Multi-responsive hydrogel structures from patterned droplet networks.

Responsive hydrogels that undergo controlled shape changes in response to a range of stimuli are of interest for microscale soft robotic and biomedical devices. However, these applications require fabrication methods capable of preparing complex, heterogeneous materials. Here we report a new approach for making patterned, multi-material and multi-responsive hydrogels, on a micrometre to millimetre scale. Nanolitre aqueous pre-gel droplets were connected through lipid bilayers in predetermined architectures and photopolymerized to yield continuous hydrogel structures. By using this droplet network technology to pattern domains containing temperature-responsive or non-responsive hydrogels, structures that undergo reversible curling were produced. Through patterning of gold nanoparticle-containing domains into the hydrogels, light-activated shape change was achieved, while domains bearing magnetic particles allowed movement of the structures in a magnetic field. To highlight our technique, we generated a multi-responsive hydrogel that, at one temperature, could be moved through a constriction under a magnetic field and, at a second temperature, could grip and transport a cargo.

DNA-Inspired Strand-Exchange for Switchable PMMA-Based Supramolecular Morphologies.

Inspired by nanotechnologies based on DNA strand displacement, herein we demonstrate that synthetic helical strand exchange can be achieved through tuning of poly(methyl methacrylate) (PMMA) triple-helix stereocomplexes. To evaluate the utility and robustness of helical strand exchange, stereoregular PMMA/polyethylene glycol (PEG) block copolymers capable of undergoing crystallization driven self-assembly via stereocomplex formation were prepared. Micelles with spherical or wormlike morphologies were formed by varying the molecular weight composition of the assembling components. Significantly, PMMA strand exchange was demonstrated and utilized to reversibly switch the micelles between different morphologies. This concept of strand exchange with PMMA-based triple-helix stereocomplexes offers new opportunities to program dynamic behaviors of polymeric materials, leading to scalable synthesis of "smart" nanosystems.

Dimensional Control and Morphological Transformations of Supramolecular Polymeric Nanofibers Based on Cofacially-Stacked Planar Amphiphilic Platinum(II) Complexes.

Square-planar platinum(II) complexes often stack cofacially to yield supramolecular fiber-like structures with interesting photophysical properties. However, control over fiber dimensions and the resulting colloidal stability is limited. We report the self-assembly of amphiphilic Pt(II) complexes with solubilizing ancillary ligands based on polyethylene glycol [PEGn, where n = 16, 12, 7]. The complex with the longest solubilizing PEG ligand, Pt-PEG16, self-assembled to form polydisperse one-dimensional (1D) nanofibers (diameters <5 nm). Sonication led to short seeds which, on addition of further molecularly dissolved Pt-PEG16 complex, underwent elongation in a "living supramolecular polymerization" process to yield relatively uniform fibers of length up to ca. 400 nm. The fiber lengths were dependent on the Pt-PEG16 complex to seed mass ratio in a manner analogous to a living covalent polymerization of molecular monomers. Moreover, the fiber lengths were unchanged in solution after 1 week and were therefore "static" with respect to interfiber exchange processes on this time scale. In contrast, similarly formed near-uniform fibers of Pt-PEG12 exhibited dynamic behavior that led to broadening of the length distribution within 48 h. After aging for 4 weeks in solution, Pt-PEG12 fibers partially evolved into 2D platelets. Furthermore, self-assembly of Pt-PEG7 yielded only transient fibers which rapidly evolved into 2D platelets. On addition of further fiber-forming Pt complex (Pt-PEG16), the platelets formed assemblies via the growth of fibers selectively from their short edges. Our studies demonstrate that when interfiber dynamic exchange is suppressed, dimensional control and hierarchical structure formation are possible for supramolecular polymers through the use of kinetically controlled seeded growth methods.

Engineering live cell surfaces with functional polymers via cytocompatible controlled radical polymerization.

The capability to graft synthetic polymers onto the surfaces of live cells offers the potential to manipulate and control their phenotype and underlying cellular processes. Conventional grafting-to strategies for conjugating preformed polymers to cell surfaces are limited by low polymer grafting efficiency. Here we report an alternative grafting-from strategy for directly engineering the surfaces of live yeast and mammalian cells through cell surface-initiated controlled radical polymerization. By developing cytocompatible PET-RAFT (photoinduced electron transfer-reversible addition-fragmentation chain-transfer polymerization), synthetic polymers with narrow polydispersity (Mw/Mn < 1.3) could be obtained at room temperature in 5 minutes. This polymerization strategy enables chain growth to be initiated directly from chain-transfer agents anchored on the surface of live cells using either covalent attachment or non-covalent insertion, while maintaining high cell viability. Compared with conventional grafting-to approaches, these methods significantly improve the efficiency of grafting polymer chains and enable the active manipulation of cellular phenotypes.

Light-Mediated Atom Transfer Radical Polymerization of Semi-Fluorinated (Meth)acrylates: Facile Access to Functional Materials.

A highly efficient photomediated atom transfer radical polymerization protocol is reported for semi-fluorinated acrylates and methacrylates. Use of the commercially available solvent, 2-trifluoromethyl-2-propanol, optimally balances monomer, polymer, and catalyst solubility while eliminating transesterification as a detrimental side reaction. In the presence of UV irradiation and ppm concentrations of copper(II) bromide and Me6-TREN (TREN = tris(2-aminoethyl amine)), semi-fluorinated monomers with side chains containing between three and 21 fluorine atoms readily polymerize under controlled conditions. The resulting polymers exhibit narrow molar mass distributions (D ≈ 1.1) and high end group fidelity, even at conversions greater than 95%. This level of control permits the in situ generation of chain-end functional homopolymers and diblock copolymers, providing facile access to semi-fluorinated macromolecules using a single methodology with unprecedented monomer scope. The results disclosed herein should create opportunities across a variety of fields that exploit fluorine-containing polymers for tailored bulk, interfacial, and solution properties.

Dual-pathway chain-end modification of RAFT polymers using visible light and metal-free conditions.

We report a metal-free strategy for the chain-end modification of RAFT polymers utilizing visible light. By turning the light source on or off, the reaction pathway in one pot can be switched between either complete desulfurization (hydrogen chain-end) or simple cleavage (thiol chain-end), respectively. The versatility of this process is exemplified by application to a wide range of polymer backbones under mild, quantitative conditions using commercial reagents.

Desulfurization-bromination: direct chain-end modification of RAFT polymers.

We report a simple and efficient transformation of thiol and thiocarbonylthio functional groups to bromides using stable and commercially available brominating reagents. This procedure allows for the quantitative conversion of a range of small molecule thiols (including primary, secondary and tertiary) to the corresponding bromides under mild conditions, as well as the facile chain-end modification of polystyrene (PS) homopolymers and block copolymers prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization. Specifically, the direct chain-end bromination of PS prepared by RAFT was achieved, where the introduced terminal bromide remained active for subsequent modification or chain-extension using classical atom transfer radical polymerization (ATRP). This transformation sets the foundation for bridging RAFT and ATRP, two of the most widely used controlled radical polymerization (CRP) strategies, and enables the preparation of chain-end functionalized block copolymers not directly accessible using a single CRP technique.

Microfibres and macroscopic films from the coordination-driven hierarchical self-assembly of cylindrical micelles.

Anisotropic nanoparticles prepared from block copolymers are of growing importance as building blocks for the creation of synthetic hierarchical materials. However, the assembly of these structural units is generally limited to the use of amphiphilic interactions. Here we report a simple, reversible coordination-driven hierarchical self-assembly strategy for the preparation of micron-scale fibres and macroscopic films based on monodisperse cylindrical block copolymer micelles. Coordination of Pd(0) metal centres to phosphine ligands immobilized within the soluble coronas of block copolymer micelles is found to induce intermicelle crosslinking, affording stable linear fibres comprised of micelle subunits in a staggered arrangement. The mean length of the fibres can be varied by altering the micelle concentration, reaction stoichiometry or aspect ratio of the micelle building blocks. Furthermore, the fibres aggregate on drying to form robust, self-supporting macroscopic micelle-based thin films with useful mechanical properties that are analogous to crosslinked polymer networks, but on a longer length scale.

Monodisperse Cylindrical Micelles and Block Comicelles of Controlled Length in Aqueous Media.

Cylindrical block copolymer micelles have shown considerable promise in various fields of biomedical research. However, unlike spherical micelles and vesicles, control over their dimensions in biologically relevant solvents has posed a key challenge that potentially limits in depth studies and their optimization for applications. Here, we report the preparation of cylindrical micelles of length in the wide range of 70 nm to 1.10 µm in aqueous media with narrow length distributions (length polydispersities <1.10). In our approach, an amphiphilic linear-brush block copolymer, with high potential for functionalization, was synthesized based on poly(ferrocenyldimethylsilane)-b-poly(allyl glycidyl ether) (PFS-b-PAGE) decorated with triethylene glycol (TEG), abbreviated as PFS-b-(PEO-g-TEG). PFS-b-(PEO-g-TEG) cylindrical micelles of controlled length with low polydispersities were prepared in N,N-dimethylformamide using small seed initiators via living crystallization-driven self-assembly. Successful dispersion of these micelles into aqueous media was achieved by dialysis against deionized water. Furthermore, B-A-B amphiphilic triblock comicelles with PFS-b-poly(2-vinylpyridine) (P2VP) as hydrophobic "B" blocks and hydrophilic PFS-b-(PEO-g-TEG) "A" segments were prepared and their hierarchical self-assembly in aqueous media studied. It was found that superstructures formed are dependent on the length of the hydrophobic blocks. Quaternization of P2VP was shown to cause the disassembly of the superstructures, resulting in the first examples of water-soluble cylindrical multiblock comicelles. We also demonstrate the ability of the triblock comicelles with quaternized terminal segments to complex DNA and, thus, to potentially function as gene vectors.

Transformation and patterning of supermicelles using dynamic holographic assembly.

Although the solution self-assembly of block copolymers has enabled the fabrication of a broad range of complex, functional nanostructures, their precise manipulation and patterning remain a key challenge. Here we demonstrate that spherical and linear supermicelles, supramolecular structures held together by non-covalent solvophobic and coordination interactions and formed by the hierarchical self-assembly of block copolymer micelle and block comicelle precursors, can be manipulated, transformed and patterned with mediation by dynamic holographic assembly (optical tweezers). This allows the creation of new and stable soft-matter superstructures far from equilibrium. For example, individual spherical supermicelles can be optically held in close proximity and photocrosslinked through controlled coronal chemistry to generate linear oligomeric arrays. The use of optical tweezers also enables the directed deposition and immobilization of supermicelles on surfaces, allowing the precise creation of arrays of soft-matter nano-objects with potentially diverse functionality and a range of applications.

Length control of supramolecular polymeric nanofibers based on stacked planar platinum(II) complexes by seeded-growth.

The formation of high aspect ratio supramolecular polymeric nanofibers from square-planar platinum(II) complexes through Pt···Pt and π-π stacking interactions has been achieved with a small width (<15 nm), tunable length, and relatively narrow length distributions up to ca. 400 nm under conditions of kinetic control using small seed fibers as initiators.

Self-assembly of "patchy" nanoparticles: a versatile approach to functional hierarchical materials.

The solution-phase self-assembly or "polymerization" of discrete colloidal building blocks, such as "patchy" nanoparticles and multicompartment micelles, is attracting growing attention with respect to the creation of complex hierarchical materials. This approach represents a versatile method with which to transfer functionality at the molecular level to the nano- and microscale, and is often accompanied by the emergence of new material properties. In this perspective we highlight selected recent examples of the self-assembly of anisotropic nanoparticles which exploit directional interactions introduced through their shape or surface chemistry to afford a variety of hierarchical materials. We focus in particular on the solution self-assembly of block copolymers as a means to prepare multicompartment or "patchy" micelles. Due to their potential for synthetic modification, these constructs represent highly tuneable building blocks for the fabrication of a wide variety of functional assemblies.

Gradient crystallization-driven self-assembly: cylindrical micelles with "patchy" segmented coronas via the coassembly of linear and brush block copolymers.

Block copolymers (BCPs) with a short crystallizable poly(ferrocenyldimethylsilane) (PFS) core-forming block self-assemble in selective solvents to afford cylindrical micelles, the ends of which are active to further growth via a process termed living crystallization-driven self-assembly (CDSA). We now report studies of the CDSA of a series of crystalline-brush BCPs with C6 (BCP(6)), C12 (BCP(12)), and C18 (BCP(18)) n-alkyl branches that were prepared by the thiol-ene functionalization of PFS-b-PMVS (PMVS = poly(methylvinylsiloxane)). Although the increased n-alkyl brush length of BCP(12) and BCP(18) hindered micelle growth, the increased intercoronal chain repulsion could be alleviated by their coassembly with linear PFS-b-PMVS. When the coassembly was initiated by short cylindrical seed micelles, monodisperse block comicelles of controllable length with "patchy" coronal nanodomains were accessible. TEM and AFM analysis of micelles prepared from BCP(18) and PFS-b-PMVS were found to provide complementary characterization in that the OsO4-stained PMVS coronal domains were observed by TEM, whereas the brush block domains of BCP(18) (which displayed greater height) were detected by tapping mode AFM. The results showed that the coassembly afforded a gradient structure, with an initial bias for the growth of the linear BCP over that of the more sterically demanding brush BCP, which was gradually reversed as the linear material was consumed. This represents the first example of living gradient CDSA, a process reminiscent of a living covalent gradient copolymerization of two different monomers. Although other possible explanations exist, simulations based on a statistical model indicated that the coronal nanodomains detected likely result from a segmented, gradient comicelle architecture that arises as a consequence of: (i) different rates of addition of BCP unimer to the micelle termini, and (ii) a cumulative effect resulting from steric hindrance associated with the brush block.

Colour-tunable fluorescent multiblock micelles.

Emerging strategies based on the self-assembly of block copolymers have recently enabled the bottom-up fabrication of nanostructured materials with spatially distinct functional regions. Concurrently, a drive for further miniaturization in applications such as optics, electronics and diagnostic technology has led to intense interest in nanomaterials with well-defined patterns of emission colour. Using a series of fluorescent block copolymers and the crystallization-driven living self-assembly approach, we herein describe the synthesis of multicompartment micelles in which the emission of each segment can be controlled to produce colours throughout the visible spectrum. This represents a bottom-up synthetic route to objects analogous to nanoscale pixels, into which complex patterns may be written. Because of their small size and high density of encoded information, these findings could lead to the development of new materials for applications in, for example, biological diagnostics, miniaturized display technology and the preparation of encoded nanomaterials with high data density.

Uniform, high aspect ratio fiber-like micelles and block co-micelles with a crystalline π-conjugated polythiophene core by self-seeding.

Monodisperse fiber-like micelles with a crystalline π-conjugated polythiophene core with lengths up to ca. 700 nm were successfully prepared from the diblock copolymer poly(3-hexylthiophene)-block-polystyrene using a one-dimensional self-seeding technique. Addition of a polythiophene block copolymer with a different corona-forming block to the resulting nanofibers led to the formation of segmented B-A-B triblock co-micelles by crystallization-driven seeded growth. The key to these advances appears to be the formation of a relatively defect-free crystalline micelle core under the self-seeding conditions.

Dimensional control of block copolymer nanofibers with a π-conjugated core: crystallization-driven solution self-assembly of amphiphilic poly(3-hexylthiophene)-b-poly(2-vinylpyridine).

With the aim of accessing colloidally stable, fiberlike, π-conjugated nanostructures of controlled length, we have studied the solution self-assembly of two asymmetric crystalline-coil, regioregular poly(3-hexylthiophene)-b-poly(2-vinylpyridine) (P3HT-b-P2VP) diblock copolymers, P3HT23-b-P2VP115 (block ratio=1:5) and P3HT44-b-P2VP115 (block ratio=ca. 1:3). The self-assembly studies were performed under a variety of solvent conditions that were selective for the P2VP block. The block copolymers were prepared by using Cu-catalyzed azide-alkyne cycloaddition reactions of azide-terminated P2VP and alkyne end-functionalized P3HT homopolymers. When the block copolymers were self-assembled in a solution of a 50% (v/v) mixture of THF (a good solvent for both blocks) and an alcohol (a selective solvent for the P2VP block) by means of the slow evaporation of the common solvent; fiberlike micelles with a P3HT core and a P2VP corona were observed by transmission electron microscopy (TEM). The average lengths of the micelles were found to increase as the length of the hydrocarbon chain increased in the P2VP-selective alcoholic solvent (MeOH3 µm) fiberlike micelles were prepared by the dialysis of solutions of the block copolymers in THF against iPrOH. Furthermore the widths of the fibers were dependent on the degree of polymerization of the chain-extended P3HT blocks. The crystallinity and π-conjugated nature of the P3HT core in the fiberlike micelles was confirmed by a combination of UV/Vis spectroscopy, photoluminescence (PL) measurements, and wide-angle X-ray scattering (WAXS). Intense sonication (iPrOH, 1 h, 0 °C) of the fiberlike micelles formed by P3HT23-b-P2VP115 resulted in small (ca. 25 nm long) stublike fragments that were subsequently used as initiators in seeded growth experiments. Addition of P3HT23-b-P2VP115 unimers to the seeds allowed the preparation of fiberlike micelles with narrow length distributions (L(w)/L(n) < 1.11) and lengths from about 100-300 nm, that were dependent on the unimer-to-seed micelle ratio.

Cylindrical micelles of controlled length with a π-conjugated polythiophene core via crystallization-driven self-assembly.

Solution self-assembly of the regioregular polythiophene-based block copolymer poly(3-hexylthiophene)-b-poly(dimethylsiloxane) yields cylindrical micelles with a crystalline P3HT core. Monodisperse nanocylinders of controlled length have been prepared via crystallization-driven self-assembly using seed micelles as initiators.

Automated covariate selection and Bayesian model averaging in population PK/PD models.

We illustrate the use of 'reversible jump' MCMC to automate the process of covariate selection in population PK/PD analyses. The output from such an approach can be used not only to determine the 'best' covariate model for each parameter, but also to formally measure the spread of uncertainty across all possible models, and to average inferences across a range of 'good' models. We examine the substantive impact of such model averaging compared to conditioning inferences on the 'best' model alone, and conclude that clinically significant differences between the two approaches can arise. The illustrative data that we consider pertain to the drug vancomycin in 59 neonates and infants, and all analyses are conducted using the WinBUGS software with newly developed 'Jump' interface installed.

A Bayesian toolkit for genetic association studies.

We present a range of modelling components designed to facilitate Bayesian analysis of genetic-association-study data. A key feature of our approach is the ability to combine different submodels together, almost arbitrarily, for dealing with the complexities of real data. In particular, we propose various techniques for selecting the "best" subset of genetic predictors for a specific phenotype (or set of phenotypes). At the same time, we may control for complex, non-linear relationships between phenotypes and additional (non-genetic) covariates as well as accounting for any residual correlation that exists among multiple phenotypes. Both of these additional modelling components are shown to potentially aid in detecting the underlying genetic signal. We may also account for uncertainty regarding missing genotype data. Indeed, at the heart of our approach is a novel method for reconstructing unobserved haplotypes and/or inferring the values of missing genotypes. This can be deployed independently or, alternatively, it can be fully integrated into arbitrary genotype- or haplotype-based association models such that the missing data and the association model are "estimated" simultaneously. The impact of such simultaneous analysis on inferences drawn from the association model is shown to be potentially significant. Our modelling components are packaged as an "add-on" interface to the widely used WinBUGS software, which allows Markov chain Monte Carlo analysis of a wide range of statistical models. We illustrate their use with a series of increasingly complex analyses conducted on simulated data based on a real pharmacogenetic example.

Bayesian hierarchical approach to estimate insulin sensitivity by minimal model.

We adopted Bayesian analysis in combination with hierarchical (population) modelling to estimate simultaneously population and individual insulin sensitivity (SI) and glucose effectiveness (SG) with the minimal model of glucose kinetics using data collected during insulin-modified intravenous glucose tolerance test (IVGTT) and made comparison with the standard non-linear regression analysis. After fasting overnight, subjects with newly presenting Type II diabetes according to World Health Organization criteria (n =65; 53 males, 12 females; age, 54 +/- 9 years; body mass index, 30.4 +/- 5.2 kg/m2; means+/-S.D.) underwent IVGTT consisting of a 0.3 g of glucose bolus/kg of body weight given at time zero for 2 min, followed by 0.05 unit of insulin/kg of body weight at 20 min. Bayesian inference was carried out using vague prior distributions and log-normal distributions to guarantee non-negativity and, thus, physiological plausibility of model parameters and associated credible intervals. Bayesian analysis gave estimates of SI in all subjects. Non-linear regression analysis failed in four cases, where Bayesian analysis-derived SI was located in the lower quartile and was estimated with lower precision. The population means of SI and SG provided by Bayesian analysis and non-linear regression were identical, but the interquartile range given by Bayesian analysis was tighter by approx. 20% for SI and by approx. 15% for SG. Individual insulin sensitivities estimated by the two methods were highly correlated ( rS=0.98; P <0.001). However, the correlation in the lower 20% centile of the insulin-sensitivity range was significantly lower than the correlation in the upper 80% centile ( rS=0.71 compared with rS=0.99; P <0.001). We conclude that the Bayesian hierarchical analysis is an appealing method to estimate SI and SG, as it avoids parameter estimation failures, and should be considered when investigating insulin-resistant subjects.