Porous three-dimensional polymer composites for tailored delivery of bioactives and drugs

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Porous three-dimensional polymer composites for tailored delivery of bioactives and drugs

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Geoffrey I.N. Waterhouse1,2, Linge Wang1,3 and Dongxiao Sun-Waterhouse1,2 1

School of Materials Science and Engineering, South China University of Technology, Guangzhou, P.R. China 2School of Chemical Sciences, The University of Auckland, Auckland, New Zealand 3South China Advanced Institute for Soft Matter Science and Technology, South China University of Technology, Guangzhou, P.R. China

11.1 INTRODUCTION Globally, human populations target improved health, better healthcare options, and a longer average life span. Smart and sustainable utilization of natural resources and the efficient delivery of key nutrients and bioactives to humans are critical to achieving these targets. Nature possesses an abundance of naturally occurring biomaterials such as polysaccharides (e.g., alginates, chitosans, pectins, etc.) that are nontoxic and can be sustainably sourced, which offer wide potential for the construction of three-dimensional (3-D) composites with diverse functionalities for food and biomedical applications. Alginate and chitosan are two of the most common naturally occurring polysaccharides and are attracting increased attention in the food industry and biomedical sector, in particular as encapsulating materials for the development of delivery systems for specific bioactive substances (e.g., antioxidants, enzymes, and probiotic bacteria) and drugs. Further, rapid advancements over the past decade in material processing technologies, biotechnology, and nanotechnology allow effective manipulation of natural biopolymers to deliver novel characteristics or precisely tailored physiochemical properties such as mechanical strength, surface area, porosity, charge, solubility, and chemical reactivity. For example, creating biopolymer systems in which particle sizes are reduced to micro- or nanoscales, thus affording a high surface-to-volume ratio, can significantly increase bioactive delivery efficiency, dissolution rate, bioavailability, and efficacy. For polysaccharides, both their physical and chemical properties are important for their end applications. A polysaccharide’s 3-D molecular conformation is governed by its inherent chemical structure (e.g., arrangement of atoms and functional groups) and environmental conditions [e.g., solvent, the presence of other substance(s) in the same Materials for Biomedical Engineering: Nanomaterials-based Drug Delivery. DOI: https://doi.org/10.1016/B978-0-12-816913-1.00011-8 © 2019 Elsevier Inc. All rights reserved.

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matrix such as metal cations, anions, or biological surfaces]. The molecular conformation of a polysaccharide influences its hydration kinetics (including rate and degree of hydration) and relative solubility in aqueous media (including emulsions), its particle attributes, and rheological behavior in dietary products and the gastrointestinal (GI) tract (O’Connor et al., 1981; Rees, 1977). The chemical, structural, and physical properties of polysaccharides also influence their digestibility and biological activity, as well as their impact on the uptake of other nutrients (Heppell and Rainbird, 1985; Morgan et al., 1985). The fate of a food matrix and the behavior of its individual food components in the human GI environment are closely associated with the kinetics of nutrient bioavailability. Polysaccharides, as one of the major classes of macronutrients, strongly influence GI function through their effects on the physical properties of digesta at all stages of transit along the GI tract, including the rate and extent of nutrient absorption in the small intestine and bacterial fermentation in the colon (Eastwood and Moms, 1992; Moms, 1992). The complex effect(s) of polysaccharides on the human GI tract cannot be precisely described (Ellis et al., 1996). There are simply too many physicochemical factors involved, any one of which can significantly alter the behavior of a particular polysaccharide during ingestion and digestion of polysaccharide-containing foods or supplements. The type of polysaccharide (e.g., alginate or chitosan, native or modified forms), the ingested form (structurally intact plant cell wall or isolated ingredient), as well as food product matrix or digesta matrix surrounding the polysaccharide all influence GI function and digestion. For example, the presence of polysaccharides in the gut greatly increases the viscosity of digesta and significantly slows down the transit of digesta via the propulsive motion of intestinal contractions, thereby retarding or even inhibiting physical contact between nutrients and digestive enzymes (e.g., via the formation of an enzyme-resistant barrier around starch granules) (Edwards et al., 1988; Blackburn et al., 1984). These factors can dramatically alter the digestion efficiency and bioabsorption of nutrients through biological membranes in the human GI tract (Blackburn et al., 1984; Jenkins et al., 1976). Accordingly, tailoring the properties of polysaccharides and their derived delivery systems (including formulated foods) is critical for maximizing the functionalities of polysaccharides, such as nutrients, bioactives, and carriers. This chapter systematically explores the physicochemical properties of two nutritionally and technically important polysaccharide polymers, alginate and chitosan. Then, the uses of these two natural polymers to create 3-D polymer composites for tailored delivery of bioactives and drugs using novel encapsulation technologies such as coextrusion, spray-drying, and electrospinning are described. Practical approaches to specifically tailor each biopolymer’s processing, delivery, and biological properties via controlled depolymerization and optimized formulation are introduced. Emphasis here is placed on recent developments in functionalized polymeric composites for applications related to consumer wellness. The future growth potential of alginate and chitosan products across the food and biomedical sectors is also discussed.

11.2 Natural Biopolymers: Alginate and Chitosan

11.2 NATURAL BIOPOLYMERS: ALGINATE AND CHITOSAN In this section, positively charged chitosan and negatively charged alginate are introduced as low-cost and versatile polysaccharides for creating 3-D functionalized composites. These polysaccharides exhibit different physicochemical properties owing to the nature of individual polysaccharide molecules (e.g., molecular structure, size, and charge), and the arrangement and extent of intermolecular associations of the individual polymer chains. In solutions, these biopolymers exist as conformationally disordered polymers (“random coils”), and the specific conformations determine the processing and physiological functionalities of these polysaccharides.

11.2.1 ALGINATE Alginate is a water-soluble polysaccharide. Alginate is generally described as a linear copolymer composed of two monomeric units, α-L guluronic acid and β-D mannuronic acid, although the detailed molecular compositions of alginates including block lengths and block distributions are far more complicated. The alginate molecule contains regions made up exclusively of one unit or the other, referred to as G-blocks or M-blocks, respectively, or regions in which the monomers exist in an alternating sequence (MG blocks). The calcium reactivity of alginates is a consequence of the particular molecular geometries of each of these regions (Mishra et al., 2003). The molecular weight (MW) of sodium alginates ranges from 32,000 to 400,000 g/mol (Piacentini, 2015). The carboxylic acid groups in alginates are deprotonated at a pH above the pKa value (3.4 3.5) (Piacentini, 2015; Gu et al., 2004), with the negative charges allowing alginate chains to electrostatically interact with positively charged molecules or ions, and form gels, for example, aqueous sodium alginate can form rigid gels with calcium ions or other multivalent cations. The common forms of alginates are the sodium or potassium salts of alginic acid. The addition of calcium ions to aqueous solutions of sodium or potassium alginate triggers the alignment of the G-blocks of alginate (dimeric association of the G-block regions) resulting in the formation of egg-box-like structures, wherein calcium ions have replaced the monovalent cations and induced crosslinking between the alginate chains. Both temporary and permanent interchain associations are possible, depending on the concentration of calcium ions in the target system, that is, low calcium concentrations lead to highly viscous and thixotropic solutions with temporary associations, whilst high calcium contents cause more permanent associations resulting in precipitation or gelation. Crosslinking alginate with polyvalent cations to form a gel is an effective approach for encapsulating drugs or bioactives. External gelation involves the direct extrusion of alginate bioactive or alginate drug solutions into a CaCl2 solution, whilst internal gelation involves the extrusion of a mixture of alginate bioactive or alginate drug solution and

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insoluble CaCO3 into an acidified oil phase (liberation of Ca21 on contact with acid then reacts with alginate). Ca21 alginate gels prepared using these two gelation methods often have a weak structure, thus significant loss of target bioactives or drugs is possible during the gelation process (especially for the water-soluble substances) (Chan et al., 2006; Wong et al., 2002; Liu and Krishnan, 1999; Torre et al., 1998). Alginates are inexpensive and can be obtained conveniently from natural sources such as brown seaweeds and marine algae. Alginate is very soluble at the neutral pH (e.g., in pure water). The physical properties of alginate depend on the uronic acid composition and the relative proportion of the three M, G, and MG blocks, with its gel-forming properties affected mainly by the proportion and lengths of the G-blocks. Alginate materials show a wide variation in their specifications, which relates to their compositional variability, for example, sodium alginates sold as thickening and gelling agents have viscosities of 0.03 2 Pa
s or 30 2000 centipoise (cP), different mannuronate (M) and guluronate (G) contents, and different degrees of acetylation. Alginates can readily form hydrogels via ionic crosslinking with divalent cations like calcium, and also reduce interfacial tension between an oil and water in an emulsion (Augst et al., 2006). Certain alginates can be used as impression materials that form a fast-setting gel with water and have good accuracy and dimensional stability over time, although imbibition, shrinkage, and syneresis may occur during the production of alginate impressions (Imbery et al., 2010). Besides their widespread uses in food processing, alginates have been included in biomedical applications, including the tissue engineering of skin (Hashimoto et al., 2004), cartilage (Bouhadir et al., 2001), bone (Krebs et al., 2010), and nerve tissue (Prang et al., 2006.). Alginate has been used for encapsulating or immobilizing drugs/bioactives, immunoprotecting and proliferating cells, in wound dressings, as a physical protective barrier, for its ion exchange properties (e.g., reverse exchange of its calcium ions for sodium ions in blood), its absorption capacity (e.g., absorb wound secretions) and its nonadherent characteristics (Safi et al., 2007; Yim et al., 2006; Knill et al., 2004; El-Katatny et al., 2003; Doyle et al., 1996). Manufacturers of foods or biomedical products add fillers and smaller amounts of other proprietary ingredients to control or enhance consistency, setting time, elasticity, strength, and dimensional stability. Alginate’s dimensional stability relates to expansion processes as a result of water absorption (imbibition) and shrinkage processes (owing to evaporation of water) (both of which are significantly affected by storage conditions), as well as the syneresis process (which is influenced by alginate’s proprietary constituents) (Buchan and Peggie, 1966). A greater dimensional stability can be achieved using alginates with a high ratio of calcium to sodium, or alginates with low-MW polymer chains and a high filler to alginic polymer ratio (Fellows and Thomas, 2009). Water in an alginate gel can be in free or bound form. The free water is trapped among filler particles and its amount changes because of evaporation or imbibition (Phillips, 1973). The movement of free water, including water loss, is

11.2 Natural Biopolymers: Alginate and Chitosan

governed by diffusion kinetics, differences in entropy, and Gibbs free energy (Nallamuthu et al., 2006). Different alginate materials have proprietary complex osmotic pressures and gradient changes between the gel, sol, and environment (Saitoh et al., 2000). In comparison, bound water can be exuded due to syneresis (which results from the rearrangement of crosslinked alginic polymer chains to a more stable configuration), with the water movement occurring rapidly, irrespective of humidity (even if 100% relative humidity). A higher ratio of calcium to sodium leads to alginates losing water more rapidly compared with alginates with a lower calcium to sodium ratio (Fellows and Thomas, 2009).

11.2.2 CHITOSAN Chitosan is a linear positively charged polysaccharide derived from chitin. Chitosan consists of two repeating neutral sugar units (N-acetyl-2-amino-2-D-glucopyranose: abbreviated form GlcNAc; and 2-amino-2-deoxy-D-glucopyranose: abbreviated form GlcN) linked via β-(1-4) linkages, with one NH2 group and two OH groups on every glucosidic residue (Agrawal et al., 2009). This chemical structure and the two different types of reactive groups render chitosan a very versatile biopolymer for drug or bioactive delivery systems. The ratio of the two monomeric building units determines whether the chitosan at acidic pHs behaves predominantly as an ampholyte (typical for chitosans enriched in β-(1-4)-linked GlcNAc units) or as a polyelectrolyte (typical for chitosans enriched in the positively charged GlcN units), and influences its surface activity and sol gel transition (Va˚rum and Smidsrød, 2005). Chitosan is abundant in nature and can be found in the outer skeleton of crustaceans, insects, and fungi. Unlike alginates, naturally occurring chitosans are not structural polymers (except for those found in the cell wall of some fungi such as Mucor species) (Kaur and Dhillon, 2014). The extraction of chitin involves demineralization (removal of calcium using hot HCl or HNO3) and deproteinization (removal of proteins using alkali such as NaOH) (Kumar et al., 2005). The resultant crude chitin has a highly ordered crystalline structure and low water solubility or reactivity, and is converted into chitosan via alkaline deacetylation at an elevated temperature until the degree of acetylation of the amine groups reaches 35% 40%. Different forms of chitosan exist, including quaternary salts, hydroxypropyl chitosans (possessing a high degree of substitution; water-insoluble), and carboxymethyl chitosans (with both negative and positive substituent groups) (Sun et al., 2006; Xie et al., 2002). Commercial chitosan products differ greatly in MW and deacetylation degree (the molar ratio of glucosamine to N-acetyl glucosamine) (Abdou et al., 2008; Gupta and Jabrail, 2006; Zentz et al., 2001). In particular, the size and conformation of chitosan chains play important roles in their functionality. Depending on the purification and deacetylation method and also the origin of chitin used, the MW of chitosan may vary from a few kDa to over 1500 kDa (Kim et al., 2008). Chitosans can be classified according to their MW as low MW (,50 kDa), medium MW (50 150 kDa), or high MW (.150 kDa).

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Gels with tuneable delivery properties can readily be prepared from chitosans. The primary amino groups of the chitosan molecule are susceptible to covalent crosslinking and can form gels with excellent mechanical strength and controllable network pore sizes (Berger et al., 2004), although the complete elimination of toxic crosslinkers (e.g., glutaraldehyde) commonly used to obtain chitosan hydrogels remains challenging (Bhattarai et al., 2010). Chitosan can also form physical gels with different gel morphologies and consequently different physiological responses through different approaches. Gels containing no toxic crosslinkers are ideal for short-term bioactive/drug release applications, although poor mechanical strength and uncontrolled dissolution are inherent limitations of such gels (Bhattarai et al., 2010; Va˚rum et al., 1996). Gels of highly acetylated chitosans are typically soft and easily degraded, thus they cannot be used in cultures of human mesenchymal stem cells, though more solid gels can be formed using highly deacetylated chitosans which promote cell adhesion (Rami et al., 2014; Montembault et al., 2005). The pH-dependent solubility of chitosan allows in situ gelling systems to be developed. For example, a mixture of chitosan and polyacrylic acid is a liquid at pH 6.0 but turns into a gel at pH 7.4 (i.e., the mixture gels under the physiological pH) (Bernkop-Schnurch and Dunnhaupt, 2012). The cationic properties of chitosan chains arise through the protonation of its amino groups, and confer useful properties including solubility in mild acidic media (pHs below its pKa of 6.3 6.7) (Strand et al., 2001; Sorlier et al., 2001), gelation and membrane-forming properties under acidic conditions (Berscht et al., 1994), high reactivity at the charge sites (e.g., via forming complexes with polyanions) (Thein-Han et al., 2008; Tian and Groves, 1999; Leong et al., 1998), emulsion-stabilizing properties and ability to create multilayer interfacial membranes (Klinkesorn, 2013; McClements, 2005), antimicrobial activity (via interaction with anionic components of cell surfaces and disruption of cell membrane integrity causing leakage of intracellular components) (Ma´sson et al., 2008; Young and Kauss, 1983), and conductivity for integration in electronic biosensors (Kim et al., 2015). In addition to its desirable physical properties, chitosan is a nontoxic, nonimmunogenic, biocompatible, and biodegradable polysaccharide with unique characteristics, such as antimicrobial activity and cell/mucosa adhesivity (Lee et al., 2009; Peter, 2005; Artursson et al., 1994). Thus, chitosan has been widely used in various food, medical, and pharmaceutical applications as a nutrient (Luo et al., 2012, 2013), bioactive/drug carrier (Jayakumar et al., 2011; Bhattarai et al., 2010; van der Lubben et al., 2001), and in tissue regeneration systems (Thein-Han et al., 2008). Chitosan also possesses excellent metal-binding capacities involving its charged amine groups and hydroxyl groups for chelation, with the mechanisms underlying metal complexation varying with pH (,6 or in the range of 7 9) (Wang et al., 2005a; Helander et al., 2001). Chitosan displays excellent adsorption and biosorption characteristics for metal cations (including heavy metals), which derive from its high hydrophilicity, presence of reactive amino groups, and flexible polymer structure (Miretzky and Cirelli, 2009; Grini, 2005; Muzzarelli, 1973).

11.2 Natural Biopolymers: Alginate and Chitosan

Chitosan can behave as a surfactant with a wide-ranging hydrophilic lipophilic balance (HLB) values. Hydrophilic chitosans containing low neutral sugar GlcNAc fractions can stabilize oil-in-water emulsions, whilst more hydrophobic chitosans with a higher neutral sugar GlcNAc fraction can stabilize water-in-oil droplets (Schulz et al., 1998). Highly acetylated chitosans can act both as an emulsifier and a flocculant, thus playing a significant role in emulsion formation, stabilization, and destabilization (Laplante et al., 2005; Strand et al., 2002). Chitosan has been widely used for its antimicrobial properties in delivery systems (i.e., for bioactives, drugs, or genes), and also in wound-healing dressings and tissue-engineering scaffolds (Di Martino et al., 2005; Aksungur et al., 2004; Azad et al., 2004; Rabea et al., 2003).

11.2.3 DESIGN OF HYDROGEL AND HYDROGEL COMPOSITE DELIVERY SYSTEMS Hydrogels are hydrophilic 3-D polymeric networks that contain chemical or physical crosslinks and can imbibe water or biological fluids (electrolyte solutions). There exist many different types of hydrogels, which differ in their network morphology (amorphous or semicrystalline), network structures (macroporous, microporous, or nonporous, hydrogen-bonded or supermolecular structures), and physical crosslinks (entanglements or weak associations via hydrogen bonds or van der Waals interactions) (Lowman and Peppas, 1999; Peppas and Lustig, 1986). Hydrogel composites for bioactive or drug delivery or immobilization must possess physiologically or biologically environmentally responsive properties (i.e., properties dependent on one or more of the following: pH, ionic strength, temperature, or pressure-sensitivity associated with ionizable moieties like carboxylic and amine groups) (Lowman and Peppas, 1999). Other essential characteristics include swelling behavior (which may be affected by the nature of polymer or external stimulus), controllable porosity (porous or nonporous, tortuosity, and pore size). In addition, the physicochemical properties of the polymer solution(s) used to prepare the hydrogels and interactions among solutes, gel polymers, and solvents (Duke et al., 1994; Peppas and Lustig, 1986; Muhr and Blanshard, 1982) must also be carefully considered. The design of a hydrogel composite with specific functional properties focuses mostly on the creation of 3-D structures with exact chain conformations and appropriate tethering of reactive functional groups (to produce either a neutral or ionic system). When water penetrates in dried biopolymer gel networks, a state change occurs (i.e., a transition occurs from a dried glassy state to a rubbery state via rearrangement of macromolecular chains) leading to a lowered glass transition temperature for local regions. Hydrogel swelling is driven by ionic interactions and the redistribution or localization of charges resulting from the interactions between ionized groups and coexisiting counterions, which is counterbalanced by the retractive force induced by the crosslinks within the hydrogel network until a

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swelling equilibrium is reached (Ricka and Tanaka, 1984; Tanaka, 1979). Both the local surface structure and gel frictional behavior can be tailored to optimize network water solvation, sliding/adhesion velocity, and the amount of target bioactives/drugs incorporated (Osada and Gong, 1998; Hern and Hubbell, 1998). Efficient bioactive/drug loading is a critical step for developing a hydrogel delivery system and can be achieved based on different working mechanisms including physical adsorption, permeation, entrapment in a matrix, crosslinking, covalent binding, self-assembly, and polymerization (Bernkop-Schnurch and Dunnhaupt, 2012; Bhattarai et al., 2010; Klaypradit and Huang, 2008; Choi et al., 2005). The overall suitability of hydrogels for delivery systems can be gauged from parameters such as the equilibrium polymer volume fraction in the swollen gel (the ratio of the polymer volume to the volume of the swollen gel), the reciprocal of the volume swelling ratio, the number average MW between crosslinks (M c , representing the degree of crosslinking), the correlation length (the network mesh or pore size, ξ, indicating the distance between consecutive junctions, crosslinks, or tie points) (Peppas and Mikos, 1986; Peppas and Barr-Howell, 1986). For biomedical applications, hydrogels are often formulated to deliver specific bulk or surface features (e.g., the use of biodegradable chitosan to create wound dressings can eliminate the need to remove the dressings surgically at a later stage) (Kohn and Langer, 1996). It is feasible to create a hydrogel composite with surface characteristics that mimic those of cell membranes using immobilized lipid bilayers for cell adhesion (Hayakawa et al., 1997; Chaikof, 1996). In addition to the use of single polysaccharides for preparing hydrogels, combinations of two or more polysaccharides are often used to formulate 3-D hydrogel composites for the more effective delivery of specific bioactive substances. For example, hydrogels can be produced using both alginate(s) and chitosan(s) (Lim et al., 2006). The obtained mixed hydrogels demonstrate very different properties depending on the ratio of the two polysaccharides and the solvent medium (Saether et al., 2008; Simsek-Ege et al., 2003; Gaserod et al., 1998). Chitosan and alginate can be used to create polyelectrolyte complex delivery systems in the absence of chemical covalent crosslinkers. The resultant delivery systems can take the form of nano- or microparticles, beads, tablets, gels, films, and membranes, and exhibit desirable characteristics compared to the individual polysaccharide hydrogels, including improved mechanical strength, controllable swelling, and improved release behaviors (Luo and Wang, 2014). Polyelectrolyte polymers interact via electrostatic attraction, dipole dipole association, and hydrogen bonding to form nontoxic and biocompatible polyelectrolyte complexes (Hamman, 2010). A number of factors influence the stability of chitosan alginate polyelectrolyte complexes including the nature and concentration of chitosan and alginate, MWs of the individual polysaccharides, net charge ratios, distribution of ionic groups, degree of ionization, temperature, ionic strength, and pH of the reaction medium, order of addition to solution, and processing conditions (Saether et al., 2008; Tsuchida and Abe, 1982). Alginate does not adhere well to cells, and thus is unable to proliferate cells very well. The combined use of alginate and

11.3 Creating Porous 3-D Polymer Composites for Delivery

chitosan can increase cell adhesivity (Majima et al., 2005), because positively charged chitosan can adsorb serum proteins (Fukuda et al., 2006), thereby leading to increased adhesion of cells and promotion of cell proliferation.

11.3 CREATING POROUS 3-D POLYMER COMPOSITES FOR DELIVERY OR IMMOBILIZATION OF SPECIFIC SUBSTANCES INCLUDING BIOACTIVES AND DRUGS Targeted delivery of bioactives and drugs using controlled-release systems to combat disease requires the development of polymeric carriers with desirable chemical, physical, mechanical, and biological properties. The same carrier technologies can also be adapted to immobilize specific substances for clinical diagnostic applications. Restricting molecular mobility and compartmentalization are common approaches used to achieve chemical, physical, and microbiological stability against unwanted side reactions. Creating an appropriate carrier host matrix can provide increased stability or protection for sensitive bioactives or drugs. Such matrices can be constructed through controlled assembly of specific biomolecules into particular “architectures” or networks (3-D polymeric composites), as shown in Fig. 11.1. Careful optimization of biomolecule size, shape, and arrangement, with due consideration to the surface and bulk properties of the composites, is essential. The proposed end use of the 3-D polymeric composite determines the selection of biomolecules and fabrication techniques used. Understanding of dissolution, swelling, relaxation behavior, biodegradation, biocompatibility, and cellrelated functionality of the polymeric network and individual components during relevant biological processes and pathways, is critical. The absorption, distribution, and metabolism of the substances delivered will depend somewhat on the composition and form of the 3-D composite (especially in cases when the nanocomposites are used for delivery and immobilization of specific substances due to their high specific surface area). Encapsulation (microencapsulation or nanoencapsulation) is an especially attractive approach for this purpose. Encapsulation of a target bioactive substance creates a physical barrier between it and the environment, thereby minimizing undesired damage or losses of the target substance (the “core”) prior to its arrival at a specific absorption or action site. The physical barrier (the “protective matrix” or “shell material”) is often imparted with porosity or other controlledrelease characteristics to enable accurate delivery of the core substance. The nature and end use of the core substance(s) determine the selection of encapsulation method and shell material. Polymeric encapsulation composites, especially those using natural polysaccharides such as alginate or chitosan, are commonly used in controlled-release systems for food and biomedical applications because of their nontoxicity and biocompatibility. This section describes the use of coextrusion, spray-drying, and electrospinning technologies for creating 3-D polymeric

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Continuous fiber composite

Particle reinforced composite

Fiber reinforced composite

Flake reinforced composite

Chitosan

Alginate

Laminated composite

Filled composite

Substance(s) for delivery

FIGURE 11.1 Typical structures of 3-D polymer composites, and possible wall arrangements for microbeads and microcapsules prepared using chitosan and/or alginate.

composites in the beads, powders, and nanowebs/meshes, respectively, suitable for bioactive delivery and dietary intake.

11.3.1 COEXTRUSION ENCAPSULATION OF BIOACTIVES There is a growing demand for technologies that can encapsulate or immobilize bioactive substances or drugs in the form of microbeads or microcapsules for food, beverage, and biomedical applications. The purpose of encapsulation may be maximized delivery, controlled release, and/or taste masking/blocking. Encapsulation and immobilization technologies basically envelop small particles of solid, liquid, or gas (i.e., the “core” substance such as oils, antioxidants, enzyme, cells, or probiotics) within a secondary material (the “shell,” “encapsulant,” or “coating material” such as alginate, chitosan, and pectin polymers), to form nanospheres and microspheres. The shell serves as a physical barrier to protect the core substances. Coextrusion technology involves the extrusion of polymer solutions (e.g., aqueous alginate solutions) into a CaCl2 solution to produce uniform beads or

11.3 Creating Porous 3-D Polymer Composites for Delivery

Sodium alginate solution

Olive oil + caffeic acid

Electrode

Electrode

Hydrogel polymer alginate

Olive oil + caffeic acid

FIGURE 11.2 Coextrusion of microbeads with an olive oil 1 caffeic acid “core” (dashed arrows) and calcium-alginate “shell” (solid arrows).

capsules. The bioactive of interest is typically dispersed in water or oil. The polymer and bioactive solutions are then forced through nozzles to form individual fine streams, which are broken up by electrostatic or mechanical vibration into separate droplets that gel in the hardening solution (e.g., a CaCl2 bath) (Fig. 11.2) (Waterhouse et al., 2014; Sun-Waterhouse et al., 2011). The hydrogel shell protects the core substance(s) (probiotic bacteria, antioxidants, and unsaturated fatty acids) against the detrimental environments. Fig. 11.3 shows optical microscopy, environmental SEM, and cryo-SEM images of beads with alginate hydrogels as both the shell material and the core carrier for probiotic bacteria (Shinde et al., 2014). Factors such as nozzle size, flow rates of core and shell solutions, vibration frequency, and polymer solution properties (viscosity, density, and surface tension) all influence the attributes of extruded beads/ capsules. Coextrusion is scalable through the use of multinozzle systems, rotating disc atomizes, or jet-cutting technique to produce extruded beads (bead diameter in the range of 0.1 3 mm). Hydrogels comprise a network of polymer chains

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FIGURE 11.3 Demonstration of the use of coextrusion technology for encapsulating probiotic bacteria using alginate hydrogels of different concentrations as both the “shell” material and “core” carrier.

with reversible interactions between the individual polymer chains via noncovalent bonding interactions such as electrostatic interactions, π-stacking effects, hydrophobic effects, hydrogen bonding, or van der Waals forces. Compared to conventional ionotropic gelation methods (using water only) to produce aqueous hydrogel beads, emulsion gelation methods (using both water and oil) can also be used to generate oil-encapsulated hydrogel beads (affording hydrogel beads that are buoyant). The mean diameter and sustaining release action of the beads prepared by the two methods exhibit significant differences. The emulsion gelation method is simple and efficient (especially for delivering highly water-soluble bioactives or drugs like metformin hydrochloride, an antidiabetic drug) (Choudhury and Kar, 2005). An increase in concentration of oil causes an increase in size and shape of the emulsion gelation beads. A lower oil density

11.3 Creating Porous 3-D Polymer Composites for Delivery

results in a lesser amount of oil needed to achieve buoyancy (Rouge et al., 1996). The presence of oil in the delivery system offers an additional barrier to protect the core bioactive substances, especially water-soluble species. The release rate of such water-soluble species is controlled by diffusion through the gel and oil layers. Frequently, the release of core substances is also dependent on the characteristics of core substance(s), especially charge and size. Some studies have indicated that a drawback of conventionally extruded alginate Ca21 gel beads is their loose structure and subsequently the loss of core substances during the gelation process, such as water-soluble drugs (Wong et al., 2002), bovine methemoglobin (Ribeiro et al., 2005), or serum albumin (Vandenberg et al., 2001). Accordingly, the limitations of conventional calcium alginate beads can be overcome through the use of polyelectrolyte complexes between chitosan and alginate based on the strong electrostatic interactions between the positively charged amino groups of chitosan and the negatively charged carboxyl groups of alginate (Saether et al., 2008). As described above, chitosan and alginate can form polyelectrolyte complexes and a wide range of bead composites (Fig. 11.1) can be generated from the two polysaccharides, for example, via layer-by-layer assembly techniques to deposit interfacial layers with different characteristics, with each layer thickness of 1 100 nm. It is technically feasible to use both chitosan and alginate to produce extruded beads, although chitosan alginate beads may not necessarily be advantageous over pure alginate beads in all properties (e.g., chemical stability and release profile) (Yeung et al., 2016; Wong et al., 2002). The effectiveness of coextrusion encapsulation methods is influenced by many additional factors, such as the nature of the core substance (including physicochemical characteristics like molecular size), core loading percentage, charge ratio, processing methods (e.g., one-stage or two-stage procedure; air drying or freeze drying; with/without microwave treatments), and environmental factors (e.g., pH, temperature, pressure, shear, and motion) (Tavakol et al., 2009; Wong et al., 2002). The use of combinations of polysaccharide hydrogels for bioactive/ drug delivery has to be examined on a case-by-case basis. For example, air drying of beads has advantages in terms of retention of bead spherical shape, smooth surfaces, and a retarded release profile under simulated GI conditions, whilst freezedrying causes loss of spherical shape, increases surface area, and results in greater bead swelling (Tavakol et al., 2009). When the same coextrusion method was used for encapsulating canola oil with added quercetin, the loading efficiency and mean diameter were 76% and 543 μm for chitosan alginate beads, and 62% and 380 μm for alginate beads. The total phenolic content released from the chitosan alginate beads after incubation in an acidic aqueous solution (pH 3) for 2 hours was lower by 13% compared to the alginate beads. Thus, the introduction of chitosan into the alginate shell can slow the release of encapsulated phenolic compounds. Encapsulation of probiotic bacteria within food-grade hydrogels can protect the probiotic bacteria against environmental stresses and processing impacts, thus it is a feasible approach for maintaining the cell viability of

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probiotic strains during food storage and GI transit (Shinde et al., 2014). However, Yeung et al. (2016) indicated that adding an extra chitosan coating to alginate microgels did not improve the cell viability of Bifidobacterium longum strains compared to cells encapsulated with alginate microgels alone.

11.3.2 SPRAY-DRYING ENCAPSULATION OF BIOACTIVES Drying can be an effective trade-off between improved stability of products (owing to reduced moisture content) and drying-induced physicochemical changes (including color, shape, flavor, and structure). Drying-induced alteration in structure is not necessarily isotropic. Drying causes viscoelastic matrices to contract into the space initially occupied by water that has subsequently been removed by dehydration (which typically manifests as shrinkage or wrinkling in products). Encapsulation in the context of powder products refers to the formation of an amorphous polymeric composite as a “coating matrix” around some specific “core” substances of interest such as antioxidants, flavor compounds, pigments, enzymes, and drugs, to provide protection of the “core” substance(s) in the dry state against external stresses through regulating mass transfer (including moisture for chemical reactions). Controlled release is also feasible for encapsulated powders and accomplished through monitoring their dissolution in a target medium. In food systems, encapsulated powders can be produced to impart desirable sensory and processing characteristics to foods during processing or reconstitution, or offer specific health properties after ingestion. Producing powdered products of high stability requires thorough consideration of the matrix material and to-beprotected substance (“core” substance), as well as their fates and interactions during processing and digestion. In particular, structure-dependent dynamic mass transfer (during drying), product stability (during storage and handling), and dissolution and release behviors (during reconstitution or consumption) all need to be considered. Spray drying is widely used in food and pharmaceutical industries to produce powders, granules, and agglomerates in the form of microspheres. Spray-drying processes (Fig. 11.4) employ an atomizer or spray nozzle to disperse the liquid feed or slurry into droplets of a controlled size (ranging from 10 to 500 μm), to achieve a consistent powder particle size distribution. Modern industrial spray dryers use multiple processing stages that allow initially very small dried particles to clump in a humid environment near an integrated static bed at the bottom of the chamber, thereby yielding free-flowing powders of a uniform and specific particle size (i.e., typically final sizes range from 100 to 300 μm) (Thalberg et al., 2004). Spray-drying encapsulation is an extension of conventional spray drying, in which in situ encapsulation and drying are accomplished in a single process. Spray-drying encapsulation can provide accurate control of powder characteristics such as morphology, size, dissolution efficiency, storage stability, as well as bioactivities of the encapsulating active substances, thereby satisfying consumer

11.3 Creating Porous 3-D Polymer Composites for Delivery

Heater

Gas (in)

Drying chamber

Gas (out)

Feed (Encapsulant + Bioactive)

Cyclone

Powder

FIGURE 11.4 Schematic representation of the spray-drying (encapsulation) process.

demand for powdered beverage products that confer “convenience,” “wellness,” and “tastiness” (Sun-Waterhouse and Waterhouse, 2015). In this technology, the feed is tailored to contain nanosized emulsion/suspension droplets typically in the size range from 200 to 800 nm, and spray-drying conditions (e.g., drying temperature and type of atomizing device) are monitored to enable product powders to have a size .20 μm. Generally, there is an “optimal” powder particle size for functional ingredients and pharmaceutical applications. When the ratio of cohesive forces to the gravitational force (i.e., Bond number) is less than 1, the powder products exist in a free-flowing form (Jallo et al., 2012). Free-flowing powders afford easy handling and high dissolution efficiencies on reconstitution in water. A successful functional ingredient or pharmaceutical supplement powder should also possess maximal efficacy for target functionality. To achieve such an “optimal” size, appropriate carrier material(s), feed formulations, and spray-drying encapsulation and processing conditions must be used. Since spray drying is a process that uses a hot gas (usually temperatures .150 C for a few seconds) to rapidly dry and desolvate substances in the feed solution. Heat-induced damage and also oxygen-triggered oxidation of the constituents in the product powders (if hot air rather than an inert gas is used) are possible detrimental side reactions. Also, undesirable physical (e.g., caking or melting) or chemical reactions (e.g., discoloration or aggregation of proteins in the powder) may also occur (Chiou and Langrish, 2007). Therefore, careful design of the powder matrix is more important for spray drying compared to other drying processes with minimal heating such as freeze drying. Biopolymer composites such as hydrogels are excellent encapsulants to protect sensitive bioactives or drugs

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FIGURE 11.5 SEM images of alginate-quercetin and alginate-limonin powders produced by spray-drying encapsulation technology.

during spray drying. Fig. 11.5 shows the spray-dried alginate powders containing bitter bioactives quercetin and limonin. For oral consumption, the alginate composite serves dual roles (i.e., preserving quercetin and limonin while masking their undesired bitterness). Producing chitosan-containing spray-dried powders is more challenging due to its insolubility above pH 6.3 and reactivity under thermal conditions. Approaches to overcome these issues include the preparation of slightly acidic feed solutions containing bioactive/drug and chitosan (Rege et al., 2003; Shi and Tan, 2002), preparation of a colloidal chitosan suspension at neutral pH or under alkaline conditions using NH4HCO3 (Muzzarelli et al., 2003), and the use of a crosslinking agent or a secondary polymer such as alginate at an appropriate alginate/chitosan ratio (Gupta and Jabrail, 2006; Gonzalez-Rodriguez et al., 2002). Similar to coextrusion, the spray drying of two or more biopolymers allows the creation of specificially tailored 3-D composite powders containing bioactives or drugs, which offer desirable mechanical, processing, or health properties. The choice of polysaccharide combinations should consider the compatibility and stability of the constituent polysaccharides over the heat and mass transfer courses of the spray-drying process, and also the rehydration and dissolution properties of

11.3 Creating Porous 3-D Polymer Composites for Delivery

powders for consumption. Factors influencing product quality are similar to those described above for coextruded hydrogel materials (e.g., film-forming, oxygen permeability, and moisture barrier), formulated matrix characteristics (e.g., composition, concentration, pH, ionic strength, dielectric constant, temperature, and viscoelasticity) and processing conditions (e.g., feed flow rate, inlet and outlet temperatures). Particular attention also needs to be directed towards tailoring the polysaccharide matrix to reduce powder hygroscopicity and minimize stickiness (which is a common technical problem encountered during spray drying, especially for the bioactive extracts containing high concentrations of low-MW sugars and organic acids) (Righetto and Netto, 2005; Bhandari et al., 1997).

11.3.3 ELECTROSPINNING OF POLYMER FIBERS CONTAINING BIOACTIVES Electrospinning is a simple but efficient technology for the creation of 3-D nanofiber structures from solutions of natural biopolymers or synthetic polymers (Huang et al., 2003; Buchko et al., 1999, 2001). The method can be used to generate scaffolds and webs/meshes to support cell growth and/or to deliver bioactive agents at a site of interest via protection and controlled-release mechanisms. In a typical electrospinning process, a high electric potential is applied between a spinneret (e.g., a syringe needle attached to a syringe containing a polymer solution) and a collector (normally earthed) to create an electrically charged jet of polymer solution or even a melt at sufficiently large voltage differences (when the electrostatic force is able to overcome the surface tension of the polymer solution droplet at the tip of the metal syringe needle) (Pham et al., 2006; Yarin et al., 2001). The polymer solution (in a high vapor pressure solvent) is ejected in the form of a polymer liquid-jet through the needle toward the collector, during which the jet elongates owing to the electrostatic interactions between charges on neighboring segments of the jet. The solvent evaporates during transit and the polymer jet dries or solidifies as polymer nanofibers on the collector (Fig. 11.6). The charged jet is unstable and undergoes bending/whipping instabilities caused by electrostatic repulsion during its transit toward the collector, causing bending and stretching of the jet (Badrossamay et al., 2010; Frenot and Chronakis, 2003; Reneker et al., 2000). Upon deposition on the collector, the polymer fibers may fuse together to form a nonwoven mesh. A decrease in the needle tip collector distance or increasing voltage can reduce the flight time and solvent evaporation time, while raising the electric field strength causes beads to form along the fiber chain (Huang et al., 2003; Frenot and Chronakis, 2003). Further, the use of different methods for collecting the electrospun nanofibers can lead to end products with very different attributes and characteristics (Li and Xia, 2004). Common collection methods include electro-centrifuge spinning (which utilizes electrical and centrifugal forces) (Dabirian et al., 2010, 2011), rotary jet-spinning technique (which is able to build uniaxial aligned nanofiber structures)

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Nano web or mesh

Needle Polymer solution Pressure

Nanofibers

Collector

Power supply

Section of composite nanofibers

Nano web or mesh

Polymer solution

Needle

Pressure

Collector

Power supply

Nanofibers with target drugs or bioactives

Section of composite nanofibers

Core-sheath nanofibers

Section of core-sheath nanofibers

Nano web or mesh

Core polymer solution Needle Shell polymer solution Pressure

Collector

Power supply

Nano web or mesh Core polymer solution Needle Shell polymer solution Pressure

Power supply

Collector

Core-sheath nanofibers with target drugs or bioactives

Section of core-sheath nanofibers

FIGURE 11.6 Schematic representation of different electrospinning setups for fabricating fiber composites with/without embedded microspheres.

(Badrossamay et al., 2010), rotating mandrel (Bashur et al., 2006), adjusting the gap between two collectors (Samavedi et al., 2014), or by stretching the mesh post electrospinning (Li et al., 2003). The type and concentration of polymer, transit distance, and electric potential determine the electrospun fiber diameter (Agarwal et al., 2009a; Pham et al., 2006; Huang et al., 2003). Electrospun biopolymers are attracting increasing interest in the field of regenerative medicine and functional foods because of their unique structure, enhanced mechanical properties, and biocompatibility (Kenawy et al., 2002). Electrospun collagen fiber had a tensile modulus of 262 MPa (under dry conditions) (Li et al., 2005), whilst electrospun gelatin fiber possessed a tensile modulus of 424 MPa (Zhang et al., 2006). The diameter of electrospun fibers varies with parameters

11.3 Creating Porous 3-D Polymer Composites for Delivery

such as polymer MW, concentration, conductivity, and surface tension, and external parameters including voltage, flow rate, distance between the needle tip and the collector, and environmental parameters (such as temperature and relative humidity) (Pham et al., 2006; Huang et al., 2003). Coextrusion and spray-drying can produce composites with a minimum size of B100 μm. However, electrospinning offers a size range from nanometers to a few micrometers (Pham et al., 2006; Bashur et al., 2006). Moreover, electrospinning can generate polyionic complex materials insoluble over a broad pH range (thus allowing accommodation in cell cultures) in the absence of a crosslinking step (thus avoiding alteration of nanofiber morphology or the potential damage to the incorporated bioactive substances caused by the use of toxic solvents and high temperatures to crosslink the fibers) (Penchev et al., 2008; Chunder et al., 2007). Electrospinning of natural biopolymers is not straightforward, due mainly to their ionic character in the dissolved state, their low solubility in most organic solvents, strong hydrogen-bonded 3-D network, weak mechanical properties in the hydrated state, and loss of the biopolymer native structure and biological properties when electrospun from organic solvents, and finally degradation in vivo (Kai et al., 2013; Agarwal et al., 2009b). The electrical and rheological properties of a polymer and the background solvent are thus especially critical for electrospinning applications, in particular, surface tension and viscosity are two important parameters (Homayouni et al., 2009; Amici et al., 2008). An electrospinnable solution must have a sufficiently high polymer concentration to allow the entanglement of long polymer chains and a low enough viscosity (to enable the formation of polymer solution droplets and subsequent pumping through the syringe) (Lannutti et al., 2007). The nature of polymers (e.g., MW, electrical charge, and tendency to form hydrogels) and characteristics of polymer solutions (hydrophilicity, viscosity, surface tension, dielectric strength, and conductive identities) are all factors that influence biopolymer behavior during and after electrospinning (Agarwal et al., 2009a). Alginate and chitosan have been studied in electrospinning applications, although neither alginate nor chitosan can be electrospun on their own due to limited chain entanglements and their high surface tension in solution (Lee et al., 2009; Rhim, 2004). Highly hydrophilic alginate is an anionic polymer with good colloidal properties, and thus can react with polyvalent metal cations to produce strong gels or films. Electrospinning of alignate is difficult because of the repulsive forces among the chain polyanions as well as its high intrinsic viscosity. Reducing the linkages in alginate to decrease its viscosity, and blending alginate with secondary polymers that have a flexible molecular structure and low MW such as polyvinyl alcohol (PVA) and polyethylene oxide (PEO) are feasible approaches to enable electrospinning (Amici et al., 2008; Safi et al., 2007; Rhim, 2004). Electrospinning of chitosan is challenging due to its low water solubility caused by its polycationic nature, rigid structure, high crystallinity, and strong intermolecular hydrogen bonding (Homayouni et al., 2009; Li and Hsieh, 2006). Whilst increasing the voltage may help to some extent, the common method used

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to improve electrospinnability of chitosan solutions is to select appropriate solvents based on their dielectric specifications (Homayoni et al., 2009; Geng et al., 2005) as well as to optimize the surface tension, concentration, and viscoelasticity of the polymer solution (Geng et al., 2005). The intrinsic viscosity and conductivity of chitosan solution can be modified through altering the ionic strength, pH, degree of deacetylation, and MW. Chitosan solutions have a significantly reduced viscosity on increasing the pH from 4 to 5 (Amici et al., 2008; Chen et al., 1994). Another prudent approach to improve the electrospinnability of chitosan is the combined use of chitosan and other materials such as poly(L-lactic acid), zein, hydroxyapatite, or montmorillonite (Torres-Giner et al., 2009; Xu et al., 2009; Wang et al., 2005b). Encapsulation and immobilization of bioactive substances in electrospun fibers or meshes can be achieved via physical and/or chemical approaches to preserve bioactivities or promote cell proliferation and differentiation (Fig. 11.6), the latter achieved by the incorporation of fibrinogen (Bashur et al., 2006), arginineglycine-aspartate (RGD) (Zhang and Hollister, 2009), or fibroblast growth factor-2 (FGF-2) (Sahoo et al., 2010). Physical and chemical methods for electrospinning have their inherent advantages and disadvantages. For example, both physical adsorption and chemical conjugation methods can be used to immobilize bone morphogenetic protein-2 (BMP2) via electrospinning. Physical adsorption stimulates osteogenesis but presents limitations in terms of poor reproducibility, nonspecific binding, and ease of desorption compared with chemical methods (Yoo et al., 2009; Nie et al., 2008). Often surface modification of electrospun fibers or meshes is required, using plasma treatment (in air, oxygen, and ammonia), wet chemical processes (such as aminolysis and hydrolysis), and coating approaches (e.g., dip coating and coaxial electrospinning) to introduce reactive sites (i.e., functionalizable groups like NH2, COOH, and SH) for conjugation (Qu et al., 2013; Ripamonti et al., 2012; Yoo et al., 2009; Zhang and Hollister, 2009). Coaxial electrospinning is particularly useful in this regard as compared with blend electrospinning (in which biomolecules are directly incorporated into the electrospinning solution) as the latter method tends to cause denaturation of biomolecules or loss of their bioactivity and also adversely impacts fiber mechanical properties (Qu et al., 2013; Ji et al., 2011; Huang and Zhang, 2005). In coaxial electrospinning, two polymer solutions are pumped through a twocapillary spinneret while an electric potential is applied, and the polymer jet is ejected in the form of core-sheath fibers and collected as core shell fibers with the bioactive substance incorporated in the core (Fig. 11.6). The type and nature of the core and shell polymers (including MW and MW distribution), characteristics of polymer solution (concentration, viscosity, and conductivity), solvent attributes, pH, flow rate, applied voltage, nozzle size, working distance or spinning time, and absence/presence of additives (excipients, adjuvants, coatings, or crosslinkers) all directly influence the characteristics of coaxial electrospun fibers/ meshes including uniformity, diameter, morphology, and mechanical strength (Qu et al., 2013; Lee et al., 2009; Yoo et al., 2009; Greiner and Wendorff, 2007;

11.4 Tailoring Biopolymer Physicochemical

Gupta and Jabrail, 2006). Core-sheath fibers not only possess superior properties (e.g., improved thermal and electrical conductivities) (Qu et al., 2013), but also facilitate the encapsulation and controlled release of bioactive substances (Jiang et al., 2014). The method also allows grafting of other bioactive molecules on the surface of the shell for specific biomedical function (Wang et al., 2013). Bioactive substance(s) can be delivered using coaxial electrospun chitosan-coated alginate meshes (Chang et al., 2012; Lemoine et al., 1998). As discussed earlier, the addition of a secondary polymer to alginate or chitosan is necessary for electrospinning. The combined use of chitosan and alginate for coaxial electrospinning encapsulation of target substances overcomes this issue whilst offering additional advantages over the use of alginate or chitosan alone. Rapid formation of in situ crosslinks between alginate and chitosan during electrospinning is desirable, though the efficient formation of such crosslinks in a short flight time to the collector is a technical hurdle that needs to be resolved.

11.4 TAILORING BIOPOLYMER PHYSICOCHEMICAL AND BIOLOGICAL PROPERTIES VIA CONTROLLED DEPOLYMERIZATION AND OPTIMIZED FORMULATION Natural polymers including polysaccharide polymers frequently require modification before their application in biomedical fields. For example, alginate or chitosan biopolymers are often subjected to modification prior to electrospinning in order to improve their performance for carrying nutrients, bioactives, or drugs. Appropriate modification of biopolymers includes chemical, physical, and enzymatic modification, treatments which often deliver multiple favorable physicochemical, electrochemical, mechanical, and nutritional benefits, for example, improved prebiotic properties and electrospinnability. After considering their fates under industrial processing conditions, postprocessing, and human physiological conditions, appropriate polymer materials are selected and then modified using the most suitable method(s).

11.4.1 CONTROLLED MODIFICATION Physical modification is accomplished through blending or physically mixing at least two polymers in the amorphous state to create a new single-phase composite, and represents the most straightforward approach for modifying polymers and enabling a wide range of novel chemical, physical, and biological properties for specific applications, including bioactive/drug delivery. Chemical/enzymatic modification can be achieved based on the distinct reactivity of a polymer’s functional groups (e.g., carboxylic/carbonyl, hydroxyl, and amine groups), altering a polymer’s physicochemical properties such as MW, charge, and permeability of polymeric surfaces (Gonzalez-Rodriguez et al., 2002; Peppas and Barr-Howell, 1986).

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Depolymerization is one of the most relevant approaches for the delivery and immobilization of bioactives and drugs (Tiwari and Dhakate, 2009; Chen et al., 2000).

11.4.1.1 Alginate with decreased molecular weight Decreasing the MW of polymers like chitosan or alginate can significantly decrease the viscosity and surface tension of polymer solutions (Bonino et al., 2011; Homayouni et al., 2009). The high water solubility of sodium alginate, whilst desirable for beverage applications, presents as a distinct disadvantage for carrier applications that require excellent integrity and stability in aqueous environments. A number of methods are available to modify alginate such as crosslinking with glutaraldehyde and divalent ions (although these methods may lead to increased toxicity and undesirable morphological change in crosslinked composites) (Kim et al., 2000), thermal treatments including the use of hot water (Kelishomi et al., 2016; Aida et al., 2010), gamma irradiation (Sen ¸ and Atik, 2012; Lee et al., 2003), high- and ultra-high-pressure homogenization (Villay et al., 2012), use of oxidizing agents (Li et al., 2010), use of reducing agents (Smidsrød et al., 1963), use of appropriate acids (e.g., trifluoroacetic acid or citric acid, to ensure the generation and stability of fibrous networks) (Smidsrød et al., 1969), use of alkali (Haug et al., 1967), and the use of enzymes (Falkeborg et al., 2014; Wang et al., 2006). Thermal treatments have advantages in terms of simplicity, cost-effectiveness, and the absence of harsh chemicals, as well as generation of more functional groups such as hydroxyl, carbonyl, and carboxyl groups and double bonds between C-4 and C-5 (Kelishomi et al., 2016; Aida et al., 2010). The health benefits of sodium alginate consumption as a dietary fiber source have been studied in detail, and include reduced energy intake (Paxman et al., 2008), cholesterol-lowering ability (Gunness and Gidley, 2010), antibacterial (Hu et al., 2005), antitumor (de Sousa et al., 2007), antidiabetic, and antiobesity activities (Brownlee et al., 2005). Alginate polysaccharides with low MW enhance the desirable bioactivities of alginate while generating novel functionalities, for example, increased antioxidant activity (Kelishomi et al., 2016; Cui et al., 2016), enhanced satiety and better appetite control (Georg Jensen et al., 2012), induced prebiotic properties (Wang et al., 2006), enhanced disruption of airway mucus in cystic fibrosis patients (Taylor et al., 2009), stimulation of human keratinocytes (Kawada et al., 1997), presence of antitumor effects and enhancing phagocytic activity of macrophages (Fujihara and Nagumo, 1993), and prevention of cardiovascular and cerebrovascular diseases (Xue et al., 1998). Factors such as the ratio of mannuronic to guluronic acids (M:G), distribution of M- and G-blocks along the alginate chain, and the sulfate group also influence these properties (Draget et al., 1994).

11.4.1.2 Chitosan with decreased molecular weight Most commercially available chitosans are high-MW molecules. Excellent filmforming abilities and high solution viscosities are associated with higher-MW chitosans (Srisuk and Srikulkit, 2008). A decrease in MW improves the solubility

11.4 Tailoring Biopolymer Physicochemical

of chitosan, which facilitates processing chitosan into bead and fiber forms (Li and Hsieh, 2006). Previously published studies indicated that depolymerization of native chitosan (226 kDa) to smaller chitosan fractions (7 70 kDa) enables unique molecular properties, including improved affinity for substances like cellulose, proteins, and pigments (Suitcharit et al., 2011; Janes and Alonso, 2003), enhanced absorption of hydrophilic macromolecules (Artursson et al., 1994), increased ocular mucoadhesion (Henriksen et al., 1996), improved delivery efficiency for biologically important substances like peptides, drugs, and plasmids (Maclaughlin et al., 1998; Luessen et al., 1996; Illum et al., 1994), increased bioavailability of encapsulated substances (Shiraishi et al., 1993), improved stability and transfection efficacy of genes and DNA (Sato et al., 2001; Lee et al., 2001), and increased biocompatibility and hemocompatibility of drugs (Richardson et al., 1999). In applications where film-forming properties are not highly desired but low stiffness is preferred, modification of the MW of chitosan using depolymerization techniques is also useful (Srisuk and Srikulkit, 2008; Kittinaovarat, 2004). Thus, low-MW chitosans hold great promise in the pharmaceutical sector. The biological activity of chitosan, such as antimicrobial activity, depends closely on its MW, the degree of acetylation, and the alkyl moiety (Rabea et al., 2003; Sekiguchi et al., 1994). For chitosan, a lower MW enables a greater antimicrobial action through decreasing the growth and multiplication of microorganisms (Kumar et al., 2005). There are different methods that can be used to modify the MW of chitosan, including enzymatic degradation (Zhang and Neau, 2001), oxidative degradation (Li et al., 1999), acidic cleavage (Tsao et al., 2011), ultrasonic degradation (although the rate of MW reduction varies over the ultrasound treatment process) (Baxter et al., 2005; Chen and Chen, 2000), microfluidization in an acid (Kasaai et al., 2003), and thermal treatment (Holme et al., 2001). Treatment of chitosan with sodium nitrite (NaNO2) at room temperature is a highly reproducible method, and involves oxidative degradation of chitosan. The depolymerization of chitosan using sodium nitrite in acid media allows accurately controlled degradation of the polymer because the number of moles of glycosidic linkages broken is stoichiometric (i.e., 1:1) with the number of moles of NaNO2 added (Janes and Alonso, 2003). NaNO2 treatment can increase the degree of deacetylation in the chitosan backbone, loosen the compact structure of chitosan, reduce the degree of crystallinity, decrease MW, and decrease particle size with no obvious change in the ζ-potential (for chitosan-derived ionotropic gel) (Suitcharit et al., 2011; Janes and Alonso, 2003). The depolymerization process and MW of depolymerized chitosan are governed by the origin, molecular size, degree of deacetylation, salt form and initial concentration of chitosan, chitosan:NaNO2 ratio, and the reaction time (Janes and Alonso, 2003; Carrecuno-Gomez and Duncan, 1997). There likely exists an optimal MW for the immobilization of active substances (too low an MW of chitosan may lead to limited affinity). Depolymerized chitosans obtained by nitrite treatment contain a significant amount of active aldehyde functional groups that can induce further interactions with other substances like cellulose via

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covalent bonding and adhesion (Suitcharit et al., 2011). Depolymerized chitosans with a sufficiently low MW (e.g., 10 40 kDa) can be used as carriers to deliver proteins and peptides with higher encapsulation efficiencies than the native polymer, via electrostatic interactions between the amino groups of chitosan and the negative residues on proteins/peptides (when the pH is above its pI) (Janes and Alonso, 2003).

11.4.2 OPTIMIZED DELIVERY SYSTEMS Three-dimensional polymeric composites can be created with tailored physical, chemical, electrical, and biological behaviors using suitable polymers (e.g., alginate and chitosan) and fabrication conditions. The selection of molecular size and concentration of alginate and chitosan used in composite construction should consider the target bioactive substances, their influences on the nutritional profile (e.g., prebiotic effect), and biological target(s) (e.g., impact on the permeability of intestinal mucus) of the product and individual constituents after digestion. The small intestine has a highly heterogeneous mucus layer composed mainly of MUC2 mucin with mucus pore sizes ranging from 25 to 200 nm (Round et al., 2012). Biopolymers with different sizes and concentrations may or may not diffuse freely into the mucus due to their impact on permeability of intestinal mucus and bulk rheology, thereby affecting the diffusion of digesta components (Mackie et al., 2016). Characteristics such as flotation, mobility, mucoadhesion, and membrane permeability are as important as swelling and controlled-release properties for bioactive/drug delivery. For example, floatability in gastric fluids is an important aspect for a bioactive/drug-delivery system to facilitate gastric retention and prolonged contact time with the small intestinal mucosa for better absorption and enhanced bioavailability (Arora et al., 2005; Deshpande et al., 1997). Floating units should need to be tailored to be buoyant in gastric fluids. There exist a number of approaches to impart floatation properties into bioactive/drug-delivery systems: (1) using emulsions; (2) tailoring the shell material to have a density lower than that of gastric fluid; (3) using a fluid-filled system that floats in the stomach; (4) using hollow or partial-vacuum delivery systems filled with suitable gas, liquid, or solid; and (5) using swellable polymers (such as chitosan, sodium alginate, and methylcellulose) and effervescent compounds such as sodium bicarbonate, tartaric acid, and citric acid that liberate CO2 for buoyancy upon exposure to acidic gastric contents (Gibaly, 2002; Joseph et al., 2002; Whitehead et al., 2000; Ichikawa et al., 1991). Prebiotics are receiving growing attention, and include polysaccharides sourced from marine organisms such as seaweed and seafood, as well as the widely known prebiotics such as fructo-oligosaccharides, galactooligosaccharides, inulin, and lactulose (Corzo et al., 2015). Some marine-sourced polysaccharides display antioxidant, antiinflammatory, and anticarcinogenic activities as well as prebiotic effects (Praveen and Chakraborty, 2013; Veena et al., 2007; Wang et al., 2006; Lee et al., 2002). Prebiotics can be obtained directly

11.5 Conclusions

from natural resources and agro-industrial byproducts or produced through modification of existing polysaccharides via approaches such as partial enzymatic hydrolysis (e.g., using hydrolases, lyases, and esterases), acid or basic hydrolysis, hydrothermal processes, dynamic high-pressure microfluidization, or photochemical reactions (Cui et al., 2016; Bonnin et al., 2014; Gavlighi et al., 2013; Gullo´n et al., 2013; Chen et al., 2013). The resultant oligosaccharides are often subjected to purification using technologies such as membrane filtration, ultrafiltration, or diafiltration (Sulek et al., 2014; Go´mez et al., 2013) and adsorption-based separation methods using XAD chromatography and Sephadex G-75 (Lee et al., 2014; Lama-Mun˜oz et al., 2012). When designing a polymer solution (consisting of two or more polysaccharides) for fabrication of bioactive/drug-delivery systems, one needs to consider the existence of a critical polymer concentration (C ). The interactive behaviors between the coexisting polymers will be different below or above the C (i.e., minimal interference from neighboring chains or interpenetration of individual polymer chains to form an entangled network), causing large differences in the extent of entanglement and viscosity (Sun-Waterhouse et al., 2014a,b; Bekkour et al., 2014). These changes can alter the suitability of polymers for making coextruded beads, spray-dried powders, or electrospun fibers/meshes as bioactive/ drug-delivery systems. Thus, there will inevitably exist an optimal polymer concentration for achieving good delivery and release performance, and maximal nutritional value and bioactivity of both the bioactive substances of interest and the polymer carrier(s). Knowledge of the interactions among the constituents of the whole polymeric composite, and between the polymeric composite and surrounding environment forms the basis for the rational design of 3-D polymeric composites for biomedical delivery applications.

11.5 CONCLUSIONS Biocompatible and biodegradable polymers, such as alginate and chitosan, in single form or in combination, can be used to create 3-D carriers for bioactive/drug delivery. The native biopolymers can also be modified via depolymerization (to optimize MW and functional groups) and via formulation to allow tailored or optimized performance in end applications (e.g., to impart bouyancy). Ongoing breakthroughs in formulation and assembly technologies for 3-D polymeric composites provide new pathways to deliver bioactives to target sites. Ultimately, such 3-D polymeric systems may allow the construction of molecularly rationalized systems for controllable delivery and real-time detection of drug and bioactives. The selection of a polymer material and supporting additive(s) as well as processing methods should be based on the relevant regulations of the country where the end food or pharmaceutical product will be marketed.

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Further Reading

Young, D.H., Kauss, H., 1983. Release of calcium from suspension-cultured Glycine max cells by chitosan, other polycations, and polyamines in relation to effects on membrane permeability. Plant Physiol. 73, 698 702. Zentz, F., Be´douet, L., Almeida, M.J., Milet, C., Lopez, E., Giraud, M., 2001. Characterization and quantification of chitosan extracted from nacre of the abalone Haliotis tuberculata and the oyster Pinctada maxima. Mar. Biotechnol. 3, 36 44. Zhang, H., Hollister, S., 2009. Comparison of bone marrow stromal cell behaviors on poly (caprolactone) with or without surface modification: studies on cell adhesion, survival and proliferation. J. Biomater. Sci. Polym. Ed. 20, 1975 1993. Zhang, H., Neau, S.H., 2001. In vitro degradation of chitosan by a commercial enzyme preparation: effect of molecular weight and degree of deacetylation. Biomaterials 22, 1653 1658. Zhang, Y.Z., Venugopal, J., Huang, Z.M., Lim, C.T., Ramakrishna, S., 2006. Crosslinking of the electrospun gelatin nanofibers. Polymer 47, 2911 2917.

FURTHER READING Ku¨hbeck, D., Mayr, J., Ha¨ring, M., Hofmann, M., Quignard, F., Dı´az-Dı´az, D., 2015. Evaluation of the nitroaldol reaction in the presence of metal ion-crosslinked alginates. New J. Chem. 39, 2306 2315. Yabutani, T., Waterhouse, G.I.N., Sun-Waterhouse, D., Metson, J.B., Iinuma, A., Thuy, L. T.X., et al., 2014. Facile synthesis of platinum nanoparticle-containing porous carbons, and their application to amperometric glucose biosensing. Microchim. Acta 181 (1516), 1871 1878.

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