A Synthetic,Transiently Thermoresponsive Homopolymer with UCST Behaviour within a Physiologically Relevant Window

Interactive materials that can respond to a trigger by changing their morphology, but that can also gradually degrade into a fully soluble state, are attractive building blocks for the next generation of biomaterials. Herein, we design such transiently responsive polymers that exhibit UCST behaviour while gradually losing this property in response to a hydrolysis reaction in the polymer side chains. The polymers operate within a physiologically relevant window in terms of temperature, pH, and ionic strength. Whereas such behaviour has been reported earlier for LCST systems, it is at present unexplored for UCST polymers. Furthermore, we demonstrate that, in contrast to LCST polymers, in aqueous medium the UCST polymer forms a coacervate phase below the UCST, which can entrap a hydrophilic model protein, as well as a hydrophobic dye. Because of their non‐toxicity, we also provide in vivo proof of concept of the use of this coacervate as a protein depot, in view of sustained‐release applications.     

Multi‐Stimuli‐Responsive Polymer Materials: Particles,Films, and Bulk Gels

Stimuli‐responsive polymers have received tremendous attention from scientists and engineers for several decades due to the wide applications of these smart materials in biotechnology and nanotechnology. Driven by the complex functions of living systems, multi‐stimuli‐responsive polymer materials have been designed and developed in recent years. Compared with conventional single‐ or dual‐stimuli‐based polymer materials, multi‐stimuli‐responsive polymer materials would be more intriguing since more functions and finer modulations can be achieved through more parameters. This critical review highlights the recent advances in this area and focuses on three types of multi‐stimuli‐responsive polymer materials, namely, multi‐stimuli‐responsive particles (micelles, micro/nanogels, vesicles, and hybrid particles), multi‐stimuli‐responsive films (polymer brushes, layer‐by‐layer polymer films, and porous membranes), and multi‐stimuli‐responsive bulk gels (hydrogels, organogels, and metallogels) from recent publications. Various stimuli, such as light, temperature, pH, reduction/oxidation, enzymes, ions, glucose, ultrasound, magnetic fields, mechanical stress, solvent, voltage, and electrochemistry, have been combined to switch the functions of polymers. The polymer design, preparation, and function of multi‐stimuli‐responsive particles, films, and bulk gels are comprehensively discussed here.     

Multi‐Stimuli‐Responsive Polymeric Materials

Stimuli‐responsive materials are of immense importance because of their ability to undergo alteration of their properties in response to their environment. The properties of such materials can be tuned by subtle adjustments in temperature, pH, light, and so forth. Among such smart materials, multi‐stimuli‐responsive polymeric materials are of pronounced significance as they offer a wide range of applications and their properties can be tuned through several mechanisms. Here, we aim to highlight some recent studies showcasing the multi‐stimuli‐responsive character of these polymers, which are still relatively little known compared to their single‐stimuli‐responsive counterpart.     

Synthesis of backbone thermo and pH dual‐responsive hyperbranched poly(amine‐ether)s through proton‐transfer polymerization

Stimuli‐responsive hyperbranched polymers have attracted great attention in recent years because of their wide applications in biomedicine. Through proton‐transfer polymerization of triethanolamine and 1,2,7,8‐diepoxyoctane with the help of potassium hydride, a series of novel backbone thermo and pH dual‐responsive hyperbranched poly(amine‐ether)s were prepared successfully in one‐pot. The degrees of branching of the resulting polymers were at 0.40–0.49. Turbidity measurements revealed that hyperbranched poly(amine‐ether)s exhibited thermo and pH dual‐responsive properties in water. Importantly, these responsivities could be readily adjusted by changing the polymer composition as well as the polymer concentration in aqueous solution. Moreover, in vitro evaluation demonstrated that hyperbranched poly(amine‐ether)s showed low cytotoxicity and efficient cell internalization against NIH 3T3 cell lines. These results suggest that these backbone thermo and pH dual‐responsive hyperbranched poly(amine‐ether)s are promising materials for biomedicine. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Water‐soluble triply‐responsive homopolymers of N,N‐dimethylaminoethyl methacrylate with a terminal azobenzene moiety

Novel water‐soluble triply‐responsive homopolymers of N,N‐dimethylaminoethyl methacrylate (DMAEMA) containing an azobenzene moiety as the terminal group were synthesized by atom transfer radical polymerization (ATRP) technique. The ATRP process of DMAEMA was initiated by an azobenzene derivative substituted with a 2‐bromoisobutyryl group (Azo‐Br) in the presence of CuCl/Me₆TREN in 1,4‐dioxane as a catalyst system. The molecular weights and their polydispersities of the resulting homopolymers (Azo‐PDMAEMA) were characterized by gel permeation chromatography (GPC). The homopolymers are soluble in aqueous solution and exhibit a lower critical solution temperature (LCST) that alternated reversibly in response to Ph and photoisomerization of the terminal azobenzene moiety. It was found that the LCST increased as pH decreased in the range of testing. Under UV light irradiation, the trans‐to‐cis photoisomerization of the azobenzene moiety resulted in a higher LCST, whereas it recovered under visible light irradiation. This kind of polymers should be particularly interesting for a variety of potential applications in some promising areas, such as drug controlled‐releasing carriers and intelligent materials because of the multistimuli responsive property. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 2564–2570, 2010     

Responsive Linear‐Dendritic Block Copolymers

The combination of dendritic and linear polymeric structures in the same macromolecule opens up new possibilities for the design of block copolymers and for applications of functional polymers that have self‐assembly properties. There are three main strategies for the synthesis of linear‐dendritic block copolymers (LDBCs) and, in particular, the emergence of click chemistry has made the coupling of preformed blocks one of the most efficient ways of obtaining libraries of LDBCs. In these materials, the periphery of the dendron can be precisely functionalised to obtain functional LDBCs with self‐assembly properties of interest in different technological areas. The incorporation of stimuli‐responsive moieties gives rise to smart materials that are generally processed as self‐assemblies of amphiphilic LDBCs with a morphology that can be controlled by an external stimulus. Particular emphasis is placed on light‐responsive LDBCs. Furthermore, a brief review of the biomedical or materials science applications of LDBCs is presented.

     

Triple stimuli‐responsive amphiphilic glycopolymer

Triple stimuli (temperature/pH/photo)‐responsive amphiphilic glycopolymer, poly(2‐(dimethylamino)ethyl methacrylate‐co‐6‐O‐methacryloyl‐1,2,3,4‐di‐O‐isopropylidene‐D‐galactopyranose)‐b‐poly(4‐(4‐methoxyphenylazo)phenoxy methacrylate) [P(DMAEMA‐co‐MAIpGP)‐b‐PMAZO] was synthesized by atom transfer radical polymerization, followed by the hydrolysis of MAIpGP groups, resulting in the target product poly(2‐(dimethylamino)ethyl methacrylate‐co‐6‐O‐methacryloyl‐D‐galactopyranose)‐b‐poly(4‐(4‐methoxyphenylazo)phenoxy methacrylate) [P(DMAEMA‐co‐MAGP)‐b‐PMAZO]. The composition, moleculer weight, and moleculer weight distribution of the resultant polymers were characterized by ¹H NMR and gel permeation chromatography. The micelles formed in aqueous solutions were simulated by various chemical and physical stimuli and characterized by dynamic light scattering, transmission electron microscopy, and UV‐vis spectroscopy. It was found that the glycopolymer is responsive to three different types of stimulus (light, temperature, and pH). The poly(2‐(dimethylamino) ethyl methacrylate) segments give thermo‐ and pH‐responsiveness. The presence of the azobenzene moiety endows the block copolymer to exhibit light‐responsiveness due to its reversible trans‐cis isomerization conversion. The triple stimuli‐responsive glycopolymer micelles can simulate biomacromolecues in vivo/in vitro environment and can be expected to open up new applications in various fields. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 2131–2138     

A Straightforward Method for Preparing Well‐Defined Responsive Diselenide‐Containing Polymers Based on ATRP

Diselenide‐containing polymers are facilely synthesized from polymers prepared by atom transfer radical polymerization (ATRP). Benefiting from the ATRP technology, this protocol provides a flexible route for controlling the polymer structure, which allows for a great variety of architectures of selenium‐containing polymer materials for applications in various fields. The oxidative and reductive responsive behavior of the obtained diselenide‐containing polymers is also investigated.

     

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     

A Conventional Surfactant Becomes CO2‐Responsive in the Presence of Switchable Water Additives

We have developed a new benign means of reversibly breaking emulsions and latexes by using “switchable water”, an aqueous solution of switchable ionic strength. The conventional surfactant sodium dodecyl sulfate (SDS) is not normally stimuli‐responsive when CO₂ is used as the stimulus but becomes CO₂‐responsive or “switchable” in the presence of a switchable water additive. In particular, changes in the air/water surface tension and oil/water interfacial tension can be triggered by addition and removal of CO₂. A switchable water additive, N,N‐dimethylethanolamine (DMEA), was found to be an effective and efficient additive for the reversible reduction of interfacial tension and can lower the tension of the dodecane/water interface in the presence of SDS surfactant to ultra‐low values at very low additive concentrations. Switchable water was successfully used to reversibly break an emulsion containing SDS as surfactant, and dodecane as organic liquid. Also, the addition of CO₂ and switchable water can result in aggregation of polystyrene (PS) latexes; the later removal of CO₂ neutralizes the DMEA and decreases the ionic strength allowing for the aggregated PS latex to be redispersed and recovered in its original state.     

Polymerization of oligo(ethylene glycol) (meth)acrylates: Toward new generations of smart biocompatible materials

Monomers composed of a (meth)acrylate moiety connected to a short poly(ethylene)glycol (PEG) chain are versatile building‐blocks for the preparation of “smart” biorelevant materials. Many of these monomers are commercial and can be easily polymerized by either anionic, free‐radical, or controlled radical polymerization. The latter approach allows synthesis of well‐defined PEG‐based macromolecular architectures such as amphiphilic block copolymers, dense polymer brushes, or biohybrids. Furthermore, the resulting polymers exhibit fascinating solution properties in aqueous medium. Depending on the molecular structure of their monomer units, non linear PEG analogues can be either insoluble in water, readily soluble up to 100 °C, or thermoresponsive. Thus, these polymers can be used for building a wide variety of modern materials such as biosensors, artificial tissues, smart gels for chromatography, and drug carriers. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 3459–3470, 2008     

Stimuli‐Responsive Water‐Soluble Fullerene (C60) Polymeric Systems

This review documents the advances in stimuli‐responsive water‐soluble fullerene (C₆₀) polymeric systems. Stimuli‐responsive polymers, when grafted onto C₆₀ impart “smart” and “responsive” characteristics, and these novel materials adopt various morphologies when subjected to external stimuli, such as pH, temperature, and salt. Various synthetic approaches for producing C₆₀‐polymers are outlined and discussed. The responsive behavior, water solubility, and self‐assembly characteristics of these C₆₀‐polymers make them attractive for applications such as drug delivery, temperature sensors, and personal care.     

ROMP synthesis of novel thermo‐, pH‐, and salt‐responsive (co)polymers containing the morpholino functional group

We report the ring‐opening metathesis polymerization (ROMP) synthesis of novel (co)polymers containing the multiresponsive morpholino functional group [(3aR,7aS)?2‐(2‐morpholinoethyl)?3a,4,7,7a‐tetrahydro‐1H?4,7‐epoxyisoindole‐1,3(2H)‐dione ( M1 )]. All (co)polymers were prepared with the Grubbs' first generation initiator, RuCl₂(PCy₃)₂CHPh, in CH₂Cl₂ or CH₂Cl₂/2,2,2‐trifluoroethanol solvent mixtures. M1 homopolymers exhibit a pH dependent aqueous solubility being fully soluble below pH 5.0 and above pH 6.0. At these intermediate values, the polymers exhibit molecular weight (MW) independent inverse temperature dependent solubility with measured cloud points (T_CP) of 86 °C at pH 5.0 and 79 °C at pH 6.0. In the case of the lowest MW homopolymer (absolute MW of 9950 g/mol), there was a clear dependence of the T_CP on the homopolymer solution concentration and varied over the range 78–88 °C. The T_CP could be further tuned via the preparation of novel AB statistical copolymers. Incorporation of a permanently cationic comonomer as a more hydrophilic species resulted in an increase of the T_CP at low incorporations (up to 10 mol %) and the complete disappearance of any temperature dependent solubility at 20 mol %. In a complementary approach, the T_CP could also be lowered by the preparation of statistical copolymers of M1 with a more hydrophobic comonomer. Finally, we note that M1 homopolymers are also responsive to Na₂SO₄ and could be readily salted‐out of an aqueous solution salt at a [Na₂SO₄] of 2.0 M giving a third trigger for controlling aqueous solubility. These copolymers represent examples of new multiresponsive materials and demonstrate the effectiveness of ROMP as a synthetic tool for the preparation of new and interesting materials. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 50–58     

Synthesis and Characterization of PEG‐Based Drug‐Responsive Biohybrid Hydrogels

Interactive materials being responsive to a biocompatible stimulus represent a promising approach for future therapeutic applications. In this study, we present a novel biohybrid material synthesized from biocompatible components being stimulus‐responsive to the pharmaceutically approved small‐molecule novobiocin. The hydrogel design is based on the gyrase B (GyrB) protein, which is covalently grafted to multi‐arm polyethylene glycol (PEG) using a Michael‐type addition reaction. Upon addition of the GyrB‐dimerizing substance coumermycin, stable hydrogels form which can be dissolved in a dose‐adjustable manner by the antibiotic novobiocin. The switchable properties of this PEG‐based hydrogel are favorable for future applications in tissue engineering and as externally controlled drug depot.     

Heating/Solvent Responsive Shape‐Memory Polymers for Implant Biomedical Devices in Minimally Invasive Surgery: Current Status and Challenge

This review is about the fundamentals and practical issues in applying both heating and solvent responsive shape memory polymers (SMPs) for implant biomedical devices via minimally invasive surgery. After revealing the general requirements in the design of biomedical devices based on SMPs and the fundamentals for the shape‐memory effect in SMPs, the underlying mechanisms, characterization methods, and several representative biomedical applications, including vascular stents, tissue scaffolds, occlusion devices, drug delivery systems, and the current R&D status of them, are discussed. The new opportunities arising from emerging technologies, such as 3D printing, and new materials, such as vitrimer, are also highlighted. Finally, the major challenge that limits the practical clinical applications of SMPs at present is addressed.     

Effects of polydepsipeptide side‐chain groups on the temperature sensitivity of triblock copolymers composed of polydepsipeptides and poly(ethylene glycol)

To develop new types of biodegradable polymers possessing predictable responses to changes in temperature, ABA‐type and BAB‐type triblock copolymers composed of various polydepsipeptides (PDP) and poly(ethylene glycol) (PEG) (PDP‐PEG‐PDP and PEG‐PDP‐PEG) were synthesized. The specific focus of this study was on the effect of the different side‐chain groups of various amino acids on the temperature‐responsive behavior of the triblock copolymers. An ABA‐type triblock copolymer containing the less hydrophobic glycine (PGG‐PEG‐PGG) did not exhibit any temperature‐responsive behavior; however, ABA‐type triblock copolymers containing the hydrophobic α‐amino acids, L ‐leucine and L ‐phenylalanine (PGL‐PEG‐PGL or PGF‐PEG‐PGF), did exhibit temperature‐responsive behavior. The cloud point of PGF‐PEG‐PGF was 10 °C lower than that of PGL‐PEG‐PGL. It can be possible to control temperature‐sensitivity by changing not only PDP segment length but also kind of α‐amino acid in PDP segment. Moreover, BAB‐type triblock copolymer containing L ‐leucine (PEG‐PGL‐PEG) showed temperature‐responsive sol‐gel transition. Because polydepsipeptides are biodegradable polymers, the information obtained in this study is useful to design biodegradable injectable polymers having controllable temperature‐sensitivity for biomedical use.© 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 3892–3903, 2009     

Influence of the polymer structure over self‐assembly and thermo‐responsive properties: The case of PEG‐b‐PCL grafted copolymers via a combination of RAFT and ROP

During the last years, the field of drug delivery has experienced a growing interest toward the so‐called thermo‐responsive polymers: synthetic materials that, due to the specific hydrophilic–lipophilic balance of their repeating units, exhibit a lower critical solution temperature (LCST) in water associated to a characteristic coil–globule transition. In this work, thermo‐responsive amphiphilic block copolymers are synthesized via reversible addition‐fragmentation transfer (RAFT) polymerization starting from thermo‐responsive monomers and a hydrophobic biodegradable macromonomer, oligo(caprolactone)methacrylate (CL₃MA), produced via ring opening polymerization (ROP). The obtained copolymers exhibit an interesting self‐assembly behavior leading to nanoparticles (NPs) as long as temperature is kept below the LCST. Otherwise, once this value is overcome, the destabilization of the NPs causes the formation of hydrophobic superstructures that enhance the release of an entrapped lipophilic drug. This characteristic behavior has been systematically studied and related to the copolymer structure. In particular, the self‐assembly behavior as well as temperature‐triggered NP destabilization have been related to the relative length of the two blocks constituting the copolymers and to their hydrophilic–lipophilic balance (HLB). Finally, the efficacy of the thermo‐responsive triggered drug release has been tested in the case of Paclitaxel (PTX). © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 2919–2931     

Polymer Meets Frustrated Lewis Pair: Second‐Generation CO2‐Responsive Nanosystem for Sustainable CO2 Conversion

Frustrated Lewis pairs (FLP), a couple comprising a sterically encumbered Lewis acid and Lewis base, can offer latent reactivity for activating inert gas molecules. However, their use as a platform for fabricating gas‐responsive materials has not yet developed. Merging the FLP concept with polymers, we report a new generation CO₂‐responsive system, differing from the first‐generation ones based on an acid–base equilibrium mechanism. Two complementary Lewis acidic and basic block copolymers, installing bulky borane‐ and phosphine‐containing blocks, were built as the macromolecular FLP. They can bind CO₂ to drive micellar formation, in which CO₂ as a cross‐linker bridges the block chains. This dative bonding endows the assembly with ultrafast response (<20 s), thermal reversibility, and excellent reproducibility. Moreover, such micelles bound highly active CO₂ can function as nanocatalysts for recyclable C₁ catalysis, opening a new direction of sustainable CO₂ conversion.