Engineered hydrogen-bonded polymer multilayers: from assembly to biomedical applications

Over the last two decades the layer-by-layer (LbL) assembly technique has become a highly versatile platform for the synthesis of nanoengineered thin films and particles. The widespread need for highly functional and responsive materials for applications in biomedicine-such as drug and gene delivery-has recently led to considerable efforts in the assembly of LbL materials, particularly films that can be subsequently stabilised and functionalised through a range of chemistries. In this tutorial review, recent developments in hydrogen-bonded LbL-assembled materials will be discussed, focusing on the design of materials with enhanced stimuli-responsive characteristics. Emphasis will be given to materials engineered for biomedical applications, specifically films/capsules that afford controlled loading and release of therapeutic cargo for application in vitro and in vivo.     

Layer-by-layer assembled microgel films with high loading capacity: reversible loading and release of dyes and nanoparticles

Multilayer films containing microgels of chemically cross-linked poly(allylamine hydrochloride) (PAH) and dextran (named PAH-D) were fabricated by layer-by-layer deposition of PAH-D and poly(styrene sulfonate) (PSS). The successful fabrication of PAH-D/PSS multilayer films was verified by quartz crystal microbalance measurements and cross-sectional scanning electron microscopy. The as-prepared PAH-D/PSS multilayer films can reversibly load and release negatively charged dyes such as methyl orange (MO) and fluorescein sodium and mercaptoacetic acid-stabilized CdTe nanoparticles. The loading capacity of the film for MO can be as large as approximately 3.0 microg/cm2 per bilayer, which corresponds to a MO density of 0.75 g/cm3 in the film. The high loading capacity of the PAH-D/PSS films originates from the cross-linked film structure with sufficient binding groups of protonated amine groups, as well as their high swelling capability by solvent. The loaded material can be released slowly when immersing the films in 0.9% normal saline. Meanwhile, the PAH-D/PSS multilayer films could deposit directly on either hydrophilic or hydrophobic substrates such as quartz, polytetrafluoroethylene, polystyrene, poly(ethylene terephthalate), and polypropylene. The microgel films of PAH-D/PSS are expected to be widely useful as matrixes for loading functional guest materials and even for controlled release.     

Micropatterning of polymer thin films with pH-sensitive and cross-linkable hydrogen-bonded polyelectrolyte multilayers

Polyelectrolyte multilayers of poly(acrylic acid) (PAA) and polyacrylamide (PAAm) were prepared via hydrogen-bonding interactions. These multilayers as assembled were stable at low pH but dissolved quickly in neutral pH water. We developed methods for stabilizing these multilayers to high pH through cross-linking by heating or UV-irradiation. Thermal treatment of the multilayers, which resulted in a partial imidization between carboxylic acid and amide groups, gave the multilayer good stability at high pH. In addition, we introduced photoreactive groups in the multilayer, which rendered the film insoluble after UV irradiation. Using these selective stabilization approaches, we have succeeded in micropatterning these films by ink-jet printing and photolithography to create subtractive patterns.     

Radiation preparation and diffusion behavior of thermally reversible hydrogels

Temperature sensitive PolyNIPAAm hydrogels in the form of rod were prepared from the binary system of NIPAAm/water and ternary system of NIPAAm/Bis/water by γ-irradiation with ⁶⁰Co source at room temperature, respectively. The prepared hydrogels had obvious temperature sensitivity (LCST is about 35.0 °C) and suitable mechanical properties. The incorporation of cross-linking agent, N, N′-methylene-bisacrylamide (Bis), into the binary system of monomer/water reduced the gelation dose. The maximum swelling ratio of hydrogels was decreased with the increasing of dose or the incorporation of Bis. The diffusion behavior of water in hydrogels obtained in this work was investigated. In addition, the drug delivery of fluoro uracili (Fu-5) from the hydrogels was investigated.     

Loading and release of charged dyes using ultrathin hydrogels

The anionic dyes methyl orange (MO) and allura red (AR) were used as model drugs to assess the loading and release by layer-by-layer assembled ultrathin hydrogels prepared via the amide formation of poly(acrylic acid-co-N-isopropylacrylamide) with AAc contents of 5, 10, and 15 mol % plus poly(vinylamine hydrochloride). The amount of MO loaded was potentially controlled by changing the dye concentrations, film thickness, and AAc content of the copolymers. The release of AR was controlled by the NaCl concentration and pH. We conclude that the polymeric matrices of ultrathin hydrogels have great potential for the loading and release of charged drugs.     

Effect of structural isomerism and polymer end group on the pH-stability of hydrogen-bonded multilayers

Association of tannic acid (TA) with structurally isomeric poly(N-isopropylacrylamide) (PNIPAM) and poly(2-isopropyl-2-oxazoline) (PIPOX) has been examined at surfaces to understand the effect of different molecular arrangements in a polymer repeating unit of structural isomers on the construction and pH-stability of hydrogen-bonded multilayers. Films were fabricated using layer-by-layer (LbL) technique through hydrogen-bonding interactions primarily between carbonyl groups of neutral polymers and hydroxyl groups of TA molecules at pH 2. PIPOX and TA formed thinner and more stable films in the pH scale with a critical dissolution pH of 9 when compared to films of PNIPAM and TA with a critical pH of 8. The differences in the thickness and pH-stability were due to different conformational behavior of PNIPAM and PIPOX in water which affects the accessibility of carbonyl groups for participation in the hydrogen bonding and the number of binding sites between the polymer pairs. Addition of electrostatic interactions by introducing amino groups only at the PIPOX chain end shifted the critical dissolution pH to higher values and resulted in gradual dissolution of the films in a wide pH range of 9-12. Such films hold promise for use in biomedical field due to biocompatibility and lower critical solution temperature (LCST) behavior at near physiological temperature of PNIPAM and PIPOX together with the pH-response of the hydrogen-bonded films.     

Structure and fluorescence properties of merocyanine dyes derived from dimethylbarbituric acid

The fluorescence properties of positively and negatively solvatochromic di-, tetra-, and hexamethinemerocyanines derived from 1,3-dimethylbarbituric acid in solvents of various polarities were studied. The range of solvatofluorochromic effect for these compounds is narrower than the range of solvatochromic effect. Extension of the polymethine chain of these compounds causes in the fluorescence spectra, in contrast to the absorption spectra, an increase in vinylene shifts, a decrease in deviations, and band narrowing. The electronic structure of the merocyanines was analyzed by the AM1 method. Transitions between the ideal states (neutral polyene, polymethine, and charged polyene) were examined. The electronic structure of the merocyanines in the excited state was found to approach the cyanine limit. Its attainment accounts for a sharp increase in the quantum yields of the fluorescence and a decrease in the Stokes shifts in going to higher vinylogs, and also with an increase in the solvent polarity for positively solvatochromic merocyanines and with its decrease for the negatively solvatochromic derivatives.     

Conformational analysis of polymethine dyes derived from the 2-azaazulene

A systematic investigation of the conformational structure was performed for the series of symmetrical and unsymmetrical mono-, tri-, pentamethine cyanines, and styryl dyes bearing 2-azaazulenium terminal group. The rotation energy barriers of terminal groups were determined via the dynamic variable temperature NMR experiments. The conformational transformation energy was calculated by quantum chemical methods (B3LYP and M05-2X) both for the cases of considering the solvent influence and not tacking it into account. Based on the comparison of theoretical and experimental data, relative electron-donating abilities and geometrical features of the heterocyclic terminal groups in 2-azaazulenium dyes were estimated. The arrangement of certain heterocyclic nuclei in order of basicity by considering the results of the dynamic NMR investigations was proposed. Influence of the conjugated chain length and the solvent nature on the conformational lability of the investigated dye molecules was discussed.     

An NMR study of merocyanine-type dyes derived from barbituric acid

The 13C NMR of two solvatochromic dyes derived from a barbituric acid acceptor and dimethylaminophenyl donor fragments, compound 1 and the related merocyanine 2, were recorded in various solvents. The observed chemical-shift variations were used to interpret their structural differences and solvatochromic behavior in solution.     

Synthesis of some novel heterocyclic dyes derived from pyrazole derivatives

Diazotized aryl amines were coupled with 3-substituted 5-amino pyrazoles to produce a series of novel 3-substituted 5-amino-4-arylazopyrazoles. Also, 3-substituted 5-amino-pyrazoles were diazotized and coupled with different phenols to give the corresponding novel 3-substituted 5-aryl azo pyrazoles. These dyes were characterized by elemental analysis and spectral data, applied to different types of fibres (wool, polyester and a blend of wool/polyester as disperse dyes) and their fastness properties were evaluated.     

Magnetically assisted removal and separation of cationic dyes from aqueous solution by magnetic nanocomposite hydrogels

Magnetic poly(acrylic acid‐acrylamide‐butyl methacrylate) (P(AAB)) nanocomposite hydrogels were prepared and used as adsorbents for removal and separation of cationic dyes from aqueous solution. These magnetic P(AAB) nanocomposite hydrogels were characterized by scanning electron microscopy (SEM) and vibrating sample magnetometer (VSM). It was found that these magnetic P(AAB) nanocomposite hydrogels had magnetic responsive characters. The dynamic swelling, removal, and separation of cationic dye, crystal violet (CV), and basic magenta (BM) by these magnetic nanocomposite hydrogels were studied. The adsorption capacity and isotherm studies of cationic dyes onto magnetic P(AAB) nanocomposite hydrogels have been evaluated. The magnetic P(AAB) nanocomposite hydrogels containing Fe₃O₄ particles can be easily manipulated in magnetic field for removal and separation of cationic dyes from aqueous solution. Adsorption process agreed very well with the Langmuir and Freundlich models. Copyright © 2010 John Wiley & Sons, Ltd.     

A new model of protein adsorption kinetics derived from simultaneous measurement of mass loading and changes in surface energy

We describe a novel technology based on changes in the resonant frequency of an acoustically actuated surface and use it to measure temporal changes in the surface energy gamma (N m(-1)) of an elastomeric polymer membrane due to the adsorption of macromolecules from aqueous solution. The resonant elastomeric surface-tension (REST) sensor permits simultaneous determination of mass loading kinetics and gamma(t) for a given adsorption process, thereby providing a multivariable data set from which to build and test models of the kinetics of adsorption at solid-liquid interfaces. The technique is used to measure gamma(t) during the adsorption of either sodium dodecyl sulfate (SDS) or hen egg-white lysozyme (HEWL) onto an acrylic polymer membrane. The adsorption of SDS is reversible and is characterized by a decrease in gamma over a time period that coincides with that required for the mass loading of the membrane. For the adsorption of HEWL labeled with Alexa Fluor 532 dye, gamma continues to change long after the surface concentration of labeled HEWL, measured by using the elastomeric polymer membrane as an optical waveguide, reaches steady state. Gradual but significant changes in gamma(t) are observed as long as the concentration of protein in the bulk solution, c(b), remains nonzero. HEWL remains adsorbed to the membrane when c(b) = 0, but changes in gamma(t) are not observed under this condition, indicating that the interaction of bound protein molecules with those free in solution contribute to the prolonged change in the surface energy. This observation has been used to define a new model for the kinetics of globular protein adsorption to a solid-liquid interface that includes a mechanism by which the molecules in the bulk can facilitate the desorption of a sorbate molecule or change the energetic states of adsorbed molecules and, thus, the overall surface energy. The model is shown to capture the unique features of protein adsorption kinetics, including the relatively fast mass loading, the much more gradual change in surface energy that does not cease until the protein is removed from the bulk, the rapid desorption of an incubation-time-dependent fraction of bound protein when the protein is removed from the bulk, and the fixing of the residual surface concentration and surface energy at constant values once the removal of reversibly bound protein and free protein is complete.     

Hydrogels as reaction vessels: acenaphthylene dimerization in hydrogels derived from bile acid analogues

Many chemical reactions which are otherwise clean often lead to the formation of multiple products. Such products may be formed due to a lack of chemo-, regio- and/or stereoselectivity. For such reactions to be useful, one should be able to control them to yield a single desired product. Of the many approaches used in this context, the use of reaction media with features different from those of isotropic solutions has been very effective. Surfactant micelles have been shown to control the product selectivity in photochemical reactions, but the dynamic nature of the micelles probably results in differential effects on reaction selectivity. In this article we provide the results on photodimerization reactions performed in bile salt gels.     

Release of bioactive volatiles from supramolecular hydrogels: influence of reversible acylhydrazone formation on gel stability and volatile compound evaporation

In the presence of alkali metal cations, guanosine-5'-hydrazide (1) forms stable supramolecular hydrogels by selective self-assembly into a G-quartet structure. Besides being physically trapped inside the gel structure, biologically active aldehydes or ketones can also reversibly react with the free hydrazide functions at the periphery of the G-quartet to form acylhydrazones. This particularity makes the hydrogels interesting as delivery systems for the slow release of bioactive carbonyl derivatives. Hydrogels formed from 1 were found to be significantly more stable than those obtained from guanosine. Both physical inclusion of bioactive volatiles and reversible hydrazone formation could be demonstrated by indirect methods. Gel stabilities were measured by oscillating disk rheology measurements, which showed that thermodynamic equilibration of the gel is slow and requires several cooling and heating cycles. Furthermore, combining the rheology data with dynamic headspace analysis of fragrance evaporation suggested that reversible hydrazone formation of some carbonyl compounds influences the release of volatiles, whereas the absolute stability of the gel seemed to have no influence on the evaporation rates.     

Syntheses and characterization of physically crosslinked hydrogels from dithiocarbamate‐derived polyurethane macroiniferter

A dithiocarbamate (DC)‐based polyurethane macroiniferter (PUMI) was synthesized and used to prepare physically crosslinked polyurethane‐block‐poly (acrylamide) (PU‐b‐PAAm) and polyurethane‐block‐poly(vinyl pyrrolidone) (PU‐b‐PVP) hydrogels. The success of the reactions has been confirmed by FTIR, ¹H‐NMR, and ¹³C‐NMR Spectroscopy analyses. The number average molecular weight of the block copolymers increased linearly with conversion and copolymerization time and thus followed a “living” radical mechanism. The water transport behavior of these polyurethane‐based hydrogels such as water uptake rate, equilibrium water content (EWC), transport number (n), characteristic diffusion rate constant (K), diffusion coefficient (D), and pH effect on EWC has been investigated. The results revealed that PU‐b‐PAAm hydrogels followed Fickian diffusion suggesting diffusion controlled swelling kinetics, whereas the PU‐b‐PVP hydrogels followed non‐Fickian diffusion indicating that both diffusion and structural relaxation controlled the water transport. The PU‐b‐PAAm hydrogels showed higher swelling at both low and high pH than at a neutral pH. This is attributed to protonation of the tertiary amines of N,N′‐diethyl‐N,N′‐bis(2‐hydroxyethyl) thiuram disulfide (DHTD) at low pH and base hydrolysis of amide segments at high pH. In the thermogravimetric analysis; PUMI, PU‐b‐PVP and PU‐b‐PAAm have degraded in three distinct stages related to CS₂ evolution, hard segment degradation, and soft segment degradation. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 6272–6284, 2008     

Polymer/colloid surface micromachining: micropatterning of hybrid multilayers

Fabrication of multicomponent patterned films comprising polymer/nanoparticle multilayers using conventional lithography and bottom-up layer-by-layer nanofabrication techniques is described. The work is motivated by the potential to extend polymer surface micromachining capabilities toward construction of integrated systems by connecting discrete domains of active materials containing functional nanoparticles. Modified surfaces illustrate tunability of the physical (thickness, roughness, 3D structures) and chemical (inorganic/organic material combinations) properties of the nanocomposite micropatterns. Intriguing nanoscale phenomena were observed for the structures when the order of material deposition was changed; the final multilayer thickness and surface roughness and mechanical integrity of the patterns were found to be interdependent and related to the roughness of layers deposited earlier in the process.     

Impacts of some macromolecules on the characteristics of hydrogels prepared from pineapple peel cellulose using ionic liquid

Composite hydrogels were prepared from pineapple peel cellulose with the combinations of polyethylene glycol (PEG), polyvinyl alcohol (PVA), к-carrageenan (CN), or soluble starch (SH) in 1-allyl-3-methylimidazolium chloride solvent. Impacts of these macromolecules on the texture profile analysis (TPA) parameters, equilibrium swelling ratio (ESR), and sodium salicylate (NaSA) load of the prepared hydrogels were studied. The NaSA release kinetics of the composite hydrogels were also compared. The composite hydrogels exhibited differences in Fourier transform infrared spectroscopy (FTIR), TPA parameters, ESR, NaSA load ratio, and release kinetics. CN addition increased the hardness of the hydrogels, while PEG played an opposite role. SH and PVA could decrease hardness, gumminess, and resilience, and SH could increase the springiness and cohesiveness of the hydrogels. Most of the composite hydrogels exhibited the same basic FTIR features as the simple hydrogel. Freeze-dried composite hydrogels exhibited a markedly higher ESR than the oven-dried ones, and additions of PEG, PVA, CN, and SH showed the same effect. Addition of the PEG and PVA combination could lower the ESR of the hydrogels, whereas additions of the PEG and CN combination or PEG and SH combination could markedly increase the ESR of the hydrogels. Addition of PEG, PVA, CN, and SH respectively could increase the NaSA load ratio of the hydrogels. Oven-drying treatment, additions of the PEG and PVA combination or PEG and CN combination were propitious for extending the NaSA fast-release phase of the hydrogels.     

Molecules with new topologies derived from hydrogen-bonded dimers of tetraurea calix[4]arenes

Tetraurea calix[4]arenes 2 have been synthesized in which two adjacent aryl urea residues are connected to a loop by an aliphatic chain -O-(CH(2))(n)-O-. The remaining urea residues have a bulky 3,5-di-tert-butylphenyl residue and an omega-alkenyloxyphenyl residue. Since this bulky residue cannot pass through the loop, only one homodimer (22) is formed in apolar solvents, for steric reasons, in which the two alkenyl residues penetrate the two macrocyclic loops. Covalent connection of these alkenyl groups by olefin metathesis followed by hydrogenation creates compounds 3, which consist of molecules with hitherto unknown topology. Their molecular structure was confirmed by (1)H NMR spectroscopy and ESIMS, and for one example by single-crystal X-ray analysis.