LCST Behavior Research Articles

Thermo-Responsive Hydrogels: From Recent Progress to Biomedical Applications.

Thermogels are also known as thermo-sensitive or thermo-responsive hydrogels and can undergo a sol–gel transition as the temperature increases. This thermogelling behavior is the result of combined action from multiscale thermo-responsive mechanisms. From micro to macro, these mechanisms can be attributed to LCST behavior, micellization, and micelle aggregation of thermogelling polymers. Due to its facile phase conversion properties, thermogels are injectable yet can form an in situ gel in the human body. Thermogels act as a useful platform biomaterial that operates at physiological body temperatures. The purpose of this review is to summarize the recent progress in thermogel research, including investigations on the thermogel gelation mechanism and its applications in drug delivery, 3D cell culture, and tissue engineering. The review also discusses emerging directions in the study of thermogels.

Supramolecular control over thermo‐responsive systems with lower critical solution temperature behavior

AbstractLower critical solution temperature (LCST) is the critical temperature below which the solution is miscible for all compositions and above which the solution becomes a suspension. The study of LCST properties has become a central research topic due to its profound impact on the applications of stimuli‐responsive materials. Inspired by the marriage between materials science and supramolecular chemistry, the introduction of supramolecular pairs and interactions into polymeric LCST systems is increasingly practiced. Especially, supramolecular interactions provide precise control over LCST behavior in both water and organic solvents. Furthermore, supramolecular interactions not only control or adjust LCST behavior (supramolecular interaction controlled LCST), but also induce LCST phase behavior in species lack of thermo‐sensitive properties (supramolecular interaction induced LCST). In this review, we summarize the applications of supramolecular interactions in LCST systems. By examining the relationship between supramolecular interactions and LCST changes, we further discuss the differences between supramolecular interaction controlled LCST and supramolecular interaction induced LCST. We hope this review will give our readers a snapshot on how the supramolecular interactions influence the LCST behavior in various systems, and benefit them with different applications.

Pillar[5]arene-based ion-pair recognition for constructing a [2]pseudorotaxane with supramolecular interaction induced LCST behavior

Here, we report a novel [2]pseudorotaxane based on perbromoethylated pillar[5]arene/imidazolium iodide ionic liquid ion-pair recognition and this pseudorotaxane shows supramolecular interaction induced LCST behavior in solution.

Amphiphilic Molecular Brushes with Regular Polydimethylsiloxane Backbone and Poly-2-isopropyl-2-oxazoline Side Chains. 2. Self-Organization in Aqueous Solutions on Heating.

The behavior of amphiphilic molecular brushes in aqueous solutions on heating was studied by light scattering and turbidimetry. The main chain of the graft copolymers was polydimethylsiloxane, and the side chains were thermosensitive poly-2-isopropyl-2-oxazoline. The studied samples differed in the length of the grafted chains (polymerization degrees were 14 and 30) and, accordingly, in the molar fraction of the hydrophobic backbone. The grafting density of both samples was 0.6. At low temperatures, macromolecules and aggregates, which formed due to the interaction of main chains, were observed in solutions. At moderate temperatures, heating solutions of the sample with short side chains led to aggregation due to dehydration of poly-2-isopropyl-2-oxazoline and the formation of intermolecular hydrogen bonds. In the case of the brush with long grafted chains, dehydration caused the formation of intramolecular hydrogen bonds and the compaction of molecules and aggregates. The lower critical solution temperature for solutions of the sample with long side chains was higher than LCST for the sample with short side chains. It was shown that the molar fraction of the hydrophobic component and the intramolecular density are the important factors determining the LCST behavior of amphiphilic molecular brushes in aqueous solutions.

Multiresponsive Transitions of PDMAEMA Brushes for Tunable Surface Patterning.

Poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA) is an attractive polymer for switchable surface coatings based on its multiresponsiveness toward environmental triggers (temperature, pH-value, ionic strength). In this in situ study, we present the complex and tunable thermoresponsiveness of PDMAEMA Guiselin brushes (9 nm, dry thickness), which were prepared via an efficient grafting-to approach. Combining in situ atomic force microscopy (AFM) visualizing the surface topography (x-y plane) and spectroscopic ellipsometry monitoring the swelling behavior of the polymer film (layer thickness, z-direction) offers for the first time a three-dimensional insight into thermoresponsive transitions on the nanoscale. While PDMAEMA films exhibit LCST behavior in the presence of monovalent counterions, it can easily be switched toward an UCST thermoresponsiveness via the addition of small quantities of multivalent ions. In both cases, the transition temperature as well as the sharpness and reversibility of the transition can be tuned via a second external trigger, the ionic strength. Whereas homogeneous surfaces were observed both below and above the LCST in monovalent salt solutions, the UCST transition was characterized by the in situ formation of a nanostructured surface of pinned PDMAEMA micelles with entrapped multivalent counterions. Moreover, it was demonstrated for the first time that the characteristic dimensions of the nanopattern (the diameter and height of the pinned micelles) could be tuned in situ by the pH- and induced UCST thermoresponsiveness of PDMAEMA. This approach therefore provides a novel bottom-up strategy to create and control polymeric nanostructures in an aqueous environment.

Dual Self-Assembled Nanostructures from Intrinsically Disordered Protein Polymers with LCST Behavior and Antimicrobial Peptides.

Antimicrobial peptides (AMPs) have attracted great interest as they constitute one of the most promising alternatives against drug-resistant infections. Their amphipathic nature not only provides them antimicrobial and immunomodulatory properties but also the ability to self-assemble into supramolecular nanostructures. Here, we propose their use as self-assembling domains to drive hierarchical organization of intrinsically disordered protein polymers (IDPPs). Using a modular approach, hybrid protein-engineered polymers were recombinantly produced, thus combining designer AMPs and a thermoresponsive IDPP, an elastin-like recombinamer (ELR). We exploited the ability of these AMPs and ELRs to self-assemble to develop supramolecular nanomaterials by way of a dual-assembly process. First, the AMPs trigger the formation of nanofibers; then, the thermoresponsiveness of the ELRs enables assembly into fibrillar aggregates. The interplay between the assembly of AMPs and ELRs provides an innovative molecular tool in the development of self-assembling nanosystems with potential use for biotechnological and biomedical applications.

Supramolecular control over LCST behavior of hybrid macrocyclic system based on pillar[5]arene and crown ether

A hybrid system containing a pillar[5]arene unit and ten crown ether moieties was developed. The LCST behavior and thermo-responsiveness were successfully introduced into this pillar[5]arene-crown ether system. Both host–guest interactions and salting-out effect displayed great effects in realizing the supramolecular control over LCST properties and thermo-responsiveness. Compared with the individual macrocycles, this hybrid macrocycle system dramatically amplified the supramolecular control effect over LCST behavior.

Synthesis and Conformational Characteristics of Thermosensitive Star-Shaped Six-Arm Polypeptoids.

Star-shaped six-arm poly-2-alkyl-2-oxazine and poly-2-alkyl-2-oxazoline with hexaaza [26]orthoparacyclophane derivative core were synthesized successfully using cationic ring-opening polymerization. Conformational behavior of prepared polymer stars were investigated by the methods of molecular hydrodynamics and optics in molecular dispersed solutions. It was shown that conformation characteristics of star-shaped polypeptoids depends on arm length, while the chemical structure weakly affects the behavior of the studied polymers in solutions. This behavior is caused by the close equilibrium rigidity of arms. The star-shaped polypeptoids have relatively high intramolecular density. All synthesized stars exhibit LCST behavior. Phase separation temperature depends on arm structure. It is lower for poly-2-alkyl-2-oxazines, monomer units of which contains one methylene group more than monomers of poly-2-alkyl-2-oxazoline.

LCST Behaviors of Amphiphilic Pyridine Derivatives with Oligo(ethylene glycol) Chains

Water-soluble pyridine derivatives linked with gallic acid bearing oligo(ethylene glycol) (OEG) side chains on the hydroxyl groups or with aryl ether dendron moiety having OEG chains on the periphe...

Precise synthesis of poly(IBVE-co-HBVE) with tunable thermo-response via fast flow polymerization

A new type of thermosensitive copolymers composed of isobutyl vinyl ether (IBVE) units and 4-hydroxybutyl vinyl ether (HBVE) units were synthesized within 4.34 s in a microflow platform. The synthesis started from the living cationic copolymerization of IBVE and 4-(tert-butyldimethylsilyloxy) butyl vinyl ether (BMS-Bu) using cationogen/SnCl4 initiation system in the presence of an added base, resulting in a copolymer with a narrow dispersity. This new platform enabled very low concentrations of added base (0.1 M) and offered highly controllability on fast living cationic copolymerization, making it possible to determine the reactivity ratio of IBVE and BMS-Bu at low-conversion within 0.15 s. Subsequently, after desilylation, poly(IBVE-co-HBVE) with narrow dispersity (Mw/Mn ≈ 1.10) was obtained, presenting strictly controllable LCST behavior. Particularly, the phase transition experienced sharp and almost reversible process, and Tps can be tuned from 22.5 to 38.5 °C by changing the ratio of two monomers in feeding.

Unification of lower and upper critical solution temperature phase behavior of globular protein solutions in the presence of multivalent cations.

In globular protein systems, upper critical solution temperature (UCST) behavior is common, but lower critical solution temperature (LCST) phase transitions are rare. In addition, the temperature sensitivity of such systems is usually difficult to tune. Here we demonstrate that the charge state of globular proteins in aqueous solutions can alter their temperature-dependent phase behavior. We show a universal way to tune the effective protein interactions and induce both UCST and LCST-type transitions in the system using trivalent salts. We provide a phase diagram identifying LCST and UCST regimes as a function of protein and salt concentrations. We further propose a model based on an entropy-driven cation binding mechanism to explain the experimental observations.

Thermo-Responsive Polymer Brushes with Side Graft Chains: Relationship Between Molecular Architecture and Underwater Adherence.

During the last few decades, wet adhesives have been developed for applications in various fields. Nonetheless, key questions such as the most suitable polymer architecture as well as the most suitable chemical composition remain open. In this article, we investigate the underwater adhesion properties of novel responsive polymer brushes with side graft chain architecture prepared using “grafting through” approach on flat surfaces. The incorporation in the backbone of thermo-responsive poly(N-isopropylacrylamide) (PNIPAm) allowed us to obtain LCST behavior in the final layers. PNIPAm is co-polymerized with poly(methyl ethylene phosphate) (PMEP), a poloyphosphoester. The final materials are characterized studying the surface-grafted polymer as well as the polymer from the bulk solution, and pure PNIPAm brush is used as reference. PNIPAm-g-PMEP copolymers retain the responsive behavior of PNIPAm: when T > LCST, a clear switching of properties is observed. More specifically, all layers above the critical temperature show collapse of the chains, increased hydrophobicity and variation of the surface charge even if no ionizable groups are present. Secondly, effect of adhesion parameters such as debonding rate and contact time is studied. Thirdly, the reversibility of the adhesive properties is confirmed by performing adhesion cycles. Finally, the adhesive properties of the layers are studied below and above the LCST against hydrophilic and hydrophobic substrates.

A Multifunctional Hybrid[4]arene-Based Macrocyclic Amphiphile: Self-Assembly, Tunable LCST Behavior, and Construction of Fluorescent Nanoparticles for Cell Imaging.

A novel macrocyclic amphiphile based on hybrid[4]arene containing tri(ethylene glycol) chains as the hydrophilic part and benzene rings as the hydrophobic part was synthesized. It self-assembled to produce nanoparticles and showed lower critical solution temperature behavior that was affected by its concentration and K+. Moreover, amphiphilic H can encapsulate dye G to form host-guest complexes H⊃G, accompanied by significant fluorescence enhancement. H⊃G can further self-assemble to form fluorescent nanoparticles that can be applied in cell imaging.

LCST behavior controlled by size-matching selectivity from low molecular weight monomer systems

LCST behavior was controlled by crown ether–cation recognition motifsviasize-matching selectivity.

Ionic strength and ion-specific effects on the cloud point and the gel swelling of thermo-sensitive polymers in water

In the present study, we have confirmed that the LCST behavior of thermosensitive polymers such as poly(vinyl methyl ether) (PVME) may be notably influenced by addition of small amount of neutral salts. In fact, the PVME gel swelled with increasing NaCl concentration in the immersing solution up to 10−3 M and then deswelled. Further, ionic effects on the hydrophobic interaction of PVME proved to be significantly dependent on the ionic species; for example, in the presence of 10−4 M halide ions (Cl−, Br−, and I−), the cloud point of PVME solution significantly increased in the order of Cl− < I− < Br−. This is different from the typical Hofmeister series, Cl− < Br− < I−, which is observed in much higher salt concentration region. All these ion effects have been interpreted in terms of the dual adsorption model for OH− and H+ on hydrophobic interface.

Facile Synthesis of Thermoresponsive Poly(NIPAAm-g-PDMS) Copolymers Using Room Temperature Alkylborane Chemistry

Synthesis of poly(NIPAAm-g-PDMS) polymers using monomethacrylate-functional PDMS macromonomers was carried out over a range of compositions and graft lengths using a facile ambient initiation scheme based on the decomplexation of stabilized alkylborane–amine complexes that is triggered by simple mixing. The copolymerization of NIPAAm with MA-PDMS by this technique was confirmed by monitoring the reaction kinetics and estimating the reactivity ratios via online 1H NMR spectroscopy. These copolymers were confirmed to contain immiscible grafts that are dispersed into nanosegregated domains by AFM, with supporting DSC analysis showing separate Tgs for each polymer phase. DSC studies also show that both the monomer ratio and the PDMS graft length affect the locus of composition-dependent demixing temperature (Tdem) points that delineates the LCST behavior of the copolymer in water. The contrasting impact of low molecular weight (Mn ∼ 1000 Da) PDMS grafts and higher molecular weight (∼5000 and ∼120 000 Da) PDMS...

LCST behavior of poly(2-ethyl-2-oxazoline) containing diblock and triblock copolymers

Mono- and bifunctional macro chain transfer agents were prepared via the living cationic ring opening polymerization of EtOx. A series of well-defined P(eTEGA)-b-PEtOx-b-P(eTEGA) triblock copolymers, PEtOx-b-P(eTEGA) as well as PEtOx-b-PNiPAm diblock copolymers were obtained by subsequent reversible addition fragmentation chain transfer polymerization of eTEGA or NiPAm, respectively. While the molar mass of the PEtOx was kept constant, the DP of the PNiPAm or P(eTEGA) block was varied and covers a wide range. Turbidimetry, NMR spectroscopy and dynamic light scattering investigations of the aqueous polymer solutions revealed that the lower critical solution temperature behavior of the triblock copolymers is strongly affected by the hydrophobic end groups whereas the presence of hydrogen bond donating moieties does not play any role. For diblock copolymers with a sufficiently long PEtOx block, the PNiPAm blocks collapsed independently, resulting in multiple phase transitions and the formation of well-defined aggregated structures.

Poly(2-isopropenyl-2-oxazoline) as a versatile platform towards thermoresponsive copolymers

Thermoresponsive (co)polymers with LCST behavior based on a well-defined PiPOx scaffold showing high versatility in tuning up the TCP as well as the interval of response.

Tunable Dual-Thermoresponsive Core-Shell Nanogels Exhibiting UCST and LCST Behavior.

Thermoresponsive polymers change their physical properties as the temperature is changed and have found extensive use in a number of fields, especially in tissue engineering and in the development of drug delivery systems. The synthesis of a novel core-shell nanogel composed of N-isopropylacrylamide and sulfobetaine by reversible addition fragmentation chain transfer polymerization is reported. The core-shell architecture of the nanogels is confirmed using energy dispersive X-ray spectroscopy in scanning transmission electron microscopy. These nanogels exhibit dual thermoresponsive behavior, i.e., the core of the nanogel exhibits lower critical solution temperature, while the shell displays upper critical solution temperature behavior. Transition temperatures can be easily tuned by changing the molecular weight of the constituent polymer. These nanogels can be efficiently used in temperature-triggered delivery of therapeutic proteins and drugs.

Synthesis of sulfur-rich nanoparticles using self-assembly of amphiphilic block copolymer and a site-selective cross-linking reaction

Water soluble sulfur-rich nanoparticles (S-NPs) having the sulfur content of more than 80 wt% were synthesized using a self-assembled block copolymer structure comprising 4-bromophenyl vinyl sulfide (BPVS) and N-isopropyl acrylamide (NIPAM), and a site-selective cross-linking reaction in selective aqueous solution. The core cross-linking reaction of sodium polysulfide with 1,2,3-trichloropropane as a cross-linker in the presence of poly(BPVS-b-NIPAM) was conducted in water, in which the site selective reaction takes place inside the micelles. DLS analysis demonstrated the formation of stable S-NPs with uniform sizes, which could be controlled by the nature of the cross-linking agents and reaction conditions (Dh = 140–170 nm in CHCl3). UV-vis, fluorescence, and cyclic voltammetry measurements led to the optical and electrochemical properties derived from polysulfide units and incorporated cross-linked units in the resulting products, supporting the successful preparation of desired S-NPs. The S-NPs exhibited LCST behavior around 32 °C, which stems from the poly(NIPAM) shell.