C and confirmed the temperature‐responsive nature of the hydrogel systems. The ability of the gels to collapse in response to rapid temperature changes when exposed to an AMF was demonstrated showing their potential use in biomedical applications such as controlled drug delivery and hyperthermia therapy. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 3229–3235, 2010     

pH/temperature double responsive behaviors and mechanical strength of laponite‐crosslinked poly(DEA‐co‐DMAEMA) nanocomposite hydrogels

A nanocomposite (NC) hydrogel crosslinked by inorganic Laponite XLG was successfully synthesized via in situ free radical polymerization of monomers N,N‐diethylacrylamide and (2‐dimethylamino) ethyl methacrylate (DMAEMA). Polymerization was carried out at room temperature due to the accelerating effect of DMAEMA. The as‐prepared hydrogels displayed controlled transformation in optical transmittance and volume in response to small diversification of environmental factors, such as temperature and pH. The compressive strength of swollen D_6:1G₆ hydrogels was as high as 2219 kPa while compressive strain was 95%. Cyclic compression measurement exhibited good elastic properties of NC hydrogels. This work provides a facile method for fabricating stimuli‐responsive hydrogels with superior mechanical property. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2015 , 53, 876–884     

A novel sodium carboxymethylcellulose/poly(N‐isopropylacrylamide)/Clay semi‐IPN nanocomposite hydrogel with improved response rate and mechanical properties

A novel semi‐IPN nanocomposite hydrogel (CMC/PNIPA/Clay hydrogel) based on linear sodium carboxymethylcellulose (CMC) and poly(N‐isopropylacrylamide) (PNIPA) crosslinked by inorganic clay was prepared. The structure and morphology of these hydrogels were investigated and their swelling and deswelling kinetics were studied in detail. TEM images showed that the clay was substantially exfoliated to form nano‐dimension platelets dispersed homogeneously in the hydrogels and acted as a multifunctional crosslinker. The CMC/PNIPA/Clay hydrogels swell faster than the corresponding PNIPA/Clay hydrogels at pH 7.4, whereas they swell slower than the PNIPA/Clay hydrogels at pH 1.2. The CMC/PNIPA/Clay nanocomposite hydrogels showed much higher deswelling rates, which was ascribed to more passway formed in these hydrogels for water to diffuse in and out. The deswelling process of the hydrogels could be approximately described by the first‐order kinetic equation and the deswelling rate decreased with increasing clay content. The mechanical properties of the CMC/PNIPA/Clay nanocomposite hydrogels were analyzed based on the theory of rubber elasticity. It was found that with increasing clay content, the effective crosslink chain density, v_e, increased whereas the molecular weight of the chains between crosslinks M_c decreased. © 2008 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 46: 1546–1555, 2008     

Stretchable and transparent hydrogels as soft conductors for dielectric elastomer actuators

A soft ionic conductor can serve as an artificial nerve in an artificial muscle. A polyacrylamide hydrogel is synthesized containing a hygroscopic salt, lithium chloride. Two layers of the hydrogel are used as ionic conductors to sandwich a dielectric elastomer and fabricate a highly stretchable and transparent actuator. When the two layers of the hydrogels are subject to a voltage, the actuator reduces its thickness and expands. An areal strain of 134% is demonstrated. The voltage‐strain curves are calculated by using a model that accounts for the elastic constraint of the hydrogel and the inhomogeneous deformation of the actuator. For actuators fabricated with the hydrogel of various thicknesses and with the dielectric elastomer of various prestretches, excellent agreements are found between experimental data and theoretical predictions. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2014 , 52, 1055–1060     

Self‐assembled graphene oxide–gelatin nanocomposite hydrogels: Characterization,formation mechanisms,and pH‐sensitive drug release behavior

Novel physically crosslinked graphene oxide (GO)‐gelatin nanocomposite hydrogels were obtained by self‐assembly. The hydrogels with various ratios of GO to gelatin were prepared, and characterized by X‐ray diffraction, Fourier transform infrared spectroscopy, Raman spectroscopy, and scanning electron microscopy. The static and dynamic rheological properties of the hydrogels were investigated, along with the underlying hydrogel formation mechanisms. The storage modulus of the hydrogels (containing 98–98.5 wt % water) reached 114.5 kPa, owing to the relatively strong physical bonding (i.e., hydrogen bonding and electrostatic forces) between GO and gelatin. Drug release tests showed that the drug release from the hydrogel was pH‐dependent, with 96% of the model drug released in a neutral environment, compared to 28% released in an acidic medium. These hydrogels could have potential in pH‐sensitive drug delivery. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2015 , 53, 356–367     

“Click” chemistry for in situ formation of thermoresponsive P(NIPAAm‐co‐HEMA)‐based hydrogels

The strategy for in situ chemical gelation of poly(N‐isopropylacrylamide‐co‐hydroxylethyl methacrylate) [P(NIPAAm‐co‐HEMA)]‐based polymers was demonstrated. Two types of new P(NIPAAm‐co‐HEMA) derivatives with alkyne and azide pendant groups, respectively, were prepared. When the solutions of the two derivatives were mixed together, a crosslinking reaction, a type of Huisgen's 1,3‐dipolar azide‐alkyne cycloaddition, in the presence of Cu(I) catalyst occurs. The morphology, equilibrium swelling ratio, swelling kinetics, and temperature response kinetics of the in situ gelated hydrogels were studied. In comparison with the conventional PNIPAAm hydrogel, because of the spatial hindrance of polymeric chains, the resulted hydrogels had a macroporous structure as well as a fast shrinking rate. The strategy described here presents a potential alternative to the traditional synthesis techniques for the in situ formation of thermoresponsive hydrogels. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 5263–5277, 2008     

Three‐dimensional microfabrication of protein hydrogels via two‐photon‐excited thiol‐vinyl ester photopolymerization

Engineering three‐dimensional (3D) hydrogels with well‐defined architectures has become increasingly important for tissue engineering and basic research in biomaterials science. To fabricate 3D hydrogels with (sub)cellular‐scale features, two‐photon polymerization (2PP) shows great promise although the technique is limited by the selection of appropriate hydrogel precursors. In this study, we report the synthesis of gelatin hydrolysate vinyl esters (GH‐VE) and its copolymerization with reduced derivatives of bovine serum albumin (acting as macrothiols). Photorheology of the thiol‐ene copolymerization shows a much more rapid onset of polymerization and a higher end modulus in reference to neat GH‐VE. This allowed 2PP to provide well‐defined and stable hydrogel microstructures. Efficiency of the radical‐mediated thiol‐vinyl ester photopolymerization allows high 2PP writing speed (as high as 50 mm s^?1) with low laser power (as low as 20 mW). MTT assays indicate negligible cytotoxicities of the GH‐VE macromers and of the thiol‐ene hydrogel pellets. Osteosarcoma cells seeded onto GH‐VE/BSA hydrogels with different macromer relative ratios showed a preference for hydrogels with higher percentage of GH‐VE. This can be attributed both to a favorable modulus and preferable protein environment since gelatin favors cell adhesion and albumin incurs nonspecific binding. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 4799–4810     

Organic–inorganic hybrid hydrogels involving poly(N‐isopropylacrylamide) and polyhedral oligomeric silsesquioxane: Preparation and rapid thermoresponsive properties

3‐Acryloxypropylhepta(3,3,3‐trifluoropropyl) polyhedral oligomeric silsesquioxane (POSS) was synthesized and used as a modifier to improve the thermal response rates of poly(N‐isopropylacrylamide) (PNIPAM) hydrogel. The radical copolymerization among N‐isopropylacrylamide (NIPAM), the POSS macromer and N,N′‐methylenebisacrylamide was performed to prepare the POSS‐containing PNIPAM cross‐linked networks. Differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) showed that the POSS‐containing PNIPAM networks displayed the enhanced glass transition temperatures (T_g's) and improved thermal stability when compared with plain PNIPAM network. The POSS‐containing PNIPAM hydrogels exhibited temperature‐responsive behavior as the plain PNIPAM hydrogels. It is noted that with the moderate contents of POSS, the POSS‐containing PNIPAM hydrogels displayed much faster response rates in terms of swelling, deswelling, and re‐swelling experiments than plain PNIPAM hydrogel. The improved thermoresponsive properties of hydrogels have been interpreted on the basis of the formation of the specific microphase‐separated morphology in the hydrogels, that is, the POSS structural units in the hybrid hydrogels were self‐assembled into the highly hydrophobic nanodomains, which behave as the microporogens and promote the contact of PNIPAM chains and water. © 2009 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 47: 504–516, 2009     

DOSY NMR as a tool for predicting optimal conditions for hydrogel formation: The case of a hyperbranched polyglycidol cross‐linked with boronic acids

This article demonstrates the utility of DOSY NMR for the determination of the optimal conditions for the efficient covalent, reversible cross‐linking of macromolecules in water for hydrogel formation. The studied model system was hyperbranched polyglycidol (HbPGL) containing numerous diol groups in peripheral regions and two types of boronic acids, that is, B(OH)₄^? and benzene‐1,4‐boronic diacid, as cross‐linking agents. Diffusion coefficient changes of a polymer in solution, under the influence of various concentrations of cross‐linking agent and pH, which influences the equilibrium of the reaction between boronic acids and diols, were recorded. These data are consistent with the rheological properties, namely the G′_max(ω) of hydrogels prepared under analogous conditions, from more concentrated solutions of HbPGL. This approach appears to be promising as it facilitates avoiding the loss of a large amount of polymer that is necessary for the elaboration of appropriate conditions for network formation in aqueous media. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2016 , 54, 2171–2178     

Poly(2‐oxazoline) hydrogels crosslinked with aliphatic bis(2‐oxazoline)s: Properties,cytotoxicity, and cell cultivation

A series of hydrogels from 2‐ethyl‐2‐oxazoline and three bis(2‐oxazoline) crosslinkers—1,4‐butylene‐2,2′‐bis(2‐oxazoline), 1,6‐hexamethylene‐2,2′‐bis(2‐oxazoline), and 1,8‐octamethylene‐2,2′‐bis(2‐oxazoline)—are prepared. The hydrogels differ by the length of aliphatic chain of crosslinker and by the percentage of crosslinker (2–10%). The influence of the type and the percentage of the crosslinker on swelling properties, mechanical properties, and state of water is studied. The equilibrium swelling degree in water ranges from 2 to 20. With a proper selection of the crosslinker, Young's modulus can be varied from 10 kPa to almost 100 kPa. To evaluate the potential for medical applications, the cytotoxicity of extracts and the contact toxicity toward murine fibroblasts are measured. The hydrogels with the crosslinker containing a shorter aliphatic exhibit low toxicity toward fibroblast cells. Moreover, the viability and the proliferation of pancreatic β‐cells incubated inside hydrogels for 12 days are analyzed. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 1548–1559