Stimuli-Responsive Materials

Materials with active microstructure represent a class of adaptive material that offers dynamic properties based on their ability to undergo phase transformations. An early structural alloy (hard matter) example of this class of material is partially stabilized zirconia, PSZ, developed by Hannink and co-workers at CSIRO, and dubbed ‘ceramic steel’ PSZ utilizes non-equilibrium to equilibrium phase transformation under the application of stress to respond to cracks by closing them and making their propagation more difficult. This invention changed future development of engineering ceramic alloys. Recently we have successfully demonstrated the ability to alter the transformation pathway in a structural aluminium alloy. Critical to our proof of concept was the ability to tailor the atomic mobility. Also, we have successfully used the phase transformations in soft matter to alter the porosity for the purpose of drug delivery. In both hard and soft matter materials applications, further design and optimisation of next generation materials relies on the development of methods to tailor microstructure (the bonding of atoms, ions and molecules) and porosity (the pathways by which atoms, ions, and molecules move through materials to perform chemistry, i.e. to rearrange and alter properties). We intend to develop microstructures that can respond to a change in the environment that causes movement and utilization of equilibrium or non-equilibrium material as if it is a reservoir of both energy and atoms or molecules. By incorporating various microstructural property-enhancing mechanisms, engineering materials and biomaterials can be designed which adapt their property requirements to their service environments.

The behaviour of amphiphilic block copolymers has attracted growing attention in recent years. The interest is sustained by the fact that these polymers are self-assembling materials capable of forming polymeric aggregates or micelles under selected conditions. In particular, these self-assemblies of macromolecules are often used as molecular tools for the engineering of functional nano-materials like nano-carriers for poorly water soluble drugs, nano-reactors for chemical synthesis or catalysis, or templates for ordered deposition of nano-objects. An interesting class of self-assembling polymers are block copolymers in which one of the hydrophilic blocks is stimuli-sensitive i.e. undergoes transition from soluble to insoluble in water by applying an external stimulus. The most common stimuli are temperature, pH, or ionic strength. Among a variety of stimuli-induced self-assembling systems, polymers based on poly(N-isopropylacrylamide) (PNIPAAm) were investigated as components of different temperature responsive copolymer systems.

Simplified routes to well-defined “smart” polymer-protein conjugates with tunable bioactivity will be discussed. Protein modification with a reversible addition-fragmentation chain transfer (RAFT) agent and subsequent room temperature polymerization in aqueous media led to conjugates of responsive polymers with model proteins. Representing the first example of polymer-protein conjugation with RAFT agent immobilization via the “R-group,” high molecular weight and reductively stable conjugates were accessible without extensive purification or adverse effects on the protein structure. Alternatively, postpolymerization conjugation of the responsive polymers labeled with maleimides, thiols, or activated esters also allowed polymer-protein conjugates to be prepared in a straightforward manner. The responsive behavior of the immobilized polymer facilitated conjugate isolation and allowed environmental modulation of bioactivity.

“Thiol-Click” Chemistry: A Versatile Route to Functional Polymer Surfaces

Engineering the chemistry and topography of surfaces affords technological advancements for a variety of applications ranging from biosensors to microelectronics. In this presentation, thiol-yne click chemistry is demonstrated as a modular platform for rapid and practical fabrication of highly functional, multicomponent surfaces under ambient conditions. The principle is illustrated using a postmodification strategy in which poly(propargyl methacrylate) brushes were generated via surface-initiated photopolymerization and sequentially functionalized using the radical-mediated thiol-yne reaction. Brush surfaces expressing a three-dimensional configuration of “yne” functionalities were modified with high efficiency and short reaction times using a library of commercially available thiols, including functional thiols that demonstrate applicability for pH responsive surfaces and for bioconjugation. Sequential thiol-yne reactions in conjunction with simple UV photolithography were also applied to afford micropatterned, multicomponent surfaces. The practicality of the platform was further demonstrated by carrying out thiol-yne surface reactions in sunlight, suggesting the possibility of large scale modifications using renewable energy resources. Considering the mild reaction conditions, rapid throughput, and compatibility with orthogonal chemistries, we expect this platform to find widespread use among the materials science community.

Functionalization of Polymers and Polymer-modified Interfaces us Reactive Azlactone-containing Macromolecules

Creating polymer-modified interfaces decorated with biologically-relevant materials with precise control over the nanoscale structure and properties is of increasing technological importance for a large number of advanced materials applications, including adaptive and/or lubricious biomaterial coatings, electro-actuators (synthetic muscles), biosensors, coatings for stealth drug delivery, supports for enzymatic catalysts, protein or antibody arrays, and high affinity separation agents. The ability to design and decorate interfaces with biologically-relevant molecules and understand synthesis-structure-function relationships remains a significant challenge. Here we describe our efforts to harness the potential of the reactive monomer, vinyl dimethyl azlactone (VDMA), to create stimuli-responsive (co)polymers. Reaction of nucleophiles with the azlactone moiety proceeds rapidly, quantitatively, and in the absence of byproducts, which are essential criteria governing the click-type nature of this procedure. The conversion of VDMA-based polymers into polyelectrolytes and bioconjugates can be monitored in real-time using infrared spectroscopy. Additionally, pVDMA polymers and block copolymers prepared using reversible addition fragmentation chain transfer (RAFT) polymerization are the basis for creating polymer brushes by a “grafting to” approach. Subsequent immobilization of model biomolecules (e.g., dansylcadaverine, Na,Na-bis(carboxymethyl)-L-lysine hydrate) on pVDMA-containing surface scaffolds causes dramatic changes in structure and functionality. We will describe how neutron reflectivity can be brought to bear to understand how compositional differences and changes in the design of the polymer affect nanoscale structure and responsiveness of pVDMA-based polymers.

Recent Advances in Responsive Polymer Systems for Pharmaceutical Applications

Our research efforts have been directed towards enhancing drug, biopolymer and cell delivery, using responsive polymers as ‘triggered’ agents for release of therapeutics. A specific focus has been to develop responsive materials from monomers and polymers that are likely to be acceptable to the pharmaceutical industry.

Figure 1: Left-hand side. a) Synthesis of biocompatible responsive polymers b) LCST response and c) generation of co-polymer vesicles Right-hand side - Top; schematic of responsive polymer bioconjugates. Middle; polymer-biopolymer complexes for enhanced delivery. Bottom; cell delivery agents

Currently, we are preparing stimuli-responsive materials by a range of polymerization techniques including ATRP and RAFT routes and are evaluating the behavior of these materials in biological and biomedical applications. At the meeting our latest data from these areas will be presented.

Biorecognition – a Bridge from Smart Biomaterials to Drug-Free Macromolecular Therapeutics

Molecular biorecognition is at the center of all biological processes. It forms the basis for the design of precisely defined smart systems, including targeted therapeutics, imaging agents, stimuli-sensitive and self-assembled biomaterials, and biosensors.
Conformational changes accompanying protein – ligand recognition have been used in the design of smart biomaterials. A new design of enzyme-based hybrid hydrogels that employs substrate-enzyme (adenylate kinase – ATP) recognition to induce a conformational change with concomitant decrease of the hydrogel volume was recently described. This provides a new paradigm for hybrid hydrogel design, where biorecognition induced nano-scale conformational changes translate into macroscale mechanical motion.
The coiled-coil, a supercoil formed by two or more strands of a-helices, is an example that reveals the potential for the design of well-organized assemblies. Self-assembly of macromolecules mediated by protein domains demonstrated that it is possible to impose properties of a well-defined coiled-coil peptide motif onto a hybrid hydrogel containing synthetic polymer primary chains.
For example, two distinct, oppositely charged, pentaheptad peptides (CCE and CCK) were designed to create a dimerization motif. Their structure was designed with the goal of achieving an antiparallel heterodimeric conformation. A mixture of graft copolymers, CCE-P and CCK-P (P is the N-(2-hydroxypropyl)methacrylamide copolymer backbone), spontaneously self-assembled into hybrid hydrogels.
We hypothesized that this unique biorecognition of CCK and CCE peptide motifs could be applied to a living system and mediate a biological process. This would provide a bridge between the designs of biomaterials and macromolecular therapeutics. Indeed, the biorecognition of peptide motifs at the cellular surface is able to control the apoptosis of cells. Graft copolymers containing biorecognition motifs may crosslink non-internalizing receptors on cell surfaces resulting in apoptosis. This is a new concept, where the biological activity of drug-free macromolecular therapeutics is based on the biorecognition of peptide motifs.

“Polysaccharide-based Multilayer Capsules with Tailor-made Functional Properties for Drug Delivery"

Rachel Auzély-Velty
Centre de Recherches sur les Macromolécules Végétales, France

In recent years, polyelectrolyte microcapsules prepared by the Layer-by-Layer deposition technique have attracted a great deal of interest for their potential applications in various fields such as drug delivery, biotechnology and catalyst research. One of the advantages of these multicompartment systems is the possibility to introduce a high degree of multifunctionality within their nanoshell by the nature of materials and assembly conditions used for their preparation. This in particular may allow the design of original drug vehicles with controlled encapsulation and triggered-release properties. In this context, we proposed to develop new tailor-made capsules taking advantage of the specific properties of carbohydrate polymers. We thus demonstrated the possibility to obtain from hyaluronic acid, a biologically important polysaccharide, biocompatible capsules showing enzyme-responsive shell permeability. Moreover, other well-defined carbohydrate polymers were self-assembled into multilayer capsules with the purpose to produce “intelligent” insulin delivery systems able to release insulin in a self-regulated and long acting but modulated manner. Such carriers may be used to form a subcutaneous depot to treat insulin-dependent diabetic patients.

An overview of a new technology platform for the design of chromogenic polymer materials with “self-assessing” capabilities will be presented. Cyano-substituted oligo(p-phenylene vinylene)s (cyano-OPVs) are members of a family of photoluminescent (PL) dyes that exhibit strong tendencies toward excimer formation and charge-transfer complexes. As a result the emission and/or absorption color of the dye molecules can strongly depend on the extent of their aggregation. This effect is used for the design of molecular sensors that are easily integrated into a polymer of interest and allow one to monitor mechanical deformation, exposure above a threshold temperature, or exposure to moisture. Small amounts of the sensor molecules are blended with conventional host polymers. The phase behavior and nano-scale structure of the resulting blends or nanocomposites is responsive to external stimuli such as temperature, mechanical deformation, or moisture which can cause a pronounced, easy-to-detect variation of the fluorescence and/or absorption color of the sensor molecules. For example, phase-separated systems with nanoscale dye aggregates can be produced by quenching melt-processed blends of semicrystalline polymers and cyano-OPVs. Mechanical deformation of these blends leads to a pronounced change of the materials PL and/or absorption characteristics. The inverse mechanism, i.e. kinetically trapping molecular mixtures of cyano-OPVs and amorphous host materials in a thermodynamically unstable glassy state, which spontaneously phase separates when the material is heated above its glass transition. A similar mechanism can be applied to hygroscopic polyamides where exposing an initially quenched blend to water would plasticize the polyamide, and trigger the self-assembly of sensor molecules. The sensing approach bears significant potential for exploitation in safety and security applications, for example low-cost materials with built-in indicators that provide an early failure warning, evidence for tampering, or exposure to inappropriate temperatures or moisture.
Pictures of stimuli-responsive cyano-OPV/polymer blends exposed to (a) mechanical deformation, (b) temperatures above the polymer’s Tg, and (c) water. Blends undergo PL color changes due to a difference in the extent of aggregation of the dye molecules upon exposure to stimuli. The samples are shown under illumination with UV light of a wavelength of 365 nm.

Thermo-responsive Behavior of Polymeric Systems based on Hyperbranched Aliphatic Polyesters

Dendritic polymers possess unusual structures and exhibit properties that differ dramatically from the properties of linear polymers. Dendritic macromolecules exhibit compact globular structures which lead to their low viscosity in the melt or in the solution. Furthermore, dendritic macromolecules are characterized by very large number of available functional groups, which lead to unprecedented freedom for changing/tuning/tailoring the properties of these multivalent scaffolds via complete or partial derivatization with other chemical moieties. However, in contrast to linear polymers, the lack of chain entanglements between the dendritic units makes dendritic polymers very weak when in the bulk. So, for making functional films and coatings, dendritic macromolecules must be chemically or physically cross-linked.
The focus of this research program is directed towards development of advanced, stimuli-responsive polymeric materials via cross-linking and/or functional derivatization of commercially available hyperbranched polyester, BoltornTM H40. Current presentation consists of several interrelated topics such as probing and modeling using molecular dynamics simulation protocol the structure of basic dendritic polyester, in particular its unusual hydrogen bonding structure which is formed by peripheral hydroxyl groups; 1H NMR investigation of the reactivity of terminal and linear hydroxyl groups; development of cross-linked networks; preparation and study structure-property relationships in temperature responsive materials prepared via derivatization of hydroxyl moieties with crystallizable alkyl pendant groups.

One of the hallmarks of living systems is irritability, the ability to sense and respond to a potentially harmful stimulus. Among the challenges in designing synthetic biomimetic systems that exhibit analogous behavior is creating macroscopic objects that sense and respond in a prescribed manner to the “adverse” external conditions. Recently, we have developed theoretical and computational models for chemo-responsive polymer gels and through these models, have been attempting to design such adaptive systems. Our efforts are focused on a particular class of responsive gels, namely those undergoing the Belousov-Zhabotinsky (BZ) reaction. Here, we show that by harnessing the inherent properties of these polymer networks, it is possible to design active coatings that emit a chemical “alarm signal” and directed motion in response to a mechanical impact. More specifically, we show that such active coatings respond to a spatially localized mechanical force by exhibiting a range of signaling behavior. For example, an initially stationary gel can emit transient waves in response to a sufficiently weak, localized impact. A stronger localized impact, however, can generate a global signal, which encompasses both chemical waves and surface ripples that propagate across the entire sample. This complex dynamical response persists even after the force is lifted; the spatial patterns formed reveal the location and magnitude of the applied force. In the second part of the presentation, we show that BZ gels also respond in a prescribed manner to an external non-uniform illumination. We demonstrate how one can design a polymeric “worm” that moves away from light of a certain wavelength, which is an adverse stimuli for the BZ reaction.

Using Monte Carlo simulations we studied formation of reversible metallo-supramolecular networks based on 3:1 ligand–metal complexes between end-functionalized oligomers and lanthanide or transition metal ions. The fraction of 1:1, 2:1 and 3:1 ligand–metal complexes in reversibly associated structures was analyzed as a function of oligomer concentration,
c and metal-to-oligomer ratio. We studied the onset of network formation, which occurs in a limited range of metal-to-oligomer ratios at sufficiently large oligomer concentrations as well as the properties of metallo-supramolecular networks. We found that the mesh size of the network decreases with oligomer concentration and reaches its minimum at the stoichiometric composition, where the high-frequency elastic plateau modulus approaches its maximal value. At high oligomer concentrations the elastic plateau modulus follows a c1.8 concentration dependence, similar to recent experimental results for metallo-supramolecular networks. For transition-metal based supramolecular polymers we investigated the influence of cis-trans isomerization of 2:1 ligand-metal complexes on formation and properties of metallo-supramolecular networks. We found that metallo-supramolecular polymers containing a substantial fraction of cis- isomers exhibit a higher average molecular weight and allow formation of reversible network in a wider range of metal-to-oligomer ratios at lower oligomer concentrations than the corresponding polymers preferentially containing trans-isomers. The cis-trans isomerization also significantly influences the elastic properties of metallo-supramolecular network such as elastic plateau modulus. We show that the sol-to-network transition can be induced by trans-cis isomerization in a large range of oligomer number densities and metal-to-oligomer ratios. Our results indicate that the most dramatic change in material properties can be observed in the metal-rich region. These switchable properties of metallo-supramolecular networks suggest interesting application opportunities.

Interaction of Protein Building Blocks and Surfactants with Shaped Surfaces of Au, Pd, and Silica in Aqueous Solution

The nature of molecular interactions involved in the binding of amino acids and short peptides (8-12 aa) to metal surfaces in aqueous solution can be explained as a soft epitaxial process on the basis of molecular dynamics simulation and experimental data. Binding energies are also influenced by the surface shape, e.g., small spherical nanoparticles (diameter <3 nm) attract peptides binding to even surfaces to a much lesser extent, and stepped surfaces can exhibit an increased attraction of peptides such as Tyr-12. Besides, polarization effects on even metal surfaces are estimated to contribute about 1 kcal/mol per amino acid to the total binding energy. We also show progress of the binding mechanism of peptides to regular and amorphous Q3 and Q2 surfaces of silica, including an analysis of conformational changes and computed NMR data. Individual peptides such as His-4 show much weaker affinity to the surface compared to metals and adsorption binding is more strongly observed for agglomerations of peptides.

Hydrogel-based PiezoreSistive Biochemical Microsensors for Real Time Monitoring of Organic and Inorganic Analytes

The application of “stimuli-responsive” or “smart” cross-linked copolymers of N-isopropylacrylamide in biochemical sensors is based on their ability to a phase transition under the influence of external excitations (pH, concentration of additives in water, temperature). Combining a smart hydrogel and a micro fabricated pressure sensor chip in piezoresistive biochemical sensors allows to continuously monitor the analyte-dependent swelling of a hydrogel and hence the analyte concentration in ambient aqueous solutions. The sensitivity of hydrogels with regard to the concentration of such additives as H+-ions (pH sensor), transition-metal ions, salts, organic compounds and proteins in water was investigated at different temperatures. It has been demonstrated that the sensor’s sensitivity depends on the polymer composition as well as on the polymer cross-linking degree. A higher sensitivity was observed for polyelectrolyte hydrogels with higher concentrations of ionizable groups. Gel stiffening was observed in the presence of protein in the solution by means of both a hydrogel-based biochemical sensor and an AFM cantilever. Not only the measuring principle was adapted to different species in aqueous solutions but also the implemented sensor has been used as an instrument for the investigation of the gel sensitivity to different external stimuli and for on-line monitoring of the gel behaviour kinetics. The measured kinetic curves have been analysed by means of appropriate models and some methods improving the properties of the chemical sensors have been proposed. The polymer film preparation conditions and measurement conditions, which are necessary for high signal reproducibility and high long-term stable sensor sensitivity, were determined.

Chemical sensors, biosensors, and other lab-on-a-chip devices are increasingly being used in biomedical fields to automate testing, monitor patients, or improve existing medical devices. Specifically, sensing systems responsive to a stimulus such as temperature, pH, glucose, oxygen, or light have been actively studied as smart materials for diagnosis and therapies. In general, chemo-/biosensing requires intimate binding events or reactions to take place either in solution or at the surfaces of sensing devices.
Light-driven processes can be used to induce reversible conformational transitions in molecules and produce surfaces with switchable behavior. In our laboratory, novel photoswitchable polymer systems bearing spiropyran (BIPSD) or spirooxazine dimers (SPOD) at the terminal of linear polymers have been prepared. Bispiro-compounds were designed to have a specific angle. Upon exposure to UV light, both bispiro-compounds showed unique transformation from spiro (Sp) to merocyanine (MC) forms, and they exhibited contrast photochromism kinetics based on the solvent polarity. Polymer systems such as spirodimer-polylactic acid, spirodimer-polycaprolactone, and several spirodimer-block copolymers, also showed repeating photochromism by UV and visible lights: a transformation from Sp to MC, further aggregation into assembled micelle structure in selective solvent of polymers, and returning to Sp form. The binding studies indicated that the dimers were highly selective to bind copper ions or an aromatic palladium catalyst. In addition, surface properties of bispiro-immobilized polymers were investigated. These new polymer systems will serve as smart devices to deliver drugs or as sensors.

Over the last decade, polymer micelles and nanoparticles have attracted an increasing interest as efficient drug delivery systems. Polymer micelles from amphiphilic block copolymers are supramolecular core-shell type assemblies of some tens of nanometers in suitable for intravenous injection. Indeed, the combination of poly(ethylene oxide) (PEO) with hydrophobic aliphatic polyesters, such as poly(e-caprolactone) (PCL) or polylactide (PLA), allows to prepare stealthy drug nanocarriers (thanks to PEO), which are biodegradable and biocompatible and capable of encapsulating a hydrophobic drug (due to the aliphatic polyester).

In this field, the inclusion of an additional pH-responsive block in the supramolecular assembly is a promising strategy to improve the targeting of tumor tissues by taking advantage of the lower pH at the vicinity of tumor cells.

Various types of pH-sensitive copolymers have been synthesized and tested as building blocks for the design of smart nanocarriers. Hybrid micelles based on the mixture of two appropriate block copolymers have been prepared and were found to be able to switch their morphology in function of the pH of each biological compartment. These hybrid systems are thus able to deliver more selectively hydrophobic drugs to the tumor cells. The use of star shaped pH sensitive copolymers has evidenced quite unique efficiency for such application.

The concept has been demonstrated with a non-degradable pH sensitive block of poly-2-vinylpyrridine, but efforts are currently focus on the synthesis of degradable pH sensitive copolymers. Click-chemistry applied to aliphatic polyesters has been extensively studied and remains a powerful technique to reach highly functional systems.