Chitosan: An Attractive Biocompatible Polymer for Microencapsulation

Chitosan is a weak cationic polysaccharide composed essentially of β(1 → 4) linked glucosamine units together with some N‐acetylglucosamine units. It is obtained by extensive deacetylation of chitin, a polysaccharide common in nature. Chitosan is a biocompatible, biodegradable, and nontoxic natural polymer that exhibits excellent film‐forming ability. As a result of its cationic character, chitosan is able to react with polyanions giving rise to polyelectrolyte complexes. Therefore, because of these interesting properties, it has become the subject of numerous scientific reports and patents on the preparation of microspheres and microcapsules. The techniques employed to microencapsulate with chitosan include, among others, ionotropic gelation, spray drying, emulsion phase separation, simple and complex coacervation, and polymerization of a vinyl monomer in the presence of chitosan. The aim of this work is to review some of the more common techniques used and to put forward the results obtained by our research group in preparing chitosan‐based microcapsules: for taste masking and improving the stability of a nutritional oil, the sustained release of drugs, as well as the preparation of chitosan superparamagnetic microcapsules for the immobilization of enzymes.

Scanning electron micrograph of some superparamagnetic chitosan particles and magnetic hysteresis loop of the microparticles.     

Drug Delivery Systems Based on Porous Chitosan/Polyacrylic acid Microspheres

Porous microspheres have been prepared by suspension free radical polymerization of acrylic acid (AA) in the presence of chitosan (CHI). The microspheres were characterized by FTIR and environmental SEM. The PAA content of the microspheres was estimated to be in the range 45–50 wt.‐%. The swelling degree of these particles is almost constant in the range 2 < pH < 5, but it increases considerably as the pH is raised from 5 to 10. The release profiles of microspheres loaded with meclofenamic acid (MF) were determined at pH 2, 7.4, and 10. The in vitro release of MF at different pHs was modulated by the solubility of the drug. These microcapsules are biodegradable and presented good biocompatibility and biodegradability during in vivo experiments.

ESEM microphotograph of the porous PAA/CHI microspheres.     

Redox‐ and Glucose‐Induced Shape‐Memory Polymers

A novel redox‐induced shape‐memory polymer (SMP) is prepared by crosslinking β‐cyclodextrin modified chitosan (β‐CD‐CS) and ferrocene modified branched ethylene imine polymer (Fc‐PEI). The resulting β‐CD‐CS/Fc‐PEI contains two crosslinks: reversible redox‐sensitive β‐CD‐Fc inclusion complexes serving as reversible phases, and covalent crosslinks serving as fixing phases. It is shown that this material can be processed into temporary shapes as needed in the reduced state and recovers its initial shape after oxidation. The recovery ratio and the fixity ratio are both above 70%. Furthermore, after entrapping glucose oxidase (GOD) in the system, the material shows a shape memory effect in response to glucose. The recovery ratio and the fixity ratio are also above 70%.

     

Controlled Chemical Modifications of Chitosan. Characterization and Investigation of Original Properties

The main techniques developed to characterize chitosan are recalled. The interaction of chitosan with oppositely charged surfactants was investigated giving very important surface activity effects. A few chemical modifications are described and the new properties obtained are mentioned: alkylation gives amphiphilic polymers having interesting thickening behavior; grafting cyclodextrin (chit‐CD) gives a polymer able to include hydrophobic molecules; grafting adamantane gives an amphiphilic polymer able to specifically interact with chit‐CD forming a temporary network with gel‐like behavior.

The viscosities of adamantane‐chitosan, cyclodextrin‐chitosan, and unmodified chitosan solutions studied here.     

Novel Electrospun Nanofibers Composed of Polyelectrolyte Complexes

A simple method to obtain novel nanofibers composed of polyelectrolyte complexes (PECs) has been proposed. It consists of the electrospinning of a mixed homogeneous solution of polyelectrolyte partners, and the formation of PEC during the electrospinning. This was achieved by careful choice of the composition of the spinning solutions. Chitosan was the polycationic partner, with either a weak polyacid [poly(acrylic acid), PAA] as a counterpart or a strong one [poly(2‐acrylamido‐2‐methylpropanesulfonic acid), PAMPS]. The fibrous mats were composed of nanofibers with mean diameters of ca. 100 nm. They retained their integrity over the pH range which is typical of the corresponding PEC.

     

Diffusion Through Membranes of the Polyelectrolyte Complex of Chitosan and Alginate

The swelling of membranes of the polyelectrolyte complex (PEC) between chitosan and alginate shows a similar pattern to that of other PECs. However, if the swelled membranes are dried, a second swelling process is seen which exhibits Fickian behavior. The apparent activation energy was estimated to be 32.8 kJ · mol^?1. The release rate of model solutes was highly dependent on their molecular weight and the pH of the medium.

Arrhenius type plot of the temperature dependence of the apparent diffusion coefficients for the membrane of the polyelectrolyte complex between chitosan and alginate in water.     

Spontaneous Birefringence in Layer‐by‐Layer Films of Chitosan and Azo Dye Sunset Yellow

Layer‐by‐layer (LBL) films consisting of layers of the azo dye Sunset Yellow alternated with chitosan display spontaneous birefringence, which is attributed to the film anisotropy imparted by the LBL method. This is unusual for azobenzene‐containing materials as they normally form films with randomly oriented molecules, presenting birefringence only due to photoinduced isomerization cycles. Spontaneous birefringence does not appear in cast films, but occurs for LBL films obtained under various experimental conditions.

Chemical structures of (a) Sunset Yellow and (b) chitosan.     

Preparation of Crosslinked Chitosan/Silk Fibroin Blend Films for Drug Delivery System

Crosslinked chitosan/silk fibroin blend films were prepared by a solution casting technique using glutaraldehyde as crosslinking agent. Drug release characteristics of the blend films with various blend compositions were investigated. Theophylline, diclofenac sodium, amoxicillin trihydrate, and salicylic acid were used as model drugs. The release studies were performed at 37 °C in buffer solutions at pH 2.0, 5.5, and 7.2. It was found that the blend films with 80% chitosan content showed the maximum amount of model drug release at pH 2.0 for all the drugs studied here. This result corresponded to the swelling ability of the blend films. From a swelling study, the maximum degrees of swelling of the drug‐loaded blend films were obtained at this pH and blend composition. The amount of drugs released from the films with 80% chitosan content, from the highest to the lowest values, occurred in the following sequence: salicylic acid > theophylline > diclofenac sodium > amoxicillin.

Comparison of the amounts of drug released from chitosan and the blend film with 80% chitosan content at pH 2.0: (filled) chitosan film, and (blank) blend film with 80% chitosan content (SAL = salicylic acid, THEO = theophylline, DFS = diclofenac sodium, AMX = amoxicillin).     

In situ Localization of Molecules in Crosslinked Particles during Electrohydrodynamic Process: Simple Route to Produce Microcapsules and Fibers with Controlled Release

This study reports a spontaneous selective localization of molecules in crosslinked particles during electrospraying and electrospinning polymer solutions containing the particles. It provides a facile way of preparing microcapsules and fibers with controlled release. The dye molecules were phase separated from the crystalline polymer matrix during the electrohydrodynamic process and moved to the solvent‐rich crosslinked particles. The position of the particles in the microcapsules and fibers could be controlled by adjusting compatibility of the particles with the matrix polymer. The microcapsules and fibers did not show the initial burst release of the molecules and gave considerably prolonged release behavior.

     

Chitosan‐Hydroxybenzotriazole Aqueous Solution: A Novel Water‐Based System for Chitosan Functionalization

Summary: A chitosan‐hydroxybenzotriazole (HOBt) aqueous solution prepared by simply mixing chitosan and HOBt in water provides an effective system to functionalize chitosan in an aqueous environment. This aqueous solution in combination with water‐soluble carbodiimide (WSC) allows the conjugation of functional groups onto chitosan under mild conditions without requiring any organic solvents or acid and heat. In this contribution, a series of model reactions that use a novel water‐based system of chitosan to functionalize the polymer with boc‐L ‐phenylalanine, poly(ethylene glycol) methyl ether, and dicarboxylated poly(ethylene glycol) is demonstrated.

Chitosan‐HOBt is effectively conjugated with R‐COOH via a water‐soluble carbodiimide (WSC) conjugating agent.     

Fabrication of Diverse Microcapsule Arrays of High Density and Good Stability

Microcapsule arrays attract a lot of interest due to their potential applications in sensing technology. A strategy for fabricating diverse microcapsule arrays through covalent linking is reported here. The self‐assembly of microcapsules was directed by using a poly(allylamine hydrochloride) (PAH)‐patterned template, which was created via microcontact printing. The microcapsules with PAH as the outermost layer were treated with glutaraldehyde and then covalently immobilized on the PAH regions, resulting in ordered microcapsule arrays. The arrays had a high density of capsules and the aggregate number in a pattern could be well controlled by adjusting the area of the PAH pattern. A single microcapsule array could be obtained if the diameter of the PAH region was smaller than that of the microcapsules. These covalently assembled arrays could survive through successive incubation in solutions of high ionic strength and extreme pHs. Such good stability ensures further treatments, such as chemical reactions and loading of functional substances.

     

Synthesis of Novel Biomimetic Zwitterionic Phosphorylcholine‐Bound Chitosan Derivative

Summary: Water‐soluble biomimetic chitosan derivative conjugating zwitterionic phosphorylcholine was efficiently prepared through Atherton‐Todd reaction under the mild conditions, and the possible formation mechanism of zwitterionic product was related to the nucleophilic attack of adjacent 3‐hydroxyl on the D ‐glucosamine residue to phosphorus with the help of base. UV absorption and melting behaviors of DNA/phosphorylcholine‐bound chitosan derivative showed that the phosphorylcholine‐bound chitosan derivative could be a new carrier for long‐circulating macromolecular drug delivery.

Structure of zwitterionic PC‐chitosan.     

Microwave Accelerated Synthesis of N‐Phenylmaleimide in a Single Step and Polymerization in Bulk

Summary: This paper reports the microwave mediated direct synthesis of N‐phenylmaleimide ( 3 ) from maleic anhydride ( 1 ) and aniline ( 2 ) by using microwave irradiation. Good yields and very short reaction times were the main aspects of the method. The reaction conditions and kinetics of this process were investigated. Microwave irradiation in a boiling solvent showed the existence of a significant specific microwave effect. The microwave homopolymerization of 3 in bulk using 2,2′‐azoisobutyronitrile (AIBN) as a free radical initiator was also carried out.

Kinetic curves for the synthesis of N‐phenylmaleimide in a MW and in an oil bath at 144 °C (boiling xylene).     

Solvent‐Responsive Behavior of Polymer‐Brush‐Modified Amphiphilic Gold Nanoparticles

Amphiphilic polymer brushes grafted onto gold nanoparticles impart distinct solvent‐responsive behavior via the change to particle size and surface chemistry and, therefore, wide application prospects can be expected. Coarse‐grained simulations are performed for block and/or mixed polystyrene (PS)/poly(ethylene oxide) (PEO)‐modified amphiphilic gold nanoparticles (AuNP) to investigate their responsive behavior in five different solvents by analyzing their morphology, distribution density profiles, and gyration radii. Typical core–shell, Janus‐type, buckle‐like, ring‐like, jellyfish‐like, and octopus‐like morphologies are formed. Influence of block sequence, mixing mode, and several other effects are discussed. Responsive particle size and surface hydrophilicity can be successfully reproduced by altering solvents.

     

Cross‐Linked Conjugated Polymers for Achieving Patterned Three‐Color and Blue Polymer Light‐Emitting Diodes with Multi‐Layer Structures

Reactions between the ethylene groups in the backbone of conjugated polymers under UV illumination and heat treatment result in the cross‐linking of the main polymer chains. The cross‐linking leads to two simultaneous results in the polymer: excellent solvent resistance and increased bandgap. Using this reaction, three‐color polymer light‐emitting diodes (PLEDs) with a multi‐layer structure can be easily realized by a dry photo‐pattern in an active‐gas‐free environment. Multi‐layer blue devices with dramatically enhanced efficiency can also be achieved conveniently.

     

Encapsulation of a Single Metal Nanoparticle with Tunable Size in a Monodisperse Polymer Microcapsule

A versatile approach to fabricate monodisperse poly[styrene‐co‐(divinyl benzene)] (PS‐co‐DVB) microcapsules that contain a single gold nanoparticle (AuNP) has been demonstrated. Using the PS‐co‐DVB microcapsule as a microreactor, aqueous HAuCl₄ and NaBH₄ solutions are subsequently infiltrated. The size of the resulting AuNP inside of the PS‐co‐DVB microcapsules is easily tunable by controlling the repeated infiltration cycles of aqueous HAuCl₄ and NaBH₄. PS‐co‐DVB microcapsules that contain a single silver and palladium nanoparticle are also obtained by following a similar protocol.

     

Synthesis and Characterization of Chitosan Grafted Oligo(L‐lactic acid)

Chitosan grafted oligo(L ‐lactic acid) copolymers with different length of side chain were prepared through the reaction of terminal aldehyde group of oligo(L ‐lactic acid) (OLLA) and amino groups of chitosan. The mean molecular mass of the grafting OLLA chain was ca. 600 ～ 5 000. The graft copolymers are soluble in DMSO, DMF and acetic acid. The synthesis method and structure described here provide chitosan‐g‐OLLA copolymers with broad applicability.

Structure of chitosan‐g‐oligo(L ‐lactic acid).     

Polyphosphazene Microcapsules Fabricated through Covalent Assembly

Hollow polyphosphazene microcapsules have been fabricated by the covalent layer‐by‐layer assembly of polydichlorophosphazene (PDCP) and hexamethylenediamine (HDA) on aminosilanized silica particles, followed by core removal in a HF/NH₄F solution. The hollow and intact microcapsules in both wet and dry states have been characterized by transmission electron microscopy and confocal laser scanning microscopy. The chemical structure of the microcapsules has been verified by FT‐IR spectroscopy. The microcapsules could be hydrolytically degraded in a phosphate buffer at biological pH.

     

Chemoenzymatic Synthesis of Amylose‐Grafted Chitosan

An amylose‐grafted chitosan has been synthesized by a chemoenzymatic method according to the following two reactions. First, maltoheptaose is introduced to chitosan by a reductive amination using sodium cyanotrihydroborate in a mixed solvent of 1.0 mol · L⁻¹ aqueous acetic acid and methanol at room temperature to produce a maltoheptaose‐grafted chitosan that has a well‐defined molecular structure. A phosphorylase‐catalyzed enzymatic polymerization of α‐D ‐glucose 1‐phosphate is then performed from the maltoheptaose‐grafted chitosan to obtain the amylose‐grafted chitosan. This material does not dissolve in any solvent, e.g., aqueous acetic acid and dimethyl sufoxide, which are good solvents for chitosan and amylose, respectively.

     

Encapsulation and Stabilization of Photo‐Sensitive Antioxidants by Using Polymer Microcapsules with Controlled Phase Heterogeneity

We describe a robust method for both encapsulating and stabilizing photo‐sensitive antioxidants in polymer microcapsules prepared by a water‐in‐oil‐in‐water double emulsification and evaporation technique, in which a volatile solvent from the oil layer consisting of poly(methyl methacrylate) and methylene chloride is gradually removed. Using poly(ethylene glycol) (PEG) in this study, we demonstrate that control over its molecular weight allows to tune the phase property of the capsule wall; introducing PEG with high molecular weight results in increased heterogeneity. The heterogeneity of the capsule walls displays an ability to effectively block sunlight, which is essential for improving the molecular stability of photo‐sensitive antioxidants. In this study, we experimentally confirm this by observing natural sunlight‐driven molecular decomposition of a model antioxidant, riboflavin‐5′‐phosphate, in poly (methyl methacrylate) microcapsules.