Lower Critical Solution Temperature Of Polymers Research Articles

Membrane-Based Hybrid Method for Purifying PEGylated Proteins

PEGylated proteins are usually purified using chromatographic methods, which are limited in terms of both speed and scalability. In this paper, we describe a microfiltration membrane-based hybrid method for purifying PEGylated proteins. Polyethylene glycol (or PEG) is a lower critical solution temperature polymer which undergoes phase transition in the presence of a lyotropic salt and forms micelle-like structures which are several microns in size. In the proposed hybrid method, the PEGylated proteins are first converted to their micellar form by the addition of a lyotropic salt (1.65 M ammonium sulfate). While the micelles are retained using a microfiltration membrane, soluble impurities such as the unmodified protein are washed out through the membrane. The PEGylated proteins thus retained by the membrane are recovered by solubilizing them by removing the lyotropic salt. Further, by precisely controlling the salt removal, the different PEGylated forms of the protein, i.e., mono-PEGylated and di-PEGylated forms, are fractionated from each other. Hybrid separation using two different types of microfiltration membrane devices, i.e., a stirred cell and a tangential flow filtration device, are examined in this paper. The membrane-based hybrid method for purifying PEGylated proteins is both fast and scalable.

Tailoring a UCST-LCST-pH Multiresponsive Window through a Single Polymer Complex of Chitosan-Hyaluronic Acid.

Multistimuli-responsive polymers are important for controlled release. Owing to the fact that these polymers are derived from vinyl-based monomers, their decoration with other molecules is limited. Polysaccharides, especially chitosan (CS) and hyaluronic acid (HA), are pH-responsive biopolymers, whose chemical structures contain reactive functional groups for feasible chemical modifications to obtain add-on functions. The present work demonstrates the introduction of polymers with upper critical solution temperature (UCST) and lower critical solution temperature (LCST) performances onto CS and HA, respectively. By simply varying the mole ratio between the CS-containing UCST polymer and the HA-containing LCST polymer along with adjusting the pH, a polymer system with a UCST-LCST-pH multiresponsive window can be obtained. This multiresponsive window enables us to control the encapsulation and release with repeatability as evidenced from a model study on lysozyme. The present work, for the first time, shows a simple approach to obtain multiresponsive biodegradable polymers through the formation of a single polymer complex to tailor a specific multiresponsive window.

Electro‐Thermo Controlled Water Valve Based on 2D Graphene–Cellulose Hydrogels

AbstractNovel 2D hydrogels with coupled electro‐thermoregulation for water transport are constructed via self‐assembly of hydroxypropyl cellulose (HPC) with graphene oxide (GO) and reduced GO (rGO), where the capability of HPC to switch between hydrophobic and hydrophilic states is exploited. Amphiphilic GO surface is used to guide the ordering and alignment of liquid crystalline HPC domains. The changes in conformation and alignment of HPC serve as a switch for optical properties and water transport. A composite consisting of electrically conductive rGO and 2D hydrogel is developed to produce thermal stimulus and thus construct an electro‐thermo controlled valve for regulated water transfer. The prepared 2D hydrogel has a large swelling rate, outstanding mechanical properties (Young's modulus is 2.5 GPa), and superior electrical conductivity (176 S cm−1). The ability of HPC domains to change conformation in 2D confinement, when Joule heating is applied, can function as a 2D low footprint water switcher with optical control in smart membranes. The proposed sustainable approach to self‐assembly of HPC in 2D confinement of GO and rGO is applicable to the whole family of lower critical solution temperature polymers. Thus, a ubiquitous and sustainable synthesis of novel low dimensional robust multifunctional hydrogels is demonstrated.

Prediction of the lower critical solution temperature of poly(N-isopropylacrylamide-co-methoxy triethyleneglycol acrylate) in aqueous salt solutions using support vector regression

This study investigates the lower critical solution temperature (LCST) behavior of a novel thermosensitive NIPA-co-MTGA polymer comprising N-isopropylacrylamide (NIPA) and methoxy triethyleneglycol acrylate (MTGA) by inducing hydrophilic/hydrophobic transitions in an aqueous salt solution. The LCST of the NIPA-co-MTGA polymer was in between that of the NIPA and MTGA homopolymers, and depended on the polymer composition. The LCST of all the polymers decreased with increasing salt concentration. The extent of decrease depended on the type of salt, with the order qualitatively corresponding to the Hofmeister series of anions. The LCSTs of the polymers in aqueous salt solutions were modeled and successfully predicted using support vector regression (SVR), a machine learning methodology. This is the first study to predict the LCST of thermosensitive polymers in aqueous salt solutions using SVR.

Effect of Synthesis Temperature on Size, Structure, and Volume Phase Transition of Polysaccharide Microgels

High-molecular-weight polysaccharide microgels were synthesized at a range of temperatures above the polymer lower critical solution temperature (LCST) (ΔT = 0.6–18.1 °C), and ΔT was found to strongly influence the structure, dynamics, and volume phase transition temperature of the resulting particles. Static and dynamic light scattering studies and mean field theory analysis of the microgels below and above volume phase transition revealed several distinct regimes. At small ΔT, lower density, larger, and more polydisperse microgels that deswell by a factor 10 in volume were synthesized. At intermediate ΔT = 5–8 °C, the formed microgels were the smallest, densest, and most monodisperse below the transition, but exhibited deswelling only by a factor of 5 above the transition. Synthesis at high ΔT led to the formation of nonuniform microgels with small density, a high degree of polydispersity, and in some cases the apparent presence of the un-cross-linked polymer. Furthermore, the volume phase transition temperature dropped significantly as ΔT increased. This work suggests that synthesis temperature can be used to tune the size, deswelling capacity, and volume phase transition temperature of the polymeric microgels.

Photodynamic therapy using LCST polymers exerting pH-responsive isothermal phase transition

In photodynamic therapy (PDT), the inherent physicochemical properties of a photosensitizer (PS) critically affect its biodistribution and therapeutic outcome as well as side effect. Here, we developed a PS-polymer conjugate displaying isothermal hydrophilic-to-hydrophobic phase transition in response to tumorous acidic pH. The polymer backbone was poly(N-isopropylacrylamide (NIPAAm)/2-aminoisoprpylacrylamide (AIPAAm)) (P(NIPAAm/AIPAAm)), which shows lower critical solution temperature (LCST) of 30 °C. The amine groups in its side chains were converted to hydrophilic acid-labile 2-propionic-3-methylmaleic (PMM) amides, forming poly(NIPAAm/AIPAAm-PMM). The conjugation of PMM moieties drastically increased the LCST of the polymer to 40 °C and displayed hydrophilic character to minimalize unspecific interaction of PS-P(NIPAAm/AIPAAm-PMM) in bloodstream, diminishing potential photosensitivity. The detachment of PMM at tumorous pH lowered the LCST to that of original P(NIPAAm/AIPAAm), permitting hydrophilic-to-hydrophobic transition at a physiological temperature (37 °C). This pH-responsive isothermal phase transition facilitated interaction with the cultured cancer cells, accomplishing 8.1 times-enhanced cellular uptake and strong phototoxicity in a tumorous pH-selective manner. Even in subcutaneous tumor models, our polymer conjugates exhibited efficient tumor accumulation and significantly augmented PDT effect without inducing unfavorable photochemical toxicity to the skin. This study offers a novel concept of PS delivery systems targeting tumorous pH by the use of isothermal phase transition.

How does high-pressure CO2 affect the morphology of PCL/PLA blends? Visualization of phase separation using in situ ATR-FTIR spectroscopic imaging

Studies of phase separation in lower critical solution temperature (LCST) polymer blends exposed to high-pressure CO2 provide an insight to their physical properties. Through using in situ high-pressure ATR-FTIR spectroscopic imaging, this work visualized the dynamic process of phase separation in Polycaprolactone (PCL)/Poly (lactic acid) (PLA) blend under high-pressure CO2 for the first time. ATR-FTIR spectroscopic images revealed that phase separation in PCL/PLA blends occurs with increasing temperature or upon exposure to high-pressure CO2. The change in the morphology of PCL-rich and PLA-rich domains in the ATR-FTIR spectroscopic images can be used to compare the extent of phase separation under different conditions. It is found that the extent of phase separation in PCL/PLA blends under high-pressure CO2 is enhanced with increasing temperature, CO2 pressure and exposure time. The effect of different molecular weights of one blend component, PCL, on the phase separation in PCL/PLA blends was also studied. This pioneering methodology opens possibilities to visualize the process of phase separation in LCST polymer blend systems and it can also be applied to study the process of interdiffusion in upper critical solution temperature (UCST) polymer blends.

Tunable UCST thermoresponsive copolymers based on natural glycyrrhetinic acid

Water-soluble thermoresponsive polymers present either upper critical solution temperature (UCST) or lower critical solution temperature (LCST) depending on the location of their miscibility range with water at high temperatures or at low temperatures. Compared with LCST polymers, the water-soluble UCST polymers are still less explored until now. In this work three copolymers of P(AAm-co-GAA) were synthesized by copolymerizing two acrylamide monomers, acrylamide (AAm) and acrylamide functionalized with natural glycyrrhetinic acid (GAA), using reversible addition-fragmentation chain transfer (RAFT) polymerization. These copolymers exhibited the typical UCST thermoresponsive behavior, and their phase transition temperatures could be easily tuned to around 37 °C for potential biological applications. Moreover, the UCST of P(AAm-co-GAA) can be adjusted not only by the content of glycyrrhetinic acid (GA) and polymer concentrations, but also by the host-guest interactions between GA and cyclodextrins (β- and γ-CD). The suitable value of UCST and the biocompatible nature of GA and CDs may endow these copolymers with practical applications in biomedical chemistry

Tuneable peptide cross-linked nanogels for enzyme-triggered protein delivery.

Many diseases are associated with the dysregulated activity of enzymes, such as matrix metalloproteinases (MMPs). This dysregulation can be leveraged in drug delivery to achieve disease- or site-specific cargo release. Self-assembled polymeric nanoparticles are versatile drug carrier materials due to the accessible diversity of polymer chemistry. However, efficient loading of sensitive cargo, such as proteins, and introducing functional enzyme-responsive behaviour remain challenging. Herein, peptide-crosslinked, temperature-sensitive nanogels for protein delivery were designed to respond to MMP-7, which is overexpressed in many pathologies including cancer and inflammatory diseases. The incorporation of N-cyclopropylacrylamide (NCPAM) into N-isopropylacrylamide (NIPAM)-based copolymers enabled us to tune the polymer lower critical solution temperature from 33 to 44 °C, allowing the encapsulation of protein cargo and nanogel-crosslinking at slightly elevated temperatures. This approach resulted in nanogels that were held together by MMP-sensitive peptides for enzyme-specific protein delivery. We employed a combination of cryogenic transmission electron microscopy (cryo-TEM), dynamic light scattering (DLS), small angle neutron scattering (SANS), and fluorescence correlation spectroscopy (FCS) to precisely decipher the morphology, self-assembly mechanism, enzyme-responsiveness, and model protein loading/release properties of our nanogel platform. Simple variation of the peptide linker sequence and combining multiple different crosslinkers will enable us to adjust our platform to target specific diseases in the future.

Multifunctional temperature-responsive polymers as advanced biomaterials and beyond.

The versatility and applicability of thermoresponsive polymeric systems have led to great interest and a multitude of publications. Of particular significance, multifunctional poly(N-isopropylacrylamide) (PNIPAAm) systems based on PNIPAAm copolymerized with various functional comonomers or based on PNIPAAm combined with nanomaterials exhibiting unique properties. These multifunctional PNIPAAm systems have revolutionized several biomedical fields such as controlled drug delivery, tissue engineering, self-healing materials, and beyond (e.g., environmental treatment applications). Here, we review these multifunctional PNIPAAm-based systems with various cofunctionalities, as well as highlight their unique applications. For instance, addition of hydrophilic or hydrophobic comonomers can allow for polymer lower critical solution temperature modification, which is especially helpful for physiological applications. Natural comonomers with desirable functionalities have also drawn significant attention as pressure surmounts to develop greener, more sustainable materials. Typically, these systems also tend to be more biocompatible and biodegradable and can be advantageous for use in biopharmaceutical and environmental applications. PNIPAAm-based polymeric nanocomposites are reviewed as well, where incorporation of inorganic or carbon nanomaterials creates synergistic systems that tend to be more robust and widely applicable than the individual components.

Stretchable and Self-Healable Conductive Hydrogels for Wearable Multimodal Touch Sensors with Thermoresponsive Behavior.

Multifunctional hydrogels with properties including transparency, flexibility, self-healing, and high electrical conductivity have attracted great attention for their potential application to soft electronic devices. The presence of an ionic species can make hydrogels conductive in nature. However, the conductivity of hydrogels is often influenced by temperature, due to the change of the internal nano/microscopic structure when temperature reaches the sol-gel phase transition temperature. In this regard, by introducing a novel surface-capacitive sensor device based on polymers with lower critical solution temperature (LCST) behavior, near-perfect stimulus discriminability of touch and temperature may be realized. Here, we demonstrate a multimodal sensor that can monitor the location of touch points and temperature simultaneously, using poly(N-isopropylacrylamide) (PNIPAAm) in hybrid poly(vinyl alcohol) (PVA) and sodium tetraborate decahydrate cross-linked hydrogels doped with poly(sodium acrylate) (SA) [w/w/w = 5:2.7:1-3]. This multimodal sensor exhibits a response time of 0.3 s and a temperature coefficient of resistance of -0.58% K-1 from 20 to 40 °C. In addition, the LCST behavior of PNIPAAm-incorporated PVA/SA gels is investigated. Incorporation of LCST polymers into high-end hydrogel systems may contribute to the development of temperature-dependent soft electronics that can be applied in smart windows.

High-throughput extracellular pH monitoring and antibiotics screening by polymeric fluorescent sensor with LCST property.

Monitoring extracellular pH (pHe) is important for biology understanding, since pHe and its homeostasis are closely relevant to cellular metabolism. Hydrogel-based pHe sensors have attracted significant attention and showed wide application, while they are tedious with significant time-cost operation and reproducibility variations for high-throughput application. Herein, we synthesized two polymers for pHe monitoring which are soluble in water at room temperature with easy operations and high reproducibility among various micro-plate wells for high-throughput analysis. P1 (P(OEGMA-co-MEO2MA-co-pHS)) and P2 (P(OEGMA-co-pHS)) were synthesized via the Reversible Addition Fragmentation Chain Transfer (RAFT) copolymerization of oligo(ethylene glycol) methacrylate (OEGMA), 2-(2'-methoxyethoxy) ethyl methacrylate (MEO2MA) and the pH sensitive fluorescence moiety N-fluoresceinyl methacrylamide (pHS). P1 is soluble in water at room temperature (25 °C) while insoluble at the temperature above 33 °C, indicating its feature of lower critical solution temperature (LCST) at 33 °C. Further P1 showed higher pH sensitivity and photostability than P2 (without LCST property) when used at physiological temperature (37 °C). Thus, P1 was chosen to in-situ monitor the micro-environmental acidification of E. coli, Hela and Ramos cells during their growth, and the metabolism inhibiting activity of a representative antibiotic, ampicillin. Cell concentration-dependent cellular acidification and drug concentration-dependent inhibition of cellular acidification were observed, demonstrating that the LCST polymer (P1) is suitable for real-time cellular acidification monitoring as well as for high-throughput drug screening. This study firstly demonstrated the use of a LCST polymeric sensor for high-throughput screening of antibiotics and investigation of cell metabolism.

Poly( N-isopropylacrylamide)-Based Polymer-Inducing Isothermal Hydrophilic-to-Hydrophobic Phase Transition via Detachment of Hydrophilic Acid-Labile Moiety.

The polymerization of N-isopropylacrylamide (NIPAAm) with ionizable monomers results in pH-responsive lower critical solution temperature (LCST) polymer which works in an ionization-dependent manner. However, gradual ionization of the comonomer occurs at a broad pH range due to the electrostatic field generated by the polymers, limiting the extent of LCST shift in response to pH change. Furthermore, excess introduction of comonomer may dull phase transition behavior. Here, we report the development of an ionization-independent LCST polymer that exerts a sharp isothermal hydrophilic-to-hydrophobic phase transition in response to slight pH change. Our polymer has a poly(NIPAAm/2-aminoisoprpylacrylamide (AIPAAm)) (P(NIPAAm/AIPAAm)) backbone that retains the continuous structural similarity of N-alkyl groups for preserving phase transition sensitivity, and primary amine for forming hydrophilic acid-labile 2-propionic-3-methylmaleic (PMM) amide linkage. The PMM moiety improves the polymer's hydrophilicity and drastically increases the LCST. Detachment of the PMM moiety in response to mild acidic condition (pH < 6.8) lowers the LCST to that of original P(NIPAAm/AIPAAm), permitting isothermal pH-responsive phase transition. Utilizing this mechanism, P(NIPAAm/AIPAAm) modified with PMM amide linkage exhibits a sharp hydrophilic-to-hydrophobic transition at a physiological temperature (37 °C) and, strikingly, facilitates interaction with cultured cells. Most importantly, our polymer showed significantly higher accumulation within a solid tumor after systemic injection compared to conventional PNIPAAm, which may be due to its phase transition responding to slightly acidic tumor microenvironment. Thus, this study provides a novel polymer that offers delicate control of LCST and pH-responsiveness suitable for use in even fuzzy biological environments.

Thermoresponsive polymer nanocarriers for biomedical applications.

Polymer nanocarriers allow drug encapsulation leading to fragile molecule protection from early degradation/metabolization, increased solubility of poorly soluble drugs and improved plasmatic half-life. However, efficiently controlling the drug release from nanocarriers is still challenging. Thermoresponsive polymers exhibiting either a lower critical solution temperature (LCST) or an upper critical solution temperature (UCST) in aqueous medium may be the key to build spatially and temporally controlled drug delivery systems. In this review, we provide an overview of LCST and UCST polymers used as building blocks for thermoresponsive nanocarriers for biomedical applications. Recent nanocarriers based on thermoresponsive polymer exhibiting unprecedented features useful for biomedical applications are also discussed. While LCST nanocarriers have been studied for over two decades, UCST nanocarriers have recently emerged and already show great potential for effective thermoresponsive drug release.

LCST-Type Hyperbranched Poly(oligo(ethylene glycol) with Thermo- and CO2 -Responsive Backbone.

A novel hyperbranched lower critical solution temperature (LCST) polymer with sharp temperature and CO2 -responsive behaviors is presented in this study. The target polymer of hyperbranched poly(oligo(ethylene glycol) (HBPOEG) is constructed using POEG as the backbone and tertiary amines as branch points. Phase transition of HBPOEG in aqueous solution is investigated by heating and cooling the system; the results indicate that HBPOEG in aqueous solution has a concentration-dependent phase transition behavior with excellent repeatability. Moreover, LCST of HBPOEG can be tuned by bubbling CO2 into the solution, as the tertiary amines can be protonated and the solubility of the polymer would increase by bubbling CO2 into the system, leading to an increase of LCST of the polymer. Further bubbling N2 to remove CO2 can reversibly turn back the LCST to its original value. This backbone-based hyperbranched LCST polymer with both CO2 and temperature responsiveness can be applied in application areas like drug delivery, gene transfection, functional coatings, etc.

Composites Formed from Thermoresponsive Polymers and Conductive Nanowires for Transient Electronic Systems.

The disintegration of transient electronic systems after a preprogrammed time or a particular stimulus (e.g., water, light, or temperature) is fundamentally linked to the properties and behavior of the materials used for their construction. Herein, we demonstrate that polymers exhibiting lower critical solution temperature (LCST) behavior can work as thermoresponsive substrates for circuitry and that these materials can be coupled with conductive nanowires to form a transient electronics platform with unique, irreversible temperature-responsive behavior. The transient systems formed from composites of LCST polymers and conductive nanowires exhibit stable electrical performance in solution (Tsolution > LCST) for over 24 h until a cooling stimulus triggers a rapid (within 5 min) and gigantic (3-4 orders of magnitude) transition in electrical conductance due to polymer dissolution. Using a parylene mask, we are able to fabricate thermoresponsive electrical components, such as conductive traces and parallel-plate capacitors, demonstrating the versatility of this material and patterning technique. With this unique stimulus-responsive transient system and polymers with LCSTs above room temperature (e.g., poly(N-isopropylacrylamide), methyl cellulose), we have developed a platform in which a circuit requires a source of heat to remain viable and is destroyed and vanishes once this heat source is lost.

Effect of conjugation on phase transitions in thermoresponsive polymers: an atomistic and coarse-grained simulation study.

Using atomistic and coarse-grained molecular dynamics (MD) simulations, we explain the shifts in lower critical solution temperature (LCST)-like phase transitions exhibited by elastin-like peptides (ELPs) upon conjugation to other macromolecules (e.g. collagen-like peptides or CLPs). First, using atomistic simulations, we study ELP oligomers with the sequence (VPGFG)6 in explicit water, and characterize the LCST-like transition temperature as one at which the ELP oligomers undergo a change in "hydration state". In agreement with past experimental observations of Luo and Kiick, upon anchoring ELP oligomers to a point to mimic ELP oligomers conjugated to another macromolecule, there is an apparent slight shift in the transition temperature to lower values compared to free (unconjugated) ELP oligomers. However, these atomistic simulations are limited to small systems of short ELPs, and as such do not capture the multiple chain aggregation/phase separation observed in experiments of ELPs. Therefore, we utilize phenomenological coarse-grained (CG) MD simulations to probe how conjugating a block of generic-LCST polymer to another rigid unresponsive macromolecular block impacts the transition temperatures at concentrations and length scales larger than atomistic simulations. We find that when multiple LCST polymer chains are conjugated to a rigid unresponsive polymer block, the increased local crowding of the LCST polymers shifts the transition marked by onset of chain aggregation to smaller effective polymer-polymer attraction energies compared to the free LCST polymer chains. The driving force needed for aggregation is reduced in the conjugates compared to free LCST polymer due to reduction in the loss of polymer configurational entropy upon aggregation.

Recognition-Mediated Hydrogel Swelling Controlled by Interaction with a Negative Thermoresponsive LCST Polymer.

Most polymeric thermoresponsive hydrogels contract upon heating beyond the lower critical solution temperature (LCST) of the polymers used. Herein, we report a supramolecular hydrogel system that shows the opposite temperature dependence. When the non‐thermosesponsive hydrogel NaphtGel, containing dialkoxynaphthalene guest molecules, becomes complexed with the tetra cationic macrocyclic host CBPQT4+, swelling occurred as a result of host–guest complex formation leading to charge repulsion between the host units, as well as an osmotic contribution of chloride counter‐ions embedded in the network. The immersion of NaphtGel in a solution of poly(N‐isopropylacrylamide) with tetrathiafulvalene (TTF) end groups complexed with CBPQT4+ induced positive thermoresponsive behaviour. The LCST‐induced dethreading of the polymer‐based pseudorotaxane upon heating led to transfer of the CBPQT4+ host and a concomitant swelling of NaphtGel. Subsequent cooling led to reformation of the TTF‐based host–guest complexes in solution and contraction of the hydrogel.

Recognition‐Mediated Hydrogel Swelling Controlled by Interaction with a Negative Thermoresponsive LCST Polymer

AbstractMost polymeric thermoresponsive hydrogels contract upon heating beyond the lower critical solution temperature (LCST) of the polymers used. Herein, we report a supramolecular hydrogel system that shows the opposite temperature dependence. When the non‐thermosesponsive hydrogel NaphtGel, containing dialkoxynaphthalene guest molecules, becomes complexed with the tetra cationic macrocyclic host CBPQT4+, swelling occurred as a result of host–guest complex formation leading to charge repulsion between the host units, as well as an osmotic contribution of chloride counter‐ions embedded in the network. The immersion of NaphtGel in a solution of poly(N‐isopropylacrylamide) with tetrathiafulvalene (TTF) end groups complexed with CBPQT4+ induced positive thermoresponsive behaviour. The LCST‐induced dethreading of the polymer‐based pseudorotaxane upon heating led to transfer of the CBPQT4+ host and a concomitant swelling of NaphtGel. Subsequent cooling led to reformation of the TTF‐based host–guest complexes in solution and contraction of the hydrogel.

Polyacetals: Water-Soluble, pH-Degradable Polymers with Extraordinary Temperature Response

Temperature-responsive polymers exhibit a drastic change in solubility upon change in temperature, a property responsible for their increased use in a wide variety of emerging smart material applications. Here, we describe a flexible new family of polyacetals with lower critical solution temperature (LCST) behavior, falling out of aqueous solution upon increase in temperature. These are the first synthetic LCST polymers to be intrinsically biodegradable, forming neutral degradation products in acidic environments. The temperature response of the polyacetals is extraordinary. Their LCST cloud point temperatures can be predicted and tuned to high precision over a temperature range of ca. 6–80 °C as they are linearly dependent on the number of methylene and ethylene oxide units in the diol and divinyl ether monomers. We further demonstrate that the LCST temperatures are insensitive to salt and/or polymer concentration, properties that are important to in vivo applications, and that they are biocompatible.