Polyelectrolyte multilayer capsules as vehicles with tunable permeability

This review is devoted to a novel type of polymer micro- and nanocapsules. The shell of the capsule is fabricated by alternate adsorption of oppositely charged polyelectrolytes (PEs) onto the surface of colloidal particles. Cores of different nature (organic or inorganic) with size varied from 0.1 to 10 mum can be used for templating such PE capsules. The shell thickness can be tuned in nanometer range by assembling of defined number of PE layers. The permeability of capsules depends on the pH, ionic strength, solvent, polymer composition, and shell thickness; it can be controlled and varied over wide range of substances regarding their molecular weight and charge. Including functional polymers into capsule wall, such as weak PEs or thermosensitive polymers, makes the capsule permeability sensitive to correspondent external stimuli. Permeability of the capsules is of essential interest in diverse areas related to exploitation of systems with controlled and sustained release properties. The envisaged applications of such capsules/vesicles cover biotechnology, medicine, catalysis, food industry, etc.     

Designer polymer-based microcapsules made using microfluidics

Filled microcapsules made from double emulsion templates in microfluidic devices are attractive delivery systems for a variety of applications. The microfluidic approach allows facile tailoring of the microcapsules through a large number of variables, which in turn makes these systems more challenging to predict. To elucidate these dependencies, we start from earlier theoretical predictions for the size of double emulsions and present quantitative design maps that correlate parameters such as fluid flow rates and device geometry with the size and shell thickness of monodisperse polymer-based capsules produced in microcapillary devices. The microcapsules are obtained through in situ photopolymerization of the middle oil phase of water-in-oil-in-water double emulsions. Using polymers with selected glass transition temperatures as the shell material, we show through single capsule compression testing that hollow capsules can be prepared with tunable mechanical properties ranging from elastomeric to brittle. A quantitative statistical analysis of the load at rupture of brittle capsules is also provided to evaluate the variability of the microfluidic route and assist the design of capsules in applications involving mechanically triggered release. Finally, we demonstrate that the permeability and microstructure of the capsule shell can also be tailored through the addition of cross-linkers and silica nanoparticles in the middle phase of the double emulsion templates.     

Thermal behavior of polyelectrolyte multilayer microcapsules. 1. The effect of odd and even layer number

The temperature-dependent behavior of hollow polyelectrolyte multilayer capsules consisting of poly(diallyldimethylammonium chloride) (PDADMAC) and poly(styrene sulfonate) (PSS) with a different number of layers was investigated in aqueous media using confocal laser scanning microscopy, scanning and transmission electron microscopy, atomic force microscopy, and elemental analysis. Capsules with an even number of layers exhibited a pronounced shrinking at elevated temperature resulting in a transition to a dense sphere, whereas capsules with an odd number of layers swelled during heating to 5-fold of their initial size followed by their rupture. This effect increases for odd layer numbers and decreases for even layer numbers with increasing layer number. According to elemental analysis, an excess of PDADMAC monomers exists within the multilayers of capsules with an odd number of layers leading to a repulsion between the positive charges, whereas shells with an even number of layers have a balanced ratio between the oppositely charged polyions, so that the temperature-dependent behavior is controlled by the different interactions between polyelectrolytes and the bulk water. At a certain temperature, the polyelectrolyte material softens thus facilitating any rearrangement. Besides incubation temperature, the duration of heating has an influence on the restructuring of the multilayers.     

制备聚电解质空腔胶囊及其荧光蛋白装载

以三聚氰胺甲醛(MF)微粒为模板,采用逐层静电自组装技术交替吸附聚苯乙烯磺酸钠(PSS)和聚烯丙基胺盐酸盐(PAH),得到具有核壳结构的复合式微球,然后通过pH=1的盐酸溶液除去中心模板,得到直径约为3～4μm的空腔胶囊.使用藻红蛋白作为探针分子,通过比较空腔胶囊装载前后荧光强度的变化,发现pH在4～5之间时,胶囊呈现最大的蛋白装载量.pH在6～10的范围内,藻红蛋白在胶囊上的装载量几乎不变.pH3时,装载能力很差.此外,通过荧光共聚焦显微镜对不同pH条件下的蛋白装载规律进行了成像分析.一部分藻红蛋白在pH=4的条件下通过扩散进入了胶囊的内部,而pH=7的条件下,藻红蛋白不进入胶囊内部,而是吸附在表面.     

Triple-ion interactions for the construction of supramolecular capsules

A novel type of [2+4] capsules based on triple-ion interactions was obtained. Four monovalent anions (bromide, nitrate, acetate, and tosylate) bring together two tetrakis(pyridiniummethyl)tetramethyl cavitands by pyridinium-anion-pyridinium interactions. ESI-MS experiments have confirmed the capsule structure due to different fragmentation pathways of triple ions, cations, and ion-pairs. Each capsule encapsulates one or two anions, depending on its size. The capsules exist in equilibrium with hemicapsules containing three walls. The latter form complexes with phenols and anilines to give new unsymmetrical capsules containing both pyridinium-anion-pyridinium and pyridinium-guest-pyridinium walls.     

Effect of shear stress on adhering polyelectrolyte capsules

A parallel plate flow chamber was implemented to study the deformation and adhesion of individual spherical hollow polyelectrolyte multilayered shells adhering to a coated surface. The device provides a well-defined laminar flow allowing the determination of the shear stress to which the capsules are being exposed up to 15 N/m(2). The results of the investigations indicate a strong dependence of the adhesion and mechanical resistance on the capsule size and wall thickness. Thin walled capsules, constituted of 8 polyelectrolyte layers (thickness congruent with 12 nm), are immediately deformed when exposed to flow while thick capsules, constituted of 16 layers (thickness congruent with 24 nm), of equal dimensions are detached from the surface for drag forces below 50 nN. It was observed that adhering capsules exposed to flow undergo an increase in their adhesion area in the direction of flow, resulting in rolling of the capsules. It was also found that the resistance of the capsules decreases after acetone treatment, indicating a weakening of the polyelectrolyte multilayer structure in the presence of this solvent.     

Single-component layer-by-layer weak polyelectrolyte films and capsules: Loading and release of functional molecules

Poly(carboxylic acid) hydrogel films and hollow capsules undergo reversible size changes in response to variations in pH and/or ionic strength. The films and capsules were obtained from hydrogenbonded poly-N-vinylpyrrolidone/poly(carboxylic acid) layer-by-layer films by chemical crosslinking of the polyacid, followed by pH-induced removal of poly-N-vinylpyrrolidone. Surface-attached hydrogel films present attractive matrices for reversible pH-stimulated loading and/or controlled release of large amounts of synthetic or natural macromolecules including proteins. By varying acidity of poly(carboxylic acids), the hydrogel swelling and the corresponding values of pH for encapsulation/release of functional molecules could be tuned in a wide range from pH 5 to 10. In addition, the capsules are capable of entrapping macromolecules by “locking” the capsule wall with an electrostatically associating polycation, followed by the release of the encapsulated macromolecules at high salt concentrations. The text was submitted by the authors in English.     

Modular assembly of layer-by-layer capsules with tailored degradation profiles

Herein we report the preparation of layer-by-layer (LbL) assembled, biodegradable, covalently stabilized capsules with tunable degradation properties. Poly(L-glutamic acid) modified with alkyne moieties (PGA(Alk)) was alternately assembled with poly(N-vinyl pyrrolidone) (PVPON) on silica particles via hydrogen-bonding. The films were cross-linked with a bis-azide linker, followed by removal of the sacrificial template and PVPON at physiological pH through hydrogen bond disruption, yielding one-component PGA(Alk) capsules. To control the kinetics and location of capsule degradation, a number of approaches were investigated. First, a degradable bis-azide cross-linker was incorporated into the inherently enzymatically degradable capsules. Second, we assembled low-fouling capsules composed of nondegradable poly(N-vinyl pyrrolidone-ran-propargyl acrylate) (PVPON(Alk)) via hydrogen bonding with poly(methacrylic acid) (PMA) and combined this with the aforementioned system (PGA(Alk)/PVPON) to produce stratified hybrid capsules. The degradation profiles of these stratified capsules can be closely controlled by the number as well as the position of nondegradable barrier layers in the systems. The facile tailoring of the degradation kinetics makes this stratified LbL approach promising for the design of tailored drug-delivery vehicles.     

Polymer microcapsules with a fiber-reinforced nanocomposite shell

Polymer microcapsules can be used as controlled release systems in drugs or in foods. Using layer-by-layer adsorption of common food proteins and polysaccharides, we produced a new type of microcapsule with tunable strength and permeability. The shell consists of alternating layers of pectin and whey protein fibrils, yielding a fiber-reinforced nanocomposite shell. The strength can be tightly controlled by varying the number of layers or the density and length of the fibrils in the protein layers. The mechanical stability of these microcapsules appears to be superior to that of currently available multilayer capsules. The method involves only standard unit operations and has the potential for scaling up to industrial production volumes.     

Reversible pH‐Dependent Properties of Multilayer Microcapsules Made of Weak Polyelectrolytes

Summary: We investigated microcapsules composed of the weak polyelectrolytes poly(allylamine hydrochloride) (PAH) and poly(methacrylic acid) (PMA) assembled on calcium carbonate cores. These capsules are stable in the pH range from 2.5 to 11.5, undergoing reversible swelling in the pH interval from 2.7 to 2.6. Capsule swelling occurs at a protonation degree above 90%. The pH‐dependent size variation of PAH/PMA capsules is blocked after crosslinking of the polyelectrolyte layers.

Schematic of the swelling and de‐swelling of the capsules with changing pH.     

Influence of the temperature on polyelectrolyte microcapsules: Light scattering and confocal microscopy data

The influence of heating on polyelectrolyte (PE) microcapsules consisting of an even or uneven number of alternating layers of poly(allylamine) and poly(styrenesulfonate) is investigated by the light scattering and confocal microscopy techniques. In the formation of PE microcapsules, CaCO₃ microspherulites are used as “core” dispersed particles. It is established that the capsules decrease in size with increasing temperature and time of heating, irrespective of whether they consist of an even or uneven number of layers. The sensitivity of PE microcapsules to heat is estimated in terms of the activation energy of changes in parameters of their initial structure on heating. It is shown that PE microcapsules consisting of an uneven number of layers are more sensitive to heating as compared to those consisting of an even number of layers. A plausible mechanism is proposed for changes in structure parameters of the microcapsules on heating.     

胶束增强型聚电解质胶囊对罗丹明B的包埋和释放

研究了胶束增强型的聚电解质胶囊对正电荷小分子罗丹明B的包埋和释放情况. 胶囊对正电荷水溶性物质罗丹明B的包埋动力学和包埋量的研究结果表明, 这种胶束增强型聚电解质胶囊能够快速而高效地包埋水溶性物质. 释放研究结果表明, 胶囊在不同的pH条件下的释放行为有一定的区别, 但趋势相同, 分为突释区、释放诱导区、快速释放区和缓释区, 呈现多区释放, 前期胶囊的突释现象相当明显. 同时, 盐离子的浓度对胶囊的释放行为影响不大.     

Balance of hydrophobic and electrostatic forces in the pH response of weak polyelectrolyte capsules

A detailed study of the role of solution pH and ionic strength on the swelling behavior of capsules composed of the weak polyelectrolytes poly(4-vinylpyridine) (P4VP) and poly(methacrylic acid) (PMA) with different numbers of layers was carried out. The polyelectrolyte layers were assembled onto silicon oxide particles and multilayer formation was followed by zeta-potential measurements. Hollow capsules were investigated by scanning electron microscopy and atomic force microscopy. The pH-dependent behavior of P4VP/PMA capsules was probed in aqueous media using confocal laser scanning microscopy. All systems exhibited a pronounced swelling at the edges of stability, at pHs of 2 and 8.1. The swelling degree increased when more polymer material was adsorbed. The swollen state can be attributed to uncompensated positive and negative charges within the multilayers, and it is stabilized by counteracting hydrophobic interactions. The swelling was related to the electrostatic interactions by infrared spectroscopy and zeta-potential measurements. The stability of the capsules as well as the swelling degree at a given pH could be tuned, when the ionic strength of the medium was altered.     

Incorporation of block copolymer micelles into multilayer films for use as nanodelivery systems

This work demonstrates the potential application of stimulus responsive block copolymer micelles as triggerable delivery systems for use within multilayer films. Cationic, pH-responsive micelles of poly[2-(dimethylamino)ethyl methacrylate-block-poly(2-(diethylamino)ethyl methacrylate)] (PDMA-PDEA) were deposited on anionic polystyrene latex particles. The charge reversal of the surface and the amount of adsorbed polymer were monitored by zeta potential measurements and colloidal titrations, respectively. Prior to adsorption, the PDMA-PDEA micelles were loaded with a hydrophobic dye, and UV-vis spectroscopy was used to determine the amount of dye encapsulated within a monolayer of micelles. It was found that subtle chemical modification of the PDMA-PDEA diblock copolymer via permanent quaternization of the PDEA block results in micelles with tunable loading capacities. Multilayers of cationic micelles of partially quaternized PDMA-PDEA and anionic polyelectrolyte (poly(sodium 4-styrene sulfonate)) were deposited on the surface of polystyrene latex particles by sequential adsorption. UV-vis analysis of the dye present within the multilayer after the addition of each layer demonstrates that the micelles are sufficiently robust to retain encapsulated dye after multiple adsorption/washing cycles and can thus create a film that can be increasingly loaded with dye as more micelle layers are adsorbed. Multiple washing cycles were performed on micellar monolayers of PDMA-PDEA to demonstrate how such systems can be used to bring about triggerable release of actives. When performing several consecutive washing steps at pH 9.3, the micelle structure of the PDMA-PDEA micelles in the monolayer is retained, resulting in only a small reduction in the amount of encapsulated dye. In contrast, washing at pH 4, the structure of the micelle layers is severely disrupted, resulting in a fast release of the encapsulated dye into the bulk. Finally, if a sufficient number of micelle/homopolyelectrolyte layers are adsorbed, it is possible to selectively dissolve the latex template, resulting in hollow capsules.     

Microcapsules made of weak polyelectrolytes: templating and stimuli-responsive properties

Hollow microcapsules composed of the weak polyelectrolytes poly(allylamine hydrochloride) (PAH) and poly(methacrylic acid) (PMA) are templated on silicon oxide particles using the layer-by-layer adsorption. The colloidal template is removed with a buffer system of hydrofluoric acid and ammonium fluoride. With this buffer system, the template can be dissolved in mild pH conditions, where the polymeric layers are still stable. The morphology and the thickness of the resulting capsules are investigated with atomic force microscopy. The resulting hollow capsules show pH-dependent properties. The shells are stable over a broad pH range and swell and immediately dissolve for pH values below 2.3 and above 11. If the molecular weight of the poly(methacrylic acid) is increased, the enhanced entanglement of the polymers results in a reversible swelling of the capsules at low and at high pH. The swelling degree is probed with confocal laser scanning microscopy. In addition to the pH-dependent size variations, the different ionization degree of poly(methacrylic acid) as a function of pH is used for the selective binding of calcium ions.     

Nano engineered biodegradable capsules for the encapsulation and kinetic release studies of ciprofloxacin hydrochloride

Polyelectrolyte based nano and micro capsules have been extensively studied as promising drug carrier in recent years. Natural degradable capsules have received great deal of attention due to their fascinating structural and morphological characteristics, biocompatibility, sustained and targeted-release capabilities. In this work, chitosan - dextran sulphate nano capsules were prepared via Layer-by-Layer (L-b-L) technique using sacrificial template for drug delivery applications. The loading and in vitro release studies were performed using ciprofloxacin hydrochloride as a model drug. The release media used in the study are plain water and Phosphate Buffered Saline (PBS). The optimum drug load was 389 ​μg, at a loading pH of 2.1 and a temperature of 25 ​°C for 50 ​min encapsulation time. The drug loaded capsules exhibited a slow and sustained release up to 24 ​h and the maximum release rate was obtained at pH 1.2 in water and pH 7.4 in PBS. Least amount of drug release occurred at pH 5.0 in both the release media. The amounts of drug release in water at pH 1.2, pH 5.0 and pH 7.4 are 309 ​μg, 163 ​μg and 251 ​μg respectively where as the corresponding values in the case of PBS (at pH 1.2, pH 5.0 and pH 7.4) are 236 ​μg, 198 ​μg and 251 ​μg respectively. Two different models namely, Ritger - Peppas and Higuchi models were chosen to study the release kinetics behaviour of ciprofloxacin hydrochloride. The prepared bio-degradable capsules had potential as drug carrier for targeting antibacterial drugs with diverse functionality.     

A bioinspired 4D printed hydrogel capsule for smart controlled drug release

With the ever-increasing demands for personalized drugs, disease-specific and condition-dependent drug delivery systems, four-dimensional (4D) printing can be used as a new approach to develop drug capsules that display unique advantages of self-changing drug release behavior according to the actual physiological circumstances. Herein, a plant stomata-inspired smart hydrogel capsule was developed using an extrusion-based 4D printing method, which featured with UV cross-linked poly(N-isopropylacrylamide) (PNIPAM) hydrogel as the capsule shell. The lower critical solution temperature (LCST) of the PNIPAM hydrogels was approximately 34.9 °C and macroporous PNIPAM hydrogels were prepared with higher molecular weight polyethylene glycols (PEGs) as the pore-forming agents. Owing to the LCST-induced shrinking/swelling properties, the prepared PNIPAM hydrogel capsules exhibited temperature-responsive drug release along with the microstructure changes in the PNIPAM hydrogels. The in vitro drug release test confirmed that the PNIPAM hydrogel capsules can autonomously control their drug release behaviors on the basis of ambient temperature changes. Moreover, the increased PEG molecular weights in the macroporous PNIPAM hydrogel capsules caused an obvious improvement of drug release rate, distinctly indicating that the drug release profiles can be well programmed by adjusting the internal pore size of the hydrogel capsules. In vitro biocompatibility studies confirmed that the PNIPAM hydrogel capsules have great potential for biomedical applications. The bioinspired 4D printed hydrogel capsules pioneer the paradigm of smart controlled drug release.     

Prussian blue nanocontainers: selectively permeable hollow metal-organic capsules from block ionomer emulsion-induced assembly

Hollow polymer-based particles are useful for the encapsulation, protection, and release of active compounds. Adding a metal-organic coordination framework shell to nanocontainers is an attractive goal because it should help control their stability and permeability while yielding new properties and functions. We have discovered that polymer capsules with a Prussian blue analogue inner shell can be synthesized by emulsion-induced assembly of a metal-containing amphiphilic block ionomer. The capsules are selectively permeable and were used as nanocontainers to encapsulate and release a model compound. Further, these nanomaterials are tunable in size and organize into 2-D close-packed arrays in the solid state. Potential applications for these materials include the encapsulation and nanopatterning of pharmaceutical, biological, and catalytic compounds.     

Self-assembled polymer membrane capsules inflated by osmotic pressure

We fabricate and characterize capsules that are composite membranes, made of a polymer network stabilized by adsorption to colloids and inflated by osmotic pressure from internal free polyelectrolyte; here, poly-l-lysine forms the network and inflates the capsules. To assess these capsules' properties and structure, we deform capsules using microcantilevers and use finite element modeling to describe these deformations. Additional experimental tests confirm the model's validity. These capsules' resilient response to mechanical forces indicates that loading and shear should be good triggers for the release of contents via deformation. The osmotic pressure inflating these capsules has the potential to trigger release of contents via deflation in response to changes in the capsules' environment; we demonstrate addition of salt as a trigger for deflating capsules. Because these capsules have a variety of release triggers available and the technique used to fabricate them is very flexible and allows high encapsulation efficiency, these capsules have very high potential for application in many areas.     

Characterization of the mechanical properties of cross-linked serum albumin microcapsules: effect of size and protein concentration

A microfluidic technique is used to characterize the mechanical behavior of capsules that are produced in a two-step process: first, an emulsification step to form droplets, followed by a cross-linking step to encapsulate the droplets within a thin membrane composed of cross-linked proteins. The objective is to study the influence of the capsule size and protein concentration on the membrane mechanical properties. The microcapsules are fabricated by cross-linking of human serum albumin (HSA) with concentrations from 15 to 35 % (w/v). A wide range of capsule radii (～40–450 μm) is obtained by varying the stirring speed in the emulsification step. For each stirring speed, a low threshold value in protein concentration is found, below which no coherent capsules could be produced. The smaller the stirring speed, the lower the concentration can be. Increasing the concentration from the threshold value and considering capsules of a given size, we show that the surface shear modulus of the membrane increases with the concentration following a sigmoidal curve. The increase in mechanical resistance reveals a higher degree of cross-linking in the membrane. Varying the stirring speed, we find that the surface shear modulus strongly increases with the capsule radius: its increase is two orders of magnitude larger than the increase in size for the capsules under consideration. It demonstrates that the cross-linking reaction is a function of the emulsion size distribution and that capsules produced in batch through emulsification processes inherently have a distribution in mechanical resistance.