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Structural Design Principles for Delivery of Bioactive

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David Julian McClements , Eric Andrew Decker , Yeonhwa Park & Jochen Weiss
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Principles for Delivery of Bioactive Components in Nutraceuticals and Functional Foods, Critical Reviews in Food Science and
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 Critical Reviews in Food Science and Nutrition, 49:577–606 (2009)
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ISSN: 1040-8398
DOI: 10.1080/10408390902841529

Structural Design Principles for

Delivery of Bioactive Components in
Nutraceuticals and Functional Foods

DAVID JULIAN McCLEMENTS, ERIC ANDREW DECKER, YEONHWA PARK,

and JOCHEN WEISS
Department of Food Science, University of Massachusetts, Amherst, MA 01003, USA
Downloaded by [University of South Dakota] at 17:51 19 May 2013

There have been major advances in the design and fabrication of structured delivery systems for the encapsulation of
nutraceutical and functional food components. A wide variety of delivery systems is now available, each with its own
advantages and disadvantages for particular applications. This review begins by discussing some of the major nutraceutical
and functional food components that need to be delivered and highlights the main limitations to their current utilization
within the food industry. It then discusses the principles underpinning the rational design of structured delivery systems:
the structural characteristics of the building blocks; the nature of the forces holding these building blocks together; and, the
different ways of assembling these building blocks into structured delivery systems. Finally, we review the major types of
structured delivery systems that are currently available to food scientists: lipid-based (simple, multiple, multilayer, and solid
lipid particle emulsions); surfactant-based (simple micelles, mixed micelles, vesicles, and microemulsions) and biopolymer-
based (soluble complexes, coacervates, hydrogel droplets, and particles). For each type of delivery system we describe its
preparation, properties, advantages, and limitations.

Keywords nutraceuticals, functional foods, delivery systems, structural design, self-assembly, coacervation, micelles;
emulsions

INTRODUCTION appearance, flavor, stability, bioaccessibility), as well as pow-

Over the past decade or so, there has been a significant shift
in the scientific approach adopted by many researchers working
with food materials. In particular, there has been an increas-
ing awareness of the interrelationship between the nanoscopic,
microscopic, and macroscopic features of foods on the one
hand, and the bulk physiochemical properties, sensory attributes,
and the physiological performance of foods on the other hand
(Aguilera, 2000; 2006; Aguilera et al., 2000; Sanguansri and
Augustin, 2006). It is now widely recognized that the cre-
ation of novel foods or the improvement of existing foods de-
pends on a better understanding of the complex interrelation-
ship between food structure and performance. Our knowledge
of the structural basis of food properties is increasing at a rapid
pace, largely due to the availability of sophisticated analytical
tools to provide information about food structure (i.e., nano-,
micro-, and macro-structure) and food properties (i.e., rheology,
Address correspondence to David Julian McClements, Department of Food
Science, University of Massachusetts, Amherst, MA 01003. Tel: 413 545 1019;
Fax: 413 545 1262 E-mail: mcclements@foodsci.umass.edu
577
erful computers to store, analyze and represent the information
obtained. This knowledge is now being used to rationally design
structural features within foods that are known to provide spe-
cific functional performances. In this review article, we focus on
the structural design of delivery systems for nutraceuticals and
functional food components. This article focuses on the utiliza-
tion of structural design principles of assembling delivery sys-
tems with particular structures, rather than on the utilization of
processing operations to create these structures, e.g., spray dry-
ing, spray chilling, spray cooling, milling, grinding, spray coat-
ing, extrusion or freeze drying (Desai and Park, 2005; Gibbs et
al., 1999; Madene et al., 2006; Shefer and Shefer, 2003). In addi-
tion, the material covered is further limited by focusing on struc-
tured delivery systems suitable for utilization in aqueous-based
(wet) food products, rather than in oily or dried food products.
NUTRACEUTICAL AND FUNCTIONAL FOOD
COMPONENTS
Many nutraceutical and functional food components would
benefit from being encapsulated in appropriate edible delivery
 578 D. J. McCLEMENTS ET AL.
systems, including vitamins, bioactive peptides, antimicrobials,
antioxidants, flavors, colors, minerals, and preservatives (She-
fer and Shefer, 2003; Ubbink, 2002; Ubbink and Kruger,
2006; Chen et al., 2006). These functional components come
in a wide variety of different molecular forms, e.g., molec-
ular weights, conformations, polarities, and charges. In turn,
differences in molecular characteristics lead to differences in
physicochemical properties, such as solubility, partitioning,
physical state, interactions, optical characteristics, and chem-
ical stability. Consequently, different delivery systems are usu-
ally needed to address specific molecular and physicochemi-
cal concerns associated with each nutraceutical or functional
component.
An edible delivery system must perform a number of different
roles. First, the delivery system should efficiently encapsulate
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an appreciable amount of the functional component in a form
that is easily incorporated into food systems. Second, the deliv-
ery system may have to protect the functional component from
chemical degradation (e.g. oxidation or hydrolysis) so that it
remains in its active state. Third, the delivery system may have
to release the functional component at a particular site of action,
at a controlled rate and/or in response to a specific environ-
mental trigger (e.g., pH, ionic strength or temperature). Fourth,
the delivery system should be compatible with the specific food
matrix that surrounds it. Fifth, the delivery system should be re-
sistant to the various kinds of environmental stresses that a food
experiences during its production, storage, transport, and con-
sumption. A wide variety of different types of delivery systems
have been developed to encapsulate functional agents, includ-
ing simple solutions, association colloids, emulsions, suspen-
sions, gels, solid matrices, etc. Each type of delivery system
has its own specific advantages and disadvantages for encapsu-
lation, protection, and delivery of functional agents, as well as
in its cost, regulatory status, ease of use, biodegradability, bio-
compatibility etc. In this review article we will focus on struc-
tured delivery systems that can be fabricated entirely from food
grade materials using relatively simple processing operations.
The major types of functional food components that need to be
encapsulated and delivered are briefly highlighted below, along
with a brief overview of current challenges to their application
(Table 1).
Bioactive Lipids
Lipids contain a broad group of chemically diverse com-
pounds that are soluble in organic solvents. A variety of dif-
ferent types or classes of molecules fall within this category
in foods, including acylglycerols, fatty acids, phospholipids,
carotenoids, phytosterols, and oil-soluble vitamins. In this
section, we focus on those lipids that have been shown to
have some specific health benefit that is beyond that nor-
mally associated with their established role in growth, develop-
ment, and other normal body functions (Redgwell and Fischer,
2005).
Table 1 Summary of major lipophilic nutraceutical components that need to
be delivered into foods
Name Types Potential Nutritional Benefits
Fatty Acids ω - 3 Fatty Acids, Coronary Heart Disease,
Conjugated Linoleic Bone Health, Immune
Acid, Butyric Acid, Response Disorders,
Weight Gain, Stroke
Prevention, Mental Health,
Cancer, and Visual Acuity
Carotenoids β - Carotene, Lycopene, Cancer, Coronary Heart
Lutein, and Zeaxanthin Disease, Macular
Degeneration, and
Cataracts
Antioxidants Tocopherols, Flavonoids, Coronary Heart Disease,
Polyphenols Cancer, and Urinary Tract
Disease
Phytosterols Stigmasterol, β-Sitosterol, Coronary Heart Disease
and Campesterol
Carotenoids
Carotenoids are a diverse group of over >600 different com-
pounds that contribute to the yellow to red colors found in many
foods. Carotenoids are polyenes consisting of 3 to 13 conju-
gated double bonds and up to 6 carbon ring structures at one
or both ends of the molecule. Carotenoids containing oxygen
are known as xanthophylls (e.g. lutein and zeaxanthin) while
those without oxygen are known as carotenes (e.g., lycopene
and β-carotene). The carotenoids have several potential health
benefits. Lutein and zeaxanthin, which are found in high concen-
trations in the human eye, have been postulated to be beneficial
to age-related macular degeneration and cataracts (Stringham
and Hammond, 2005). Lycopene, which is found in high con-
centrations in tomatoes, is thought to decrease the risk of prostate
cancer (Basu and Imrhan, 2007). While some researchers sug-
gest that the health benefits attributed to these compounds are
due to their antioxidant activity, others suggest that their bioac-
tivity is related to their ability to absorb light (eye health), their
anti-inflammatory activity, or their in vivo metabolism into ac-
tive compounds (Stringham and Hammond, 2005; Lindshield
et al., 2007; Hussein et al., 2006). Although carotenoids are
generally thought to be beneficial for health, clinical trials have
found that large doses of β-carotene increase the risk of lung
cancer (Bendich, 2004). In general, carotenoids are not strong
antioxidants when added to foods (Haila et al., 1996; Heinonen
et al., 1997). An additional challenge to using carotenoids as in-
gredients in functional foods is their high melting point, making
them crystalline at food storage and body temperatures.
Endogenous carotenoids in foods are generally stable. How-
ever, as food additives, carotenoids are relatively unstable in
food systems because they are susceptible to light, oxygen,
and autooxidation (Xianquan et al., 2005). In addition, disper-
sion of carotenoids into ingredient systems can result in their
rapid degradation (Heinonen et al, 1997; Ribeiro et al., 2003).
Carotenoids can be degraded by reactions that cause the loss of
double bonds or the scission of the molecule. In addition, the
double bonds in carotenoids can undergo isomerization to the cis
 DESIGN AND FABRICATION OF STRUCTURED DELIVERY SYSTEMS
configuration (Xianquan et al., 2005). Isomerization reactions
might actually be beneficial since cis isomers of carotenoids
such as lycopene are thought to be more bioavailable and bioac-
tive (Schieber and Carle, 2005).
Conjugated Linoleic Acid (CLA)
Conjugated linoleic acid (CLA) was originally identified as
an anti-cancer principal component from ground beef extracts
(Ha et al., 1988; Pariza et al., 1979). Since then, CLA has
shown a wide range of biologically beneficial activities; de-
creased severity of atherosclerosis (Lee et al., 1994; Nicolosi
et al., 1997), reduction of adverse effects of immune stimula-
tion (Cook et al., 1998; Miller et al., 1994), growth promotion
in young rats (Chin et al., 1994), a reduction of body fat, and an
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increase in lean body mass in several animal species (Park and
Pariza, 2007).
Even though CLA implies a number of geometric and po-
sitional isomers, current research focuses mainly on the cis-
9,trans-11 and trans-10,cis-12 isomers. This is one explanation
for the variety of biological activities. The cis-9,trans-11 CLA
isomer is the main CLA isomer present in food, which originates
from biohydrogenation of linoleic acid to stearic acid by rumen
bacteria (Kepler et al., 1966). The trans-10,cis-12 CLA isomer
is found as a minor component in food, but is one of two major
isomers in synthetic CLA (Kepler et al., 1966). Studies have
found that the wide range of CLA’s activities results from inter-
action between these two CLA isomers. These major isomers
have shown additive or synergistic, independent, or antagonistic
effects (Park and Pariza, 2007).
Due to relatively low levels of CLA in natural products, CLA
has been applied into foods to promote health benefits. Most pre-
vious studies used the free fatty acid form of CLA, and this form
has potential adverse effects which include gastrointestinal dis-
turbances, such as diarrhea, constipation, and flatulence (Kepler
et al., 1966). Based on the observations that triacylglyceride and
free forms of CLA have comparable bioactivities, the triacyl-
glyceride form of CLA has been successfully incorporated in
orange juice, yogurt, and milk in Spain (Kepler et al., 1966). The
long-term oxidative stability of CLA still needs to be validated
in food systems.
Omega-3 Fatty Acids
Omega-3 (ω-3) fatty acids are unsaturated fatty acids that
have a double bond that is three carbon atoms from the methyl
end of the molecule. The most common ω-3 fatty acids are α-
linolenic acid (ALA, 18:3), eicosapentaenoic acid (EPA, 20:5),
and docosahexaenoic acid (DHA, 22:6). Of these three, the long
chain ω-3 fatty acids, EPA and DHA are the most bioactive.
Since humans are not efficient at converting ALA to the long
chain ω-3 fatty acids (Francois et al., 2003; Ismail, 2005) health
benefits have been mainly attributed to dietary EPA and DHA
(Hibbeln et al., 2006). Omega-3 fatty acids can have a major
impact on health because they have numerous physiological
579
roles such as impacting cell membrane fluidity, cellular signal-
ing, gene expression, and eicosanoid metabolism. The important
physiological role of ω-3 fatty acids has been attributed to their
ability to decrease the risks of cardiovascular disease, diseases
affected by immune response disorders (e.g., type 2 diabetes,
inflammatory bowel diseases, and rheumatoid arthritis), mental
disorders, as well as benefit infant development.
A recent study that surveyed the relationship between long
chain ω-3 fatty acid and disease in 38 different countries found
an inverse relationship between long chain ω-3 availability
and cardiovascular disease mortality in both men and women
(Hibbeln et al., 2006). Potential protective mechanisms of ω-3s
on CHD include effects on lipid metabolism, heart function,
vasodilation, platelet aggregation, and blood clotting. Clinical
trials using EPA and DHA supplementation of 875 to 1000
mg/day reported a reduced risk of sudden cardiac death but
no change in nonfatal myocardial infarction (Marchioli et al.,
2002; Giannuzzi et al., 2006). The ability of long chain ω-3’s
to decrease sudden cardiac death has been attributed to their
ability to modify conductance in muscle, making the heart less
susceptible to arrhythmias (Kang and Leaf, 2000).
Dietary long chain ω-3 fatty acids are also beneficial for
inflammatory diseases. For example, dietary long chain ω-3s
can decrease morning stiffness, joint pain, grip strength, and
reduce the need for anti-inflammatory drugs in patients suffering
from rheumatoid arthritis (Cleland et al., 1988; Kremer et al.,
1985; Geusens et al., 1994). Fish oil has also been shown to
be beneficial for inflammatory bowel diseases such as Crohn’s
disease (Belluzzi et al., 1996).
Evidence has shown that dietary ω-3 fatty acids are beneficial
for pregnant and lactating women and their children. During
pregnancy and lactation there is a preferential transport of ω-3s
from mothers to their infants that can result in depletion of the
mothers ω-3 fatty acids stores. Dietary supplementation of ω-
3s [200–400 mg docosahexaenoic acid (DHA)/d] helps reverse
depletion of maternal DHA stores (Makrides and Gibson, 2000).
In addition, supplementation (200 mg DHA/d) increases human
milk DHA concentration almost 2-fold (Fidler et al., 2000).
DHA has been associated with a decreased risk of postpartum
depression (Jensen, 2006). Dietary ω-3 fatty acids have also
been reported to improve visual acuity and cognitive function
in infants, presumably because the DHA is the major fatty acid
in visual and nervous tissue (Cheatham et al., 2006).
The growing list of disorders positively affected by dietary
ω-3 fatty acids strongly suggests that large portions of the pop-
ulation would benefit from increased consumption of ω-3 fatty
acids making them an excellent candidate for incorporation into
functional foods. However, numerous challenges exist in the
production, transportation, and storage of ω-3 fatty acid fortified
functional foods, since these lipids are extremely susceptible to
oxidative deterioration. For example, DHA has been estimated
to be over 50 times more susceptible to oxidation than oleic
acid (Frankel, 2005). In addition, the breakdown products of
ω-3 fatty acid oxidation have very low sensory threshold val-
ues meaning that they can be detected at very early stages of
 580 D. J. McCLEMENTS ET AL.

oxidation. Oxidation of ω-3 fatty acids is a complex chemical re- to use elevated temperatures), or they may adversely affect
action that often requires multiple antioxidant hurdle technolo- the long-term stability or organoleptic properties of the final
gies for adequate stabilization. Encapsulation of omega-3 fatty product.
acids has been found to be an excellent method for stabilization (iii) The bioactive lipid and associated delivery system should
(Garg et al., 2006). be compatible with the food matrix, i.e., it should not ad-
versely affect the appearance, texture, stability, or flavor of
the product. A bioactive lipid contained within an emulsion
Phytosterols
will cause a product to appear turbid or opaque due to light
Phytosterols are a group of phytochemicals that include scattering by the droplets. On the other hand, a bioactive
compounds such as stigmasterol, β-sitosterol, and campesterol. lipid contained within a microemulsion will appear trans-
Plant stanols, which are found naturally at lower concentrations parent because the particles are so small that they do not
than sterols, can be produced by the hydrogenation of phytos- scatter light strongly;
terols. Phytosterols concentrations in vegetable oils range from (iv) The lipids should maintain their potential bioactivity within
0.1 to 1.0% (Chaiyasit et al., 2007) and typical phytosterols con- the food product during its manufacture, storage, transport,
sumption is in the range of 200–400 mg/day. The production of and utilization. Some bioactive lipids are chemically labile
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phytosterol fortified foods has become popular due to the abil- and their activity may be adversely affected by light, oxy-
ity of phytosterols to decrease total and low density lipoprotein gen, or pro-oxidants (e.g., ω-3 fatty acids, β-carotene, or
cholesterol in humans by inhibiting the absorption of dietary lycopene);
cholesterol (Wong, 2001; Ostlund, 2004). Intake of 1.6 g phy- (v) The lipids should maintain their bioactivity within the hu-
tosterols/day results in an approximately 10% reduction in LDL man body prior to being delivered to the desired site-of-
cholesterol (Hallikainen et al., 2000). The intestinal absorption action, e.g., they may have to resist the high acidity and
of phytosterols is very low so dietary phytosterols do not have enzyme activity of the stomach.
adverse effects on health.
Incorporation of phytosterols into foods is difficult due to
their high melting point and their tendency to form insoluble Bioactive Proteins, Peptides, and Amino Acids
crystals. This has been overcome by esterification of phytos-
terols to polyunsaturated fatty acids which increase sterol solu- As well as providing energy and essential nutrients to the
bility. Upon ingestion of phytosterols esters, lipases hydrolyze diet, a number of proteins, peptides, and amino acids have also
the fatty acid to produce free phytosterols. Phytosterols were been claimed to have additional biological functions, such as
originally added to high fat foods (e.g. margarine) where sol- acting as growth factors, antihypertensive agents, antimicrobial
ublization and dispersion are relatively simple. For phytosterols agents, antioxidants, food intake modifiers, and immune reg-
to be introduced into aqueous-based foods, they need to be ei- ulatory factors (Playne et al., 2003; Ward and German, 2004;
ther suspended or emulsified. Phytosterols oxidation products Meisel, 1997).
have been observed in model systems, oils and food products
(Bortolomeazzi et al., 2003; Dutta, 1997; Lambelet et al., 2003;
Soupas et al., 2004; Cercaci et al., 2007). It is not clear whether Proteins
oxidized phytosterols lose their bioactivity or are toxic in a man- Proteins are natural polymers that consist of amino acids
ner similar to oxidized cholesterol. As with other bioactive lipids linked by peptide bonds. Proteins may be part of composi-
that are susceptible to oxidation, encapsulation of phytosterols tionally and structurally complex natural ingredients (such as
could increase their oxidative stability. milk, flour, eggs, or meat) or they may be isolated functional
ingredients (such as gelatin, whey protein, or caseinate). The
Challenges to Delivery of Bioactive Lipids type, number, and sequence of the amino acids within a protein
determine its molecular characteristics e.g., molecular weight,
The major challenges associated with delivering bioactive conformation, electrical charge, flexibility, and hydrophobicity.
lipids in foods are: In turn, these molecular characteristics determine a protein’s
functional and nutritional attributes, e.g., their ability to thicken
(i) Most bioactive lipids have a low water-solubility and so solutions, form gels, hold water, adsorb to interfaces, stabilize
they must be incorporated into some kind of delivery system emulsions and foams, catalyze enzyme reactions, and bind spe-
(e.g., microemulsions or emulsions) to make them readily cific molecules. Proteins (and the peptides resulting from their
dispersible in aqueous-based food products, such as bever- digestion) from a range of natural sources have been shown
ages, desserts, dressings, and sauces; to be bioactive, including soy, dairy, fish, and meat proteins
(ii) Some bioactive lipids are crystalline at room temperature (Kussmann and Affolter, 2006; Wang and de Mejia, 2005;
in their pure form, e.g., carotenoids. The crystalline nature Chatterton et al., 2006; Kim and Mendis, 2006). These bioac-
of these lipids may provide challenges in the manufacture tivity affects include inhibition of the angiotensin-converting
of certain types of food products (e.g., it may be necessary enzyme (ACE), antimicrobial activity, antioxidant activity,
 DESIGN AND FABRICATION OF STRUCTURED DELIVERY SYSTEMS
anti-carcinogenic activity, hypocholesterolemic effect, reduced
serum triglycerides, increased lean muscle mass, protection
against pathogens, regulation of blood glucose levels, and sati-
ety effects (Playne et al., 2003; Chatterton et al., 2006; Severin
and Xia, 2005; Seyler et al., 2007). For example, dairy proteins,
such as lactoferrin, lactoperoxidase, and immunoglobulin, are
believed to be important mediators of the human immune sys-
tem, as well as having antibacterial, antiviral, antiparasite, and
antifungal properties (Playne et al., 2003; Zimecki et al., 1998;
Tsuda et al., 2000; Korhonen et al., 2000).
Peptides
Certain types of peptides have been shown to have poten-
tial bioactivity, such as mineral binding, antioxidant activity,
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antimicrobial activity, cancer prevention, and protection against
heart disease (Playne et al., 2003; Muir, 2005; Korhonen and
Pihlanto, 2003; Meisel, 2005). These peptides are usually de-
rived from proteins by hydrolysis, which may be carried out
prior to consumption by a food or ingredient manufacturer
(e.g., by chemical, enzymatic, or fermentation methods), or it
may take place within the human digestive system after food
consumption (e.g., by acids or enzymes) (Playne et al., 2003;
Meisel, 1997; Wang and De Mejia, 2005; Muir, 2005; Lopez-
Fandino et al., 2006). For example, casein phosphopeptides
(CPP) are calcium binding peptides that have been demonstrated
to exhibit a number of bioactive functions, such as protection
against demineralization of teeth, antioxidant activity, antimi-
crobial activity, anti-cancer properties, and immuno-stimulation
(Playne et al., 2003; Korhonen and Pihlanto, 2003). Other pep-
tides derived from milk, plants, and fish have been shown to be
capable of reducing blood pressure (Muir, 2005).
Amino Acids
Certain amino acids have also been demonstrated to exhibit
specific biological activities. Tryptophan is a precursor of brain
serotonin synthesis while tyrosine is a precursor for dopamine.
Both amino acids are linked with mood changes and particularly
tyrosine is also linked to reduced stress responses in humans
(Banderet and Lieberman, 1989; Chinevere et al., 2002; Young,
1993). The branched-chain amino acids, leucine, isoleucine,
and valine, participate in a variety of important biological func-
tions in the brain including those from tryptophan and tyrosine
(During et al., 1988; Fernstrom, 2005; Harris et al., 2005; Russo
et al., 2003).
Challenges to Delivery of Proteins, Peptides, and Amino Acids
The main challenges associated with delivering bioactive
proteins, peptides, and amino acids in food matrices are:
(i) To ensure that they can be incorporated in a form where
they are compatible with the food matrix, i.e., they do not
581
cause adverse affects of appearance, texture, stability, or
flavor. For example, certain types of bioactive peptides and
proteins have a bitter or astringent mouthfeel that limits
their application in certain foods (Tripathi and Misra, 2005;
Pedrosa et al., 2006; Cho et al., 2004);
(ii) To ensure that they maintain their potential bioactivity dur-
ing the production, storage, transport, and utilization of the
food. Some types of proteins may lose their bioactivity
during extraction, purification, or thermal processing steps
(Chatterton et al., 2006);
(iii) To ensure that they maintain or develop their bioactivity
within the human body prior to being delivered to the re-
quired site of action. For example, some proteins or peptides
may have to be resistant to breakdown under the high acid-
ity and specific enzyme activities within the stomach so
that they can be released in the small intestine. On the other
hand, a certain type and amount of hydrolysis may have to
occur in the stomach or small intestine to release specific
bioactive peptides or amino acids (Meisel, 1997; 2005).
Bioactive Carbohydrates
The major class of bioactive carbohydrates that need to be de-
livered in foods are dietary fibers. The term “dietary fiber” refers
to a complex class of materials that includes non-digestible car-
bohydrates and lignin (Redgwell and Fischer, 2005; Dikeman
and Fahey, 2006). Specific dietary fibers can be classified in a
number of different ways, including their biological origin, their
molecular structure, their physicochemical properties, and their
physiological effects (Redgwell and Fischer, 2005; Wildman
and Kelley, 2007). In this section we are primarily concerned
with soluble non-digestible polysaccharides that have been iso-
lated from their natural environment and converted into food
ingredients, rather than the fibers naturally present in whole
foods, such as grains, fruits, and vegetables. This is because
many isolated soluble fibers have been shown to be bioactive
food components, and may need to be encapsulated in structured
delivery systems. These fibers vary according to the type, num-
ber, distribution, and bonding of the monosaccharide units they
contain: they may be neutral, anionic, or cationic; they may have
low, medium, or high molecular weights; they may be linear or
branched; they may adopt ordered or disordered conformations;
they may vary in hydrophobicity; they may be homopolymers
or heteropolymers (Cui, 2005). These differences in molecular
characteristics cause differences in their physicochemical prop-
erties, e.g., water solubility, viscosity enhancement capacity, gel
formation, opacity, surface activity, and binding capacity (Cui,
2005). In turn, these differences in molecular and physicochem-
ical characteristics cause significant alterations in their bioac-
tivity. The main bioactive functions that have been attributed
to dietary fibers are cholesterol reduction, modulation of blood
glucose levels, prevention of certain cancers, prevention of con-
stipation, and pre-biotic effects (Redgwell and Fischer, 2005).
Nevertheless, there is still a poor understanding of the molecular
 582 D. J. McCLEMENTS ET AL.
and physicochemical basis for the various bioactive functions
that have been attributed to different kinds of dietary fibers. At
present a large proportion of the general population in devel-
oped countries does not consume the 25 to 30 of dietary fiber
recommended per day for a healthy diet (Redgwell and Fischer,
2005). Consequently, there is a need to increase the consumption
of foods rich in dietary fibers in order to achieve these potential
health benefits.
Challenges to Delivery of Bioactive Carbohydrates
One of the major problems associated with increasing the
amount of dietary fiber present in foods to a level that has
demonstrated bioactivity is that they often have an adverse im-
pact on product quality and/or sensory attributes, e.g., stability,
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appearance, texture, mouthfeel, or flavor. For example, many
soluble dietary fibers cause a large increase in the viscosity of
aqueous solutions when used at relatively low concentrations,
which can impart an undesirable texture or mouthfeel on a prod-
uct. A well-designed structured delivery system may be capable
of increasing the total amount of specific dietary fibers in a food,
without adversely impacting its organoleptic or physicochemi-
cal properties.
Essential Minerals
Along with macronutrients, adequate micronutrients in the
daily diet are also important to maintain proper human health,
e.g., essential minerals (White and Broadley, 2005). Three types
of approaches are commonly used to increase the intake of es-
sential minerals in foods: supplementation, fortification, and
consumer education to encourage dietary change (Salgueiro
et al., 2002). The primary focus of this review is the development
of structured delivery systems to encapsulate and release bioac-
tive food components, and therefore we are mainly concerned
with food fortification with essential minerals. Food fortification
has proven to be effective for certain minerals, such as iodized
salt or fluoride toothpastes and tap water (Poletti et al., 2004).
However, there are still challenges for other valuable essential
minerals, such as Fe, Zn, Ca, Se, and Cr. The following section
will discuss the importance of specific minerals and will briefly
highlight the current challenges to their fortification within the
food industry.
Iron
Iron is an essential element for the proper function of sev-
eral human proteins, such as hemoglobin, myoglobin, and cy-
tochromes (Bovell-Benjamin and Guinard, 2003). Rates of iron
absorption depend on a range of factors, including the composi-
tion of the meal consumed, the physicochemical aspects of the
iron added, and the specific iron requirements of the individ-
ual. Iron fortification has proven to be the most cost-effective
approach to supplement iron in foods (Bovell-Benjamin and
Guinard, 2003). The main challenges to iron fortification of
foods are its relatively low bioavailability, its propensity to in-
duce undesirable chemical changes of certain food components
(e.g., lipid oxidation and color changes), and its undesirable
taste (Bovell-Benjamin and Guinard, 2003; Fairweather-Tait
and Teucher, 2002). Iron compounds that are generally recog-
nized as safe (GRAS) have been tabulated elsewhere (Salgueiro
et al., 2002). Water-soluble iron compounds are more bioavail-
able but they tend to promote oxidative reactions and have an
undesirable metallic taste in liquid foods. Thus these water-
soluble iron compounds are typically only used in low-moisture
foods. Water-insoluble iron compounds that are soluble in di-
lute acid solutions are less chemically reactive in foods, but
still have a high bioavailability due to their solubilization in the
stomach by gastric juices (Lynch et al., 2005). However, these
compounds can only be used in limited food applications. The
iron compounds that are water-insoluble and poorly soluble in
diluted acid solutions (such as elemental iron) have more stabil-
ity without any adverse effects on taste but their bioavailability
is poor (Salgueiro et al., 2002). Absorption of iron can be im-
proved by chelation (e.g., with ascorbic acid or EDTA) or with
certain encapsulation technologies, but the non-GRAS status of
EDTA and potentially high costs are of concern (Salgueiro et al.,
2002; Fairweather-Tait and Teucher, 2002; Lynch et al., 2005).
Phytate, polyphenols, and excessive calcium can reduce non-
heme iron absorption, while excessive iron can interfere with
zinc absorption (The Institute of Medicine, 2006).
Zinc
Zinc is an essential mineral for proper growth and develop-
ment, involved in a number of metabolic processes. Zinc com-
pounds used for supplementation and fortification have been
tabulated elsewhere (Salgueiro et al., 2002). Among these com-
pounds five are listed as GRAS by the FDA that may be used for
fortifying food; zinc sulfate, zinc chloride, zinc gluconate, zinc
oxide, and zinc stearate. The main challenge with zinc addition
in food is finding a suitable zinc compound. Zinc oxide is com-
monly used for fortifying cereals, which is cheap but has low
bioavailability. Zinc sulfate is the other commonly used com-
pound but it adversely affects sensory characteristics (Salgueiro
et al., 2002). Too much iron, calcium, phosphorous, and phytic
acid may decrease zinc absorption. On the other hand, too much
zinc can interfere with proper copper absorption (The Institute
of Medicine, 2006).
Calcium
As a main component in bone, calcium is one of the most im-
portant minerals for proper bone health. Dairy products are the
major source of calcium, therefore those who do not consume
dairy products are at risk of inadequate calcium intake (Gao
et al., 2006; Romanchik-Cerpovicz and McKemie, 2007). Cer-
tain leafy vegetables are rich sources of calcium but its bioava-
iability is limited due to the presence of oxalate and phytic acid
 DESIGN AND FABRICATION OF STRUCTURED DELIVERY SYSTEMS
(White and Broadley, 2005). In addition, too much caffeine,
sodium, and phosphorous intakes may either increase urinary
loss of calcium or interfere with calcium absorption (The Insti-
tute of Medicine 2006). Approved calcium compounds are listed
elsewhere (Fairweather-Tait and Teucher, 2002). Calcium forti-
fication in fruit juices, carbonated beverages, yeast breads, and
breakfast cereals has been used (Fairweather-Tait and Teucher,
2002; Romanchik-Cerpovicz and McKemie, 2007). In gen-
eral, calcium-fortified foods have similar physical and sensory
characteristics compared to non-fortified counterparts; however,
sensory evaluations are necessary (Romanchik-Cerpovicz and
McKemie, 2007). Too much use of calcium phosphate should
be with caution since high levels of phosphorus have potential
negative effects on bone health (Cerklewski, 2005). On the other
hand, high intakes of calcium may decrease iron, magnesium,
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and zinc absorption (The Institute of Medicine, 2006).
Selenium
Selenium is an antioxidant nutrient and is also essential for
iodine metabolism in the thyroid (White and Broadley, 2005).
Selenium is present either in organic forms (selenomethionine
and selenocysteine) in both animal tissues and plants, or inor-
ganic forms (selenate and selenite) mostly in plants (White and
Broadley, 2005; Lyons et al., 2003). Although organic forms of
selenium have high bioavailability, most fortification and sup-
plementation of selenium are as inorganic forms. Interactions
with dietary components or organoleptic characteristics of sele-
nium are currently unknown.
Chromium
Chromium potentates the action of insulin thus is known
to improve glucose tolerance. The form of chromium found in
foods is trivalent chromium or chromium III (The Institute of
Medicine, 2006). Even though the requirement for chromium is
not high, 13.4 µg/1,000 kcal, due to the low absorption rate for
chromium (ranging from 0.4–2.5%), it may need to be fortified
in food (The Institute of Medicine, 2006). There are potential
interactions between chromium and dietary components, where
phytate may decrease chromium absorption, simple sugars may
increase chromium excretion, and vitamin C may enhance the
absorption of chromium (The Institute of Medicine, 2006). The
organoleptic characteristics of chromium are currently unknown
Challenges to Delivery of Bioactive Minerals
In summary, there are a number of potential challenges as-
sociated with incorporating bioactive minerals into foods:
• Mineral ions decrease the electrostatic repulsion between
electrically charged food components (e.g., macromolecules
and colloidal particles) by binding to oppositely charged sur-
faces (multivalent ions) and by screening electrostatic interac-
tions (monovalent and multivalent ions) (McClements, 2005).
583
Consequently, they are capable of promoting the aggregation
and phase separation of charged macromolecules (e.g., pro-
teins and polysaccharides) and colloidal particles (e.g., fat
droplets, air bubbles, particulates) in some foods, which usu-
ally has a negative impact on the appearance, texture, mouth-
feel, and stability of food products.
• Some mineral ions are capable of catalyzing the chemical
degradation of specific food components. For example, tran-
sition metals such as iron and copper are capable of catalyzing
the oxidative degradation of ω-3 fatty acids and carotenoids.
• Some minerals have a naturally low bioavailability or their
bioavailability is adversely decreased by interactions with
other food components. For example, the absorption of cer-
tain essential minerals is reduced because of their interactions
with phytic acid and tannins from plants.
• Some minerals impart an undesirable taste or mouthfeel to
food products, e.g., high levels of soluble iron.
DESIRABLE CHARACTERISTICS OF DELIVERY
SYSTEMS
As will be seen later, there are a large number of different
delivery systems that could be used to deliver functional food
components. It is therefore useful to have some criteria that can
be used to distinguish between different delivery systems, so
that one can select the most appropriate system for a particular
application. Some of the most important criteria to consider
when developing or selecting a delivery system are listed below:
• Loading capacity: The loading capacity (LC) is a measure
of the mass of encapsulated material per unit mass of carrier
material: LC = ME /MC . Ideally, a delivery system should
have a high loading capacity.
• Loading efficiency: The loading efficiency (LE) is a measure
of the ability of the delivery system to retain the encapsulated
material over time: LE = 100 × ME (t)/ME (0), where ME (t)
and ME (0) are the mass of encapsulated material at time t and
0, respectively. Ideally, one would like the loading efficiency
to remain high (100%) throughout storage.
• Delivery efficiency: The delivery efficiency (DE) is a measure
of the ability of the delivery system to deliver the encapsu-
lated material at the required site of action: DE = 100 ×
ME (I))/ME (D), where ME (I) and ME (D) are the masses of en-
capsulated material in the initial delivery system and that are
delivered to the site of action, respectively. Ideally, one would
like the delivery efficiency to be high (100%).
• Delivery mechanism: The delivery system may have to be
designed so that it carries the functional component to a par-
ticular site-of-action and then releases it. The release may
have to be at a controlled rate or in response to a particu-
lar environmental trigger (e.g., pH, ionic strength, enzyme
activity, or temperature).
• Protection against chemical degradation: The delivery sys-
tem may have to be designed to protect an encapsulated
 584 D. J. McCLEMENTS ET AL.
material against some form of chemical degradation mecha-
nism, e.g., oxidation, hydrolysis, etc. The rate of these chemi-
cal degradation reactions may be promoted by certain factors
that need to be controlled, such as heat, light, oxygen, or
specific chemicals.
• Food matrix compatibility: The delivery system should be
compatible with the surrounding food matrix, i.e., it should
not adversely affect the appearance, texture, flavor, or stability
of the final product.
• Food grade: The delivery system should be fabricated from
food-grade (GRAS) ingredients using easily implemented
processing operations.
• Economic Production: The delivery system should be capa-
ble of being economically manufactured using inexpensive
ingredients. Ultimately, the benefits gained from encapsulat-
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ing the functional component (e.g. improved shelf life, en-
hanced marketability, novel functionality) should outweigh
any additional costs associated with encapsulation.
• Bioactivity: A delivery system should either improve or at
least not adversely affect the bioavailability of the encapsu-
lated component.
FOOD ARCHITECTURE: DESIGNING STRUCTURES
FROM FOOD COMPONENTS
A brief discussion of the major design principles that can
be utilized to assemble structured delivery systems is given in
this section. We will begin by giving an overview of the ma-
jor interactions responsible for the structural organization of
food components: hydrophobic interactions; electrostatic inter-
actions; hydrogen bonds; entropy effects. We will then discuss
the structural properties of the different food components that
are typically used as building blocks to assemble delivery sys-
tems. Finally, we will outline some of the major types of design
principles that are utilized to assemble these building blocks
into structured delivery systems.
Molecular and Colloidal Interactions
Knowledge of the origin and nature of the various molecular
and colloidal forces that act between food components is es-
sential for understanding how to rationally assemble structured
delivery systems with specific functional performances. In this
section, we provide a brief overview of the most important inter-
actions that operate between molecules and colloidal particles
in foods.
Electrostatic Interactions
Electrostatic interactions are important for food components
that have an electrical charge under the conditions where they
are used, e.g., proteins, ionic polysaccharides, ionic surfactants,
phospholipids, mineral ions, acids, and bases (McClements,
2005). Many food components have weak acid groups (e.g.,
-COOH) or base groups (e.g., -NH2 ) and so their electrical
charge is dependent on the prevailing pH relative to the pKa
of the ionizable groups. Electrostatic interactions may be either
attractive or repulsive depending on whether the charge groups
involved have opposite or similar signs. Electrostatic attraction
is commonly used as the driving force to assemble charged food
components into specific structures, e.g., multilayers or coac-
ervates. The electrostatic interaction that occurs when two or
more charged groups come into close proximity is comprised of
an enthalpy component due to changes in the overall electrical
forces and an entropy component due to release of counter-ions.
The strength and range of electrostatic interactions decreases
with increasing ionic strength due to electrostatic screening ef-
fects. The most common means of manipulating the electrostatic
interactions between food components is therefore to alter the
pH and/or ionic strength of the aqueous solution. Another type
of electrostatic interaction that is commonly used in the assem-
bly for food components is electrostatic bridging, i.e., a charged
component (such as a multivalent mineral ion or biopolymer) is
used to link together two or more oppositely charged compo-
nents (e.g., oil droplets or biopolymers).
Hydrophobic Interactions
Hydrophobic interactions arise between food components
that have non-polar groups when they are dispersed in aqueous
solutions, and they manifest themselves as a tendency for the
non-polar groups to associate with each other (McClements,
2005). The molecular origin of the hydrophobic interaction is
the fact that water molecules can form relatively strong hydro-
gen bonds with other water molecules, but not with non-polar
groups. The hydrophobic interaction is comprised of an enthalpy
component due to the change in the overall strength of the forces
(e.g., hydrogen bonding and van der Waals forces) when two
or more non-polar groups associate, and an entropy component
due to the change in the structural organization of the water
molecules surrounding the non-polar groups. Hydrophobic in-
teractions tend to increase in strength when the temperature is
increased, and decrease in strength when the dielectric constant
of the aqueous phase is decreased (e.g., by adding alcohol).
Hydrogen Bonding
Hydrogen bonding is important for food components that
have polar groups that are capable of forming relatively strong
hydrogen bonds with other polar groups on the same or on
different molecules (McClements, 2005). They are formed be-
tween a lone pair of electrons on an electronegative atom (such
as oxygen), and a hydrogen atom on a neighboring group, i.e.
O Hδ+ . . .Oδ− . Hydrogen bonds tend to decrease in strength as
the temperature is increased. Hydrogen bonding is partly re-
sponsible for the molecular structures found within many types
of food biopolymer (e.g., helical or sheet-like regions) and for
holding together molecules in various aggregates and gels (e.g.,
in gelatin gels).
 DESIGN AND FABRICATION OF STRUCTURED DELIVERY SYSTEMS
Excluded Volume
Exclude volume or steric exclusion effects are important for
food components that are capable of occupying relatively large
volumes within a system, thereby excluding other components
from occupying the same volume (McClements, 2005). The
thermodynamic driving force for this type of interaction is a
configurational entropy affect, i.e., a change in the number of
configurations available to the molecules or particles in the sys-
tem. Excluded volume effects tend to become more important as
the effective volume of the molecules or particles increases and
as their molar concentration in the system increases. Excluded
volume effects are important in the assembly of various kinds
of structures in foods, e.g., thermodynamic incompatibility, de-
pletion flocculation, and steric repulsion.
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Controlling Interactions
The relative importance of these interactions in a particular
system depends on the types of food components involved (e.g.,
molecular weight, charge density vs. pH profile, flexibility, hy-
drophobicity), the solution composition (e.g., pH, ionic strength,
and dielectric constant) and the environmental conditions, (e.g.,
temperature, shearing). By modulating these parameters it is
possible to control the interactions between the food compo-
nents and therefore assemble novel structures. Theoretical or
semi-empirical equations are available to calculate many of the
interactions mentioned above between molecules or particles
(McClements, 2005; Hunter, 1986; Israelachvili, 1992). These
equations are useful for identifying the most important factors
that impact the sign, strength, and range of the various interac-
tions operating between molecules and particles.
Molecular and Colloidal Architecture
Knowledge of the origin and nature of the various molecu-
lar and colloidal interactions that act between food components
is necessary but not sufficient to understand how novel struc-
tures can be designed and assembled. The rational formation
of these structures also depends on knowledge of the molecular
architecture of the various food components involved, i.e., their
molecular weight and conformation, and the arrangement of the
various functional groups (non-polar, polar, and ionic) within
the molecules. Some types of food ingredients are much more
suitable for constructing structured delivery systems than others
because of their unique molecular features.
Lipids
Lipids are compounds that are soluble in organic solvents,
but insoluble or only sparingly soluble in water (McClements,
2005). This group of compounds contains a large number
of different types of molecules, including acylglycerols,
fatty acids, and phospholipids. Triacylglycerols are the most
common lipid in foods, and therefore we will largely concern
ourselves with their properties. Food lipids are predominantly
585
non-polar molecules because they contain significantly larger
amounts of hydrocarbon groups (aliphatic or aromatic) than
polar or charged groups. Consequently, the dominant attractive
force acting between lipid molecules is the relatively weak van
der Waals interaction. The most important physicochemical
properties of lipids when used to build structured delivery
systems are their immiscibility with water, their ability to
solubilize lipophilic functional components, their rheological
properties, their solid fat content versus temperature profile,
the nature of any crystals formed, and their chemical stability.
Surfactants
The term “surfactant” is used to refer to surface-active
molecules that consist of a hydrophilic “head” group attached
to a lipophilic “tail” group (McClements, 2005). Surfactants
can be represented by the formula RX, where X represents the
hydrophilic head and R the lipophilic tail. The functional perfor-
mance of a particular surfactant depends on the characteristics
of its head and tail groups. The head group may be anionic,
cationic, zwitterionic or non-ionic, although most food grade
surfactants are non-ionic (e.g. monoglycerides, Tweens, Spans),
anionic (e.g.fatty acid salts, DATEM, CITREM), or zwitterionic
(e.g. lecithin). The tail group usually consists of one or more
hydrocarbon chains, having between 10 and 20 carbon atoms
per chain. Surfactant chains may be saturated or unsaturated,
linear or branched, aliphatic and/or aromatic, but most food-
grade surfactants have either one or two linear aliphatic chains,
which may be saturated or unsaturated. Each type of surfac-
tant has functional properties that are determined by its unique
molecular structure and the physicochemical environment that
it operates within. The choice of a surfactant for a particular ap-
plication depends on its physicochemical performance, as well
as its legal status, cost, usage levels, ingredient compatibility,
stability, and ease of utilization.
At sufficiently low concentrations, surfactants exist as
monomers in solution because the entropy of mixing overweighs
the attractive forces operating between the surfactant molecules.
Nevertheless, as their concentration is increased they can spon-
taneously aggregate into a variety of thermodynamically stable
structures known as association colloids, e.g. micelles, bilayers,
vesicles, and reverse micelles (Fig. 1). The primary driving force
for the formation of these structures is the hydrophobic effect,
which causes the system to adopt a molecular organization that
minimizes the thermodynamically unfavorable contact between
the non-polar tails of the surfactant molecules and the surround-
ing water molecules. At still higher concentrations, surfactants
may organize themselves into a variety of liquid crystalline
structures, such as hexagonal, lamellar, and reversed hexagonal
phases. In addition, the surfactant solution may separate into a
number of phases, with different compositions and molecular
organizations. The type of structures formed by surfactants is
largely determined by their molecular geometry, which in turn
depends on their chemical structure, solution composition, and
temperature. The relationship between the molecular geometry
 586 D. J. McCLEMENTS ET AL.
Figure 1 Schematic representation of the major types of association colloids
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formed by surfactants: micelles, vesicles, bilayers, and reverse micelles.
and structural organization of surfactants is shown schematically
in Fig. 2.
Biopolymers: Proteins and Polysaccharides
Proteins are polymers of amino acids, whereas polysaccha-
rides are polymers of monosaccharides (McClements, 2005).
The functional properties of food biopolymers (e.g., solubility,
surface activity, thickening, and gelling) are ultimately deter-
mined by their molecular characteristics (e.g., molecular weight,
conformation, flexibility, polarity, hydrophobicity, and interac-
tions). These molecular characteristics are determined by the
type, number, and sequence of the monomers that make up
the polymer chain. Monomers vary according to their polar-
ity, dimensions, interactions, and chemical reactivity. The fact
that biopolymers contain relatively large numbers of monomers
Figure 2 Relationship between the molecular geometry of surfactants, the
curvature of the interfacial layers they prefer to form, the type of association
colloids they tend to form, and the type of macro-emulsions they tend to stabilize.
Figure 3 Biopolymers, such as proteins and polysaccharides, can adopt a
variety of different molecular conformations in aqueous solutions e.g., rod-like
(helical), globular or flexible (“random coil”). Many biopolymers have more
than one of these structural features within the same molecule.
(typically between 20 and 20,000) and that rotation around the
links in the chain is possible, means that they can potentially
take up a huge number of different configurations in solution.
In practice, biopolymers usually adopt a fairly well-defined
conformation or range of conformations that minimizes the free
energy of the system under the prevailing environmental condi-
tions. This conformation is determined by a delicate balance of
physicochemical phenomena that depends on biopolymer type,
including, hydrophobic interactions, electrostatic interactions,
hydrogen bonding, van der Waals forces, and configurational
entropy. It should be noted that most foods are non-equilibrium
systems, and so a biopolymer may be trapped in a metastable
state, because there is a large activation energy preventing it from
reaching its most thermodynamically stable state. The configu-
rations that biopolymer chains tend to adopt in aqueous solutions
can be conveniently divided into three broad categories: glob-
ular, rod-like, or random coil (Fig. 3). Globular biopolymers
have fairly rigid compact structures, rod-like biopolymers have
fairly rigid extended structures (usually helical), and random-
coil biopolymers have highly dynamic and flexible structures.
In practice, many biopolymers do not have exclusively one type
of conformation, but have some regions that are random coil,
some that are rod-like, and some that are globular. Biopolymers
can also be classified according to the degree of branching of
the chain. Most proteins have linear chains, whereas polysac-
charides can have either linear or branched chains. In solution,
biopolymers may be present as individual molecules or they
may be present as supra-molecular structures where they are
associated with one or more molecules of the same or different
kind. Finally, it should be mentioned that biopolymers may un-
dergo transitions from one conformation to another, or from one
aggregation state to another, if their environment is altered, e.g.,
pH, ionic strength, solvent composition, or temperature. The
conformation and interactions of biopolymers play a major role
in determining their ability to form structured delivery systems.
A wide variety of different food-grade proteins are available
for utilization as building blocks to form structured delivery sys-
tems, such as casein and whey protein from milk, gelatin, and
myosin from meat or fish, and corn-zein, wheat gluten, soy pro-
tein, peanut protein, and cottonseed protein from plant sources.
Each of these proteins has different molecular characteristics
depending on its biological origin and function. For example,
they vary in their molecular weights, conformations (globular,
random coil, helix), electrical characteristics (charge versus pH),
 DESIGN AND FABRICATION OF STRUCTURED DELIVERY SYSTEMS 587
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Figure 4 Structural design principles that can be used to assemble food grade ingredients into specific structures: phase separation; spontaneous self-assembly;
directed self-assembly.

flexibilities (rigid versus flexible), and thermal stabilities (Tm ). Phase Separation
There are also a wide range of different food-grade polysaccha-
When two different materials are mixed together they may
rides that can be used to form structured delivery systems, such
be completely miscible and form a single phase, or they may
as starch and its derivates, cellulose derivates, chitosan, alginate,
separate into a number of different phases, depending on the
carrageenan, pectin, xanthan gum, guar gum, locust bean gum
relative strength of the interactions between the different types
etc (Cui, 2005). On the molecular level, these polysaccharides
of molecules present (Fig. 4). For example, consider a system
also vary according to their molecular weight, degree of branch-
that is formed by mixing two liquids (Liquid A and Liquid
ing, conformation, electrical charge, and hydrophobicity. Vari-
B) that contain different kinds of molecules (Molecules A and
ations in the molecular characteristics of biopolymers will lead
Molecules B). Before mixing there are only A-A interactions in
to variations in their ability to form structured delivery systems,
Liquid A and B-B interactions in Liquid B. After mixing, there
as well as to differences in the physicochemical properties and
are A-A, B-B, and A-B interactions in the mixed AB system. If
functional performance of the delivery systems. The food sci-
the A-B interactions are appreciably stronger than the average
entist must therefore carefully select the characteristics of the
of the A-A and B-B interactions, then the A-B interactions will
biopolymers used to fabricate a delivery system with certain
be favored and the liquids will be miscible (1 phase), but if the
desirable properties. In addition, it is important to control and
opposite is true then the A-B interactions will be unfavorable and
characterize the properties of the biopolymers used to establish
the liquids will be immiscible (2 phases). There are a number
the structure-function relationships needed to assemble struc-
of examples of phase separation involving food components
tured delivery systems in a controlled fashion. Considerable
that can be used to create novel structures. The most common
progress has been made in understanding the relationship be-
example is the phase separation of oil and water due to the fact
tween the molecular characteristics of particular biopolymers
that oil-water interactions are strongly unfavorable (compared to
and their ability to perform certain functional roles, although
the average of water-water and oil-oil interactions), which is the
this understanding is still fragmentary and much further re-
basis for the formation of emulsion systems. Another example
search is required (Benichou et al., 2002; Norton and Frith,
is the phase separation of mixed biopolymer solutions as a result
2001; Schmitt et al., 1998).
of relatively strong thermodynamically unfavorable interactions
between the different types of biopolymers (e.g., electrostatic
repulsion and/or steric exclusion). As a result of this type of
Structural Design Principles phase separation the mixed biopolymer system separates into
two different phases: one phase is enriched with one type of
In this section, we highlight some of the major structural biopolymer and depleted with the other type, while the opposite
design principles that can be used to assemble novel structures situation occurs in the other phase. If a system is capable of phase
from the food-grade building blocks discussed above. separating then it is often possible to control the microstructure
 588 D. J. McCLEMENTS ET AL.
Figure 5 A laminated coating can be formed around a macroscopic object using the electrostatic layer-by-layer deposition method, which involves dipping the
object in solutions containing oppositely charged substances.
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of the overall system, e.g., by applying mechanical forces, such
as shearing or homogenization. For example, one of the phases
can be dispersed throughout the other phase in the form of
particles, whose size, shape, and stability can often be controlled
by controlling the magnitude, duration, and nature of the applied
mechanical forces and/or by adding certain kinds of stabilizers
(e.g., surface active, thickening, or gelling agents).
Spontaneous Self-Assembly
Under appropriate environmental conditions, certain types
of food components spontaneously assemble into well-defined
structures, e.g., micelles, vesicles, fibers, tubes, liquid crystals
(Fig. 4). The driving force for self-assembly is the reduction in
the free energy of the system, i.e., the free energy of the assem-
bled structure in solution is less than that of the non-assembled
components. Bringing together various components into an as-
sembled structure leads to a reduction in the entropy of mixing
of the system which is thermodynamically unfavorable, hence
there must be some favorable enthalpy and/or entropy contribu-
tion which favors assembly that outweighs this. The nature of
this favorable contribution is highly system dependent, but often
involves hydrogen bonding, hydrophobic attraction, or electro-
static interactions. Association colloids, such as micelles, vesi-
cles, and microemulsions, are some of the most common types of
self-assembled structures in food materials (Fig. 1). The primary
driving force for the spontaneous formation of these structures is
usually the hydrophobic effect, which causes the system to adopt
a molecular organization that minimizes the unfavorable contact
area between the non-polar tails of the surfactant molecules and
water. The size, concentration, and properties of the association
colloids formed can often be controlled by careful selection of
the surfactant and other molecules present in the system, as well
as environmental conditions (such as temperature).
Directed Self-Assembly
As mentioned above, spontaneous self-assembled systems
are thermodynamically stable systems that occupy the low-
est free energy state(s). On the other hand, directed self-
assembled systems do not form spontaneously if all the compo-
nents are simply mixed together. Instead, the preparation condi-
tions (e.g., order of mixing, temperature-time, pH-time, or ionic
strength-time profiles) must be carefully controlled to direct the
different components so that they are assembled into the de-
sired structure. In other words, the final structure depends on
the path that was used to produce it and is only metastable.
The driving force for directed-assembly of food structures is
system-dependent, but again hydrophobic, electrostatic, and
hydrogen bonding interactions are common. A widely used
directed-assembly method is layer-by-layer (LbL) electrostatic
deposition of polyelectrolytes and other charged substances
onto oppositely charged surfaces due to electrostatic attrac-
tion (Fig. 4). The LbL procedure can be used to form coat-
ings with precisely controlled thickness, properties, and per-
formance around nanoscopic, microscopic, or macroscopic ma-
terials, such as lipid droplets, bacterial cells, viruses, fruits,
vegetables, meats, and hydrogels (Caruso and Mohwald, 1999;
Decher and Schlenoff, 2003). An example of how an object
might be covered with a laminated coating is shown in Fig.
5. The object to be coated is dipped into a series of different
solutions that contain oppositely charged polyelectrolytes. Be-
tween each dipping step it may be necessary to have a washing
and/or drying step to remove the excess solution attached to the
surface prior to introduction of the object into the next dipping
solution. The composition, thickness, structure, and properties
of the laminate coating formed around the object could be con-
trolled in a number of ways, including: (i) changing the type
of adsorbing substances in the dipping solutions; (ii) changing
the total number of dipping steps used; (iii) changing the order
that the object is introduced into the various dipping solutions;
(iv) changing the solution and environmental conditions used,
such as pH, ionic strength, dielectric constant, temperature etc.
Hence, it is possible to design and fabricate laminated coatings
with specific functional performances by careful selection of
ingredients and processing conditions. The formation of hydro-
gels from biopolymers can also be considered as another form
of directed self-assembly, although the level of direct control
 DESIGN AND FABRICATION OF STRUCTURED DELIVERY SYSTEMS
over the structures formed is usually much less than the LbL
technique. For example, when a solution of gelatin is cooled
below a certain temperature a coil-to-helix transition occurs,
which is followed by extensive hydrogen bond formation be-
tween helices on different gelatin molecules (Ross-Murphy,
1997). These hydrogen bonded regions act as physical cross-
links between the gelatin molecules that may eventually lead to
gelation. The gelatin molecules therefore self-assemble under
the prevailing environmental conditions, but the precise details
of the structures formed (i.e., the number, position, and length of
the cross-links) depends on the specific preparation conditions
used (e.g., time-temperature profile, shearing).
Directed Assembly
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In principle, it is also possible to form structured delivery sys-
tems by physically bringing molecules or particles together in
well-defined ways. For example, nano- or micro-manipulation
methods can be used to move atoms, molecules, or colloidal par-
ticles into specific structures (Matthews et al., 2004; Resch et al.,
1998). This is certainly an exciting area of research and leads to
the possibility of constructing extremely small structures with
particular functions. Nevertheless, most of these (nano-) tech-
nologies are unlikely to find widespread use in the food industry,
at least in the foreseeable future, due to a variety of economic and
practical constraints, such as the fact that expensive equipment
is needed to fabricate and characterize the structures formed,
and the throughput of fabricated structures is likely to be ex-
tremely low. Having said this there are certain exceptions, for
example it may be possible to rapidly and economically produce
small scale structures using the technology of “templating” or
“imprinting” (Shi and Ratner, 2000; Demirel et al., 2005). In
this technique, a template is fabricated with a specific topolog-
ical design, which is then used to create a mirror image of the
design on the material being fabricated.
Designing Structures
Knowledge of the types of food-grade building blocks that
can be utilized, the characteristics of the molecular and colloidal
interactions operating in the system, and the various structural
design principles outlined above should enable one to design
and construct delivery systems with specific functional perfor-
mances. A combination of experimental, theoretical, and com-
putation studies over the past few decades have led to con-
siderable advances in our ability to rationally design specific
structures in food materials. Nevertheless, the structural design
of foods is still very far from an exact science due to the com-
positional and structural complexity of most food systems. A
concerted research effort is still needed to establish the rela-
tionships amongst: (i) molecular and colloidal characteristics;
(ii) structural organization; (iii) bulk physicochemical proper-
ties; (iv) functional performance. In the following section we
focus on some of the most developed current technologies for
creating structured delivery systems.
589
TECHNOLOGIES FOR CREATING STRUCTURED
DELIVERY SYSTEMS
In this section, we provide a brief overview of the major
kinds of structured delivery systems that are currently or could
potentially be utilized by the food industry in the near future to
encapsulate nutraceuticals and functional food components. For
convenience we have divided these structured delivery systems
into three major categories according to the dominant struc-
tural component used in their assembly: surfactant-based, lipid-
based, and biopolymer-based. Nevertheless, there are many ex-
amples of structured delivery systems that utilize combinations
of more than one of these structural components. As mentioned
earlier, we will limit our discussion to structured delivery sys-
tems that are suitable for application in aqueous solutions.
Lipid-Based Structured Delivery Systems
Most lipid-based structured delivery systems are created us-
ing emulsion technology. Generally, an emulsion consists of at
least two immiscible liquids (usually oil and water), with one
of the liquids being dispersed as small spherical droplets in the
other (McClements, 2005; Friberg et al., 2004). Typically, the di-
ameters of the droplets in food systems lie somewhere between
0.1 and 100 µm. Emulsions can conveniently be classified ac-
cording to the spatial organization of the oil and water phases. A
system that consists of oil droplets dispersed in an aqueous phase
is called an oil-in-water (O/W) emulsion, whereas a system that
consists of water droplets dispersed in an oil phase is called a
water-in-oil (W/O) emulsion. The substance that makes up the
droplets in an emulsion is referred to as the dispersed phase,
whereas the substance that makes up the surrounding liquid is
called the continuous phase. In addition to the simple O/W or
W/O emulsions described above, it is also possible to prepare
various types of multiple emulsions, such as oil-in-water-in-oil
(O/W/O) or water-in-oil-in-water (W/O/W) emulsions (Beni-
chou et al., 2004; van der Graaf et al., 2005; Garti and Bisperink,
1998). For example, a W/O/W emulsion consists of small wa-
ter droplets trapped within larger oil droplets, which are dis-
persed in an aqueous continuous phase. Emulsions are thermo-
dynamically unfavorable systems that tend to break down over
time due to a variety of physicochemical mechanisms, including
gravitational separation, flocculation, coalescence, and Ostwald
ripening (McClements, 2005; Friberg et al., 2004). Hence, they
are different from the micelle and microemulsion systems dis-
cussed later, which are thermodynamically stable. It is possible
to form emulsions that are kinetically stable for a reasonable pe-
riod of time by including substances known as stabilizers, e.g.,
emulsifiers or texture modifiers. Emulsifiers are surface-active
molecules that absorb to the surface of freshly formed droplets
during homogenization, forming a protective layer that prevents
the droplets from aggregating. Texture modifiers thicken or gel
the continuous phase, which improves emulsion stability by re-
tarding or preventing droplet movement. Selection of the most
 590 D. J. McCLEMENTS ET AL.
Figure 6 Conventional O/W emulsions are typically formed by homogeniz-
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ing oil and aqueous phases together in the presence of a water-soluble emulsifier.
appropriate stabilizer(s) is one of the most important factors
determining the shelf-life and physicochemical properties of
emulsion-based delivery systems. In the remainder of this sec-
tion we will focus on the properties of emulsions whose continu-
ous phase is aqueous (i.e., O/W and W/O/W), since these are the
most commonly used as delivery systems in the food industry.
Conventional Emulsions
Conventionally, oil-in-water emulsions are prepared by ho-
mogenizing oil, water, and emulsifier together using a mechani-
cal device known as a homogenizer, e.g., high shear mixer, high
pressure homogenizer (Fig. 6), colloid mill, sonicator, or mem-
brane homogenizer (McClements, 2005; Walstra, 1993; 2003).
This type of emulsion consists of small oil droplets dispersed in
an aqueous medium, with the oil droplets being surrounded by a
thin interfacial layer consisting of emulsifier molecules (Fig. 7).
Oil-in-water emulsions are used as delivery systems in many
industries, including pharmaceuticals, petrochemicals, health
care products, cosmetics, agrochemicals, and foods. These sys-
tems have a number of potential advantages as delivery sys-
tems for nutraceutical and functional food components. First,
emulsions contain a non-polar region (the oil phase), a polar
region (the aqueous phase), and an amphiphilic region (the in-
terfacial layer). It is therefore possible to incorporate functional
agents that are polar, non-polar, and amphiphilic within the same
Figure 7 Examples of different kinds of lipid-based delivery systems that
can be produced: conventional emulsions; multiple emulsions; multilayer emul-
sions; solid lipid particle emulsions.
delivery system. For example, a lipophilic component could be
incorporated into the oil phase prior to homogenization, while
a hydrophilic component could be incorporated into the aque-
ous phase either before or after homogenization. Second, the
heterogeneous structure of emulsions means that it is possible
to develop novel strategies for controlling the chemical stabil-
ity of encapsulated components, e.g., by engineering the inter-
face or controlling the physical location of different reactants
(McClements and Decker, 2000; Coupland and McClements,
1996). Third, by controlling composition and microstructure it
is possible to create emulsions with different rheological prop-
erties (ranging from viscous liquids, to plastic pastes, to elastic
solids), so that they can be prepared in a form that is most conve-
nient for each specific application. Fourth, emulsions can either
be used directly in their “wet” state or they can be dried to form
powders (e.g., by spray, roller, or freeze drying), which may
facilitate their transport and utilization in some applications. Fi-
nally, emulsions can be created entirely from food grade ingre-
dients (such as water, oil, surfactants, phospholipids, proteins,
and polysaccharides) using fairly simple processing operations
(mixing and homogenization). Conventional emulsions should
therefore usually be the first system considered when one is
thinking of using a lipid-based structured delivery system be-
cause of their relative ease of preparation and low cost, compared
to more sophisticated lipid-based delivery systems.
Nevertheless, there are certain limitations of conventional
emulsion systems that may mean that more sophisticated struc-
tured systems are needed for particular applications. Conven-
tional emulsions are often prone to physical instability when
exposed to environmental stresses, such as heating, chilling,
freezing, drying, pH extremes, and high mineral concentrations.
In addition, one often has limited control over their ability to
protect and control the release of functional components be-
cause the relatively small size of the droplets (∼ µm) and thick-
ness of the interfacial layers (∼ nm) means that the time-scales
for molecular diffusion of substances out of the droplets is ex-
tremely short. Finally, there are a limited number of emulsifiers
that can be used to form the interfacial layers that surround the
oil droplets, which limits ones ability to create delivery systems
exhibiting a wide range of protection and release characteristics.
Simple oil-in-water emulsions have been used as delivery
systems for a wide variety of different functional food compo-
nents, and are probably the most common lipid-based delivery
system currently in use in the food industry. For example, O/W
emulsions have been used to encapsulate lipophilic and hy-
drophilic flavors (Tan, 2004), ω-3 fatty acids (McClements and
Decker, 2000; Klinkesorn et al., 2005; 2005), lycopene (Ribeiro
et al., 2003; 2006), lipid-soluble vitamins.
Multiple Emulsions
Water-in-oil-in-water (W/O/W) emulsions consist of small
water droplets contained within larger oil droplets that are dis-
persed in an aqueous continuous phase (Fig. 7). Water-in-oil-
in-water emulsions are more accurately designated as W1 /O/W2
 DESIGN AND FABRICATION OF STRUCTURED DELIVERY SYSTEMS
Figure 8 Multiple emulsions are often formed using a two-step procedure. Primary homogenization: an oil and aqueous phase are homogenized in the presence
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of an oil-soluble emulsifier to form a W/O emulsion. Secondary homogenization: the W/O emulsion and an aqueous phase are homogenized together in the
presence of a water-soluble emulsifier to form a W/O/W emulsion.
emulsions, where W1 is the inner water phase and W2 is the outer
water phase (which may have different compositions). These
multiple emulsions are normally produced using a two-step
procedure: (i) a W1 /O emulsion is produced by homogenizing
water, oil and an oil-soluble emulsifier together; (ii) a W1 /O/W2
emulsion is then produced by homogenizing the W1 /O emul-
sion with water containing a water-soluble emulsifier (Fig. 8).
The same kind of homogenization devices can be used to pre-
pare multiple emulsions as conventional emulsions (e.g., high
shear mixers, high pressure homogenizers, colloid mills, son-
icators, or membrane homogenizers), although the secondary
homogenization step is usually carried out using a lower energy
intensity than the primary step so as not to break the initial W1 /O
emulsion. Functional components can potentially be located in a
number of different molecular and physical environments within
a W1 /O/W2 emulsion. Water soluble components can be incor-
porated into the inner water phase by dispersing them in the W1
phase prior to the first homogenization step, or in the outer water
phase by dispersing them in the W2 phase prior to the second
homogenization step. Oil soluble components can be incorpo-
rated into the oil phase by dispersing them in the O phase either
before or after the primary homogenization step. Surface-active
functional components could be located at either the W1 /O in-
terface or the O/W2 interface depending on when they were
incorporated during the emulsion preparation procedure.
Potentially, W/O/W emulsions have a number of important
advantages over simple O/W emulsions as delivery systems:
• Encapsulation, Protection, and Release: Water-soluble
functional food ingredients (e.g., minerals, vitamins, fla-
vors, enzymes, proteins, bioactive peptides, polysaccharides)
could be trapped within the internal water phase, which may
have advantages for a number of applications. For example:
(i) functional ingredients could be trapped inside the in-
ner water droplets and released at a controlled rate or in
591
response to specific environmental triggers e.g., in the mouth,
stomach, or small intestine; (ii) functional ingredients could
be protected from chemical degradation by isolating them
from other water-soluble ingredients that they might normally
react with; (iii) water-soluble functional ingredients that have
undesirable sensory qualities (e.g., bitter, astringent, or metal-
lic flavors) could be trapped within the inner water phase so
that there undesirable sensory attributes are not perceived in
the mouth during mastication.
• Reduced Fat Products: The overall fat content of food prod-
ucts that exist as oil-in-water (O/W) emulsions (e.g., dress-
ings, dips, sauces, deserts) could be reduced by loading the
oil phase with water droplets. A W/O/W emulsion could be
produced that had the same overall dispersed phase volume
fraction and droplet size distribution as a conventional O/W
emulsion, but with a reduced fat content. Consequently, it
should be possible to produce reduced-fat products with sim-
ilar physicochemical and sensory properties as full-fat prod-
ucts, e.g., appearance, texture, mouthfeel, and flavor.
There have been numerous patents and research articles high-
lighting the great potential of multiple emulsions as delivery
systems (Benichou et al., 2004; Garti and Bisperink, 1998;
Garti, 1997). Despite this great potential there are few exam-
ples of multiple emulsions actually being used in food products
at present. The main reason for this is that multiple emulsions
are highly susceptible to breakdown during storage or when
exposed to environmental stresses commonly used in the food
industry, such as mechanical forces, thermal processing, chill-
ing, or freezing. A variety of instability mechanisms are re-
sponsible for W/O/W emulsion breakdown, with some of these
being similar to those operating in conventional O/W emul-
sions and some being unique to multiple emulsions. The oil
droplets in W/O/W emulsions are susceptible to creaming, floc-
culation, coalescence, and Ostwald ripening just as they are in
 592 D. J. McCLEMENTS ET AL.
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Figure 9 Schematic representation of some of the major instability mecha-
nisms responsible for the breakdown of multiple emulsions.
O/W emulsions. The inner water droplets in W/O/W emulsions
are also susceptible to conventional flocculation, coalescence,
and Ostwald ripening processess; however, they may also be-
come unstable due to diffusion of water molecules between the
inner and outer aqueous phases or due to the expulsion of whole
water droplets from the oil droplets (Fig. 9).
There are a number of requirements that must be met before
multiple emulsions can be successfully used in food products:
• The water droplets (W1 ) within the oil phase should remain
intact during preparation and storage of the multiple emul-
sions, i.e., they should not grow or shrink due to osmotic
stress, coalescence, or Ostwald ripening, and they should not
be completely expelled from within the oil droplets;
• Functional components trapped within the water droplets
should be protected and retained until they are ready to be
released at the required site of action;
• The oil droplets (O) should be stable to creaming, flocculation,
coalescence, and Ostwald ripening throughout the lifetime of
the product;
• The multiple emulsion should be resistant to environmental
stresses that may be experienced by the food product during
production, storage, transport, and utilization, e.g., mechani-
cal agitation, heating, chilling, and freezing.
• The overall rheology, appearance, and flavor imparted by the
multiple emulsion should be appropriate for the food product
matrix that contains it.
A variety of different strategies have been developed in an
attempt to overcome the problems associated with the prepa-
ration of stable multiple (W/O/W) emulsions (Benichou et al.,
2004; Garti and Bisperink, 1998; Garti, 1997; Benichou et al.,
2004; Garti and Benichou, 2004). A list of the most important
ones is given below:
• Emulsifier selection. The type and concentration of both the
water-soluble and oil-soluble emulsifiers used to prepare the
W/O and W/O/W emulsions have a large impact on the for-
mation, stability and properties of the system. Traditionally,
small molecule surfactants are used to prepare multiple emul-
sions, but it has been found that macromolecular emulsifiers
are often better at improving emulsion stability, e.g., caseins
or whey proteins to stabilize the oil droplets in the W/O/W
emulsions.
• Incorporation of biopolymers in inner aqueous phase. The sta-
bility of multiple emulsions can often be improved by adding
a biopolymer to the inner aqueous phase, e.g., casein, whey
protein, pectin, or xanthan. The biopolymer may form an in-
terfacial complex with the oil-soluble surfactants or it may
form a hydrogel throughout the entire water droplet.
• Solidification of oil phase. The stability of W/O/W emulsions
can be improved by crystallizing the oil phase. Solidification
of the oil phase restricts water diffusion into or out of the in-
ternal water droplets, and may slow down the creaming of the
oil droplets because of the increase in density. Nevertheless,
crystallization of the oil droplets may be undesirable in many
food products because: (i) it could lead to instability through
partial coalescence; (ii) it could produce undesirable sensory
properties during mastication; (iii) it could lead to undesir-
able nutritional requirements, such as high saturated fats or
trans-fatty acids content.
• Osmotic balancing. If there is a greater concentration of water-
soluble solutes in either the inner water droplets or the outer
aqueous phase there will be an osmotic pressure gradient that
will favor movement of water molecules either into or out of
the water droplets. This causes the total water concentration
inside the oil droplets to either increase (droplet growth) or to
decrease (droplet shrinkage), respectively. This process can
be retarded by adding solutes to either the inner and/or outer
water phases to balance the osmotic potential, e.g., sugars,
polyols, salts, or biopolymers.
It is clear that multiple emulsions have great potential as de-
livery systems for functional food components, but that there
are still a number of important issues that need to be addressed
before this technology can be successfully employed within the
food industry. In particular, it is important that they can be pro-
duced from all food grade ingredients, using simple processing
operations, and have the physical stability to resist the stresses
typically encountered in foods, e.g., mechanical stresses, heat-
ing, chilling, freezing, drying, etc.
The potential for using multiple emulsions to encapsulate
some lipophilic functional food or nutraceutical compounds has
been demonstrated, such as β-carotene (Rodriguez-Huezo et al.,
2004) and ω-3 fatty acids (Cournarie et al., 2004; Onuki et al.,
2003). However, they are mainly used to encapsulate and protect
hydrophilic bioactive components, such as vitamin B (Kukizaki
and Goto, 2007; Owusu et al., 1992), immunoglobulins (Lee
et al., 2004; Chen et al., 1999), proteins, (Su et al., 2006) and
amino acids (Owusu et al., 1992; Weiss et al., 2005).
 DESIGN AND FABRICATION OF STRUCTURED DELIVERY SYSTEMS 593
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Figure 10 Multilayer emulsions are formed by adding polyelectrolytes to an emulsion containing oppositely charged droplets so that they adsorb and form a
nano-laminated coating. This procedure can be repeated a number of times to form multilayer coatings around the oil droplets.

Multilayered Emulsions droplets coated by interfaces containing three or more layers.

Under certain circumstances, emulsions containing oil droplets
Recently, it has been shown that the stability and func-
surrounded by multi-layer interfaces have been found to have
tional performance of conventional O/W emulsions can often be
better stability to environmental stresses than conventional oil-
greatly improved by coating the droplets with nano-laminated
in-water emulsions with single-layer interfaces (Guzey et al.,
interfacial layers formed using the layer-by-layer (LbL) electro-
2004; Harnsilawat et al., 2006; 2006; Ogawa et al., 2003; 2003;
static deposition method (Klinkesorn et al., 2005; Gu et al.,
Aoki et al., 2005; Gu et al., 2004; Guzey and McClements,
2005; Guzey et al., 2004; Guzey and McClements, 2007;
2006; Moreau et al., 2003). In addition, it is also possible to
Harnsilawat et al., 2006; 2006; Klinkesorn et al., 2006;
develop smart delivery systems based on engineering the prop-
McClements, 2005; Ogawa et al., 2003; 2003). The LbL electro-
erties of the nano-structured shell around the droplets (Caruso
static deposition method begins with the adsorption of a charged
and Mohwald, 1999; Decher and Schlenoff, 2003; Caruso and
polyelectrolyte onto an oppositely charged surface through an
Schuler, 2000). It should be noted that the polyelectrolyte layers
electrostatic attraction (Fig. 10). Charge reversal of the surface
are held together by electrostatic attraction, and may therefore
occurs because the total number of charges on the adsorbed
dissociate if the pH or ionic strength is changed. Dissociation
polyelectrolyte molecules is greater than the number of charges
can be prevented by covalently cross-linking the adsorbed layers
on the surface. This charge over-compensation has two impor-
after they have been formed around a lipid droplet, e.g., using
tant consequences: (1) The adsorbing polyelectrolytes tend to
enzymes, chemicals, or heating.
form mono-layers because additional polyelectrolytes in solu-
One or more functional components could be trapped within
tion are repelled; (2) Further layers can be formed by adsorbing
the oil droplet core or within the laminated shell surrounding
oppositely charged polyelectrolytes onto the first layer, e.g.,
the droplets. For example, a lipophilic functional component
T − P1 − P2 , where T is the template surface, and P1 and P2
could be incorporated into the oil phase prior to homogenization,
are two oppositely charged polyelectrolytes. Repetition of these
whereas a hydrophilic ionic functional component could be used
adsorption steps leads to the formation of multilayer structures
to make up one of the layers surrounding the oil droplets. The
(Decher and Schlenoff, 2003). There has been a great deal of
release of a functional component trapped in the core of the
progress in understanding the formation, stability, and proper-
delivery system could be controlled by designing the response
ties of these nano-laminated layers over the past decade or so,
of the shell to the environment:
which provides a strong foundation for the rational design and
fabrication of structured delivery systems for use in the food
industry. • Complete Shell Dissociation: The shell could be made to com-
The principle behind the utilization of the LBL approach to pletely dissociate under specific solution conditions (pH, I )
form multilayer emulsions is shown in Fig. 10. A charged emul- due to weakening of electrostatic interactions. For example,
sifier that rapidly adsorbs to the surface of oil droplets during ho- the pH could be changed so that one or more of the biopoly-
mogenization is used to produce a “primary” emulsion contain- mers loses its charge, or the ionic strength could be increased
ing small droplets, then an oppositely charged polyelectrolyte is so that the electrostatic attraction holding the layers together
added to the system that adsorbs to the droplet surfaces and pro- is sufficiently weakened to promote desorption.
duces a “secondary” emulsion containing droplets coated with a • Modulation of Shell Porosity: The thickness and porosity
two-layer interface. This procedure can be repeated to form oil of shells could be changed with exposure pH and I . This
 594 D. J. McCLEMENTS ET AL.
determines the rate at which functional components trapped
inside the core will diffuse out into the surrounding medium.
By selection of the appropriate polyelectrolytes used and
the assembly conditions, one may design systems to selec-
tively release, under specific environmental triggers, func-
tional components smaller than some particular dimension.
In principle, one could vary the release of one or more encap-
sulated materials using either of these different release mecha-
nisms, either individually or in combination (simultaneously or
sequentially). This interfacial engineering technology utilizes
food-grade ingredients (such as proteins, polysaccharides, and
phospholipids) and processing operations (such as homogeniza-
tion and mixing) that are already widely used in the manufacture
of food emulsions.
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Multilayered emulsion delivery systems may have a number
of advantages over conventional single-layered emulsions:
• Improved physical stability to environmental stresses, e.g.,
pH, salt, heating, chilling, freezing, drying, and mechanical
agitation (Harnsilawat et al., 2006; 2006; Aoki et al., 2005;
Guzey and McClements, 2006; Gu et al., 2005).
• Improved chemical stability to oxidation reactions, e.g., in-
teractions between lipids and metal ions can be minimized by
controlling the interfacial charge and thickness (McClements
and Decker, 2000).
• Greater control over the release rate of functional agents due
to the ability to manipulate the thickness and permeability
of the laminated interfacial coating (Decher and Schlenoff,
2003).
• Ability to trigger release of functional agents in response to
specific changes in environmental conditions, such as dilution,
pH, or temperature. For example, it is possible to cause inter-
facial layers to detach from the droplet surfaces when the pH is
altered, since this causes either the emulsifier or biopolymers
to lose their electrical charge (Guzey et al., 2004; Harnsi-
lawat et al., 2006; Ogawa et al., 2003; 2003; Gu et al., 2006;
2005).
The potential of using multilayer emulsions as delivery sys-
tems has already been shown for some functional food com-
ponents. For example, multilayer emulsions have been used to
modulate the digestibility of edible oils (Mun et al., 2006), to en-
capsulate flavor oils and to encapsulate ω-3 fatty acids (Klinke-
sorn et al., 2005; 2005; 2006; 2005). Nevertheless, there are
many other potential applications of this interfacial engineering
technology within the food industry.
Most previous studies using food-grade components have
utilized lipid droplets as the core material and charged surfac-
tants, proteins or polysaccharides to form the shell material.
Nevertheless, it is also possible to construct structured delivery
systems using different kinds of core materials (such as micelles,
vesicles, hydrogel particles, biological cells) and shell materials
(such as charged micelles, lipid droplets, solid particles). For
example, it has recently been shown that the electrostatic LbL
deposition method can be used to form “colloidsomes” that con-
sist of a layer of protein-coated lipid droplets adsorbed to the
surface of larger polysaccharide/protein-coated lipid droplets
(Gu et al., 2006).
Solid Lipid Particle Emulsions
Solid lipid particle (SLP) emulsions consist of emulsifier-
coated (partially) solid lipid particles dispersed in an aqueous
continuous phase (Fig. 7) (Westesen et al., 1997; Radomska-
Soukharev and Muller, 2006; Schubert and Muller-Goymann,
2005; Jenning et al., 2000). These systems have been shown
to have advantages over conventional O/W emulsions for cer-
tain applications. Conventional emulsions are often prone to
physical instability due to coalescence (the merging of two or
more smaller droplets to form a larger one) or Ostwald ripen-
ing (the growth of larger droplets at the expense of smaller
ones). These instability mechanisms lead to irreversible droplet
growth, which may eventually result in accelerated creaming,
oiling off, or phase separation. In addition, lipophilic functional
components present in the lipid phase may be subject to at-
tack by chemically reactive species in the aqueous phase, e.g.,
polyunsaturated fats by iron (McClements and Decker, 2000).
By crystallizing the lipid phase it is often possible to control
the physical location of a lipophilic component and to slow
down molecular diffusion processes, thereby increasing the sta-
bility of chemically labile components (Yang et al., 2006; Zhang
et al., 2004; Sivaramakrishnan et al., 2004; Videira et al., 2002;
Wang and Wu, 2006; Muller and Keck, 2004). The internal
structure of the lipid phase (e.g., homogeneous, core-shell, or
dispersion) can be controlled by careful selection of lipid type,
emulsifier type, cooling rate, and droplet size. Like conventional
emulsions, the droplets in SLP emulsions are stabilized by an
emulsifier layer, which may consist of a single surfactant, or a
mixture of surfactants (Jenning et al., 2000). The lipids used to
form SLP are typically highly purified triglycerides, complex
glyceride mixtures, or even waxes (Wissing et al., 2004; Dubes
et al., 2003) but should be at least partly solid at ambient or
storage temperature.
Emulsions containing SLP are usually formed using the “hot
homogenization” procedure that involves homogenizing an oil
and water phase together in the presence of a hydrophilic emul-
sifier at a temperature above the melting point of the lipid phase
(Schubert and Muller-Goymann, 2005; Wissing et al., 2004;
Saupe et al., 2005; Souto et al., 2004; Uner et al., 2004; Wissing
and Muller, 2002). The emulsion is then cooled so that some or
all of the lipids within the droplets crystallize. It is of key impor-
tance that the temperature of the emulsion remains substantially
above the crystallization temperature of the highest melting lipid
to prevent any fat solidification during homogenization. The sta-
bility of the droplets produced and the spatial organization of
the lipid crystals within the droplets are usually controlled by
careful selection of the number and type of lipids present, the
nature of the surfactant(s) used to stabilize the droplets, the
 DESIGN AND FABRICATION OF STRUCTURED DELIVERY SYSTEMS
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Figure 11 Different types of solid lipid particles that can be formed by controlling the crystallization of the lipids within O/W emulsions.
initial droplet size, and concentration, and the cooling condi-
tions. In principle, it is possible to create a variety of different
internal structures within solid lipid particles, e.g., homoge-
neous, core-shell, or crystal dispersions (Fig. 11). In addition,
it is possible to control the relative location of the different
phases within the droplets, e.g., solid core—liquid shell; liquid
core—solid shell; solid core – solid shell.
To encapsulate a functional compound, the ingredient is first
dissolved in the melted lipid carrier and the mixture is dispersed
in an aqueous emulsifier solution that has been heated to the
same temperature as the melted lipid. A coarse emulsion pre-
mix is prepared and then fed into a high pressure homogenizer
or microfluidizer to be finely dispersed (McClements, 2005).
After the average droplet size has been sufficiently decreased
(typically 60–120 nm) and all lipid droplets have been covered
by the emulsifier, the emulsion is cooled down to solidify the
lipid droplets to form “solid lipid particles.” If the cooling speed
is not carefully controlled and the size of the emulsion droplets
is too large, then aggregation of SLP due to partial coalescence
may rapidly occur in addition to expulsion of the functional
compound from the lipid matrix (Jenning et al., 2000; 2000;
Ahlin et al., 2003).
For heat sensitive functional compounds that may degrade
when kept at an elevated temperature during the manufacturing
process, an alternative production method exists, the so-called
“cold homogenization.” In this case, the lipid is melted and
mixed with the functional ingredient, but is then rapidly solidi-
fied using dry ice or liquid nitrogen. The high cooling rates favor
a homogenous distribution of the bioactive component within
the lipid matrix. This solidified lipid mixture is then milled in
ball or mortal mills to produce 50–100 micrometer particles.
The milled microparticles are then suspended in a surfactant
solution and homogenized at or below room temperature. This
process requires significantly more energy than the hot homog-
enization process. Moreover, heating of the solid microparticle
suspensions due to frictional forces in the homogenizer must be
prevented and cooling of the homogenization valve or interac-
tion chamber may be required.
595
Potentially, solid lipid particles have a number of advan-
tages over conventional lipid emulsions containing liquid lipid
droplets:
• By controlling the morphology of the crystalline lipid carrier
matrix it is possible to obtain more precise control over the
release kinetics of functional compounds.
• SLP emulsions have been demonstrated to have significantly
increased physical and chemical stability than conventional
emulsions for certain systems, which is ideally suited to en-
capsulate lipophilic functional compounds that would other-
wise rapidly degrade.
• High payloads of functional components can be achieved.
• Both lipophilic and hydrophilic bioactives can be incorporated
within the same system.
• Large-scale production can be easily achieved and particles
may be sterilized prior to production making them suitable
for use in aseptic processing.
In conclusion, solid-lipid particle emulsions may provide a
good choice if chemical stability of the functional ingredient is
a concern. It should be noted that SLP emulsions could also be
used in multiple emulsions (by crystallizing the oil phase in a
W/O/W emulsion) or in multilayer emulsions (by coating the
lipid droplets with biopolymers). Most previous applications of
SLP emulsions have been for the delivery of lipophilic drug
components in the pharmaceutical industry (Muller and Keck,
2004; Wissing et al., 2004; Silva, 2007; Rawat et al., 2006;
Muller-Goymann, 2004; Hu et al., 2004), but there is no reason
why the same technology cannot be successfully applied in the
food industry.
Surfactant-Based Delivery Systems
Most surfactant-based delivery systems are based on the
self-assembly of surfactant molecules in aqueous solution
 596 D. J. McCLEMENTS ET AL.
(Mezzenga et al., 2005). Surfactants can spontaneously self-
assemble into a variety of different structures in aqueous solu-
tions, including micelles, bilayers, vesicles, liquid crystals, and
reverse micelles (Fig. 1). These structures have increasingly
found use as carriers for functional ingredients, with surfactant
micelles being the most common example (Flanagan and Singh,
2006). Micelles are formed when the surfactant concentration
exceeds a particular concentration, known as the “critical mi-
celle concentration” (CMC). The main driving force for this
kind of self-assembly is the reduction in the thermodynamically
unfavorable interactions between the lipophilic surfactant tails
and water molecules i.e., the hydrophobic effect (Rosen, 2004).
The physicochemical properties of aqueous surfactant solutions
change appreciably at the CMC because monomers and micelles
have different characteristics, e.g., surface activity, optical prop-
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erties, diffusivity, solubilizing capacity. Self-assembled surfac-
tant aggregates generally have well-defined sizes and charges,
but they are still highly dynamic structures.
Swollen Micelles and Microemulsions
The type of association colloid formed within a particular sur-
factant solution depends on the molecular properties of the sur-
factant (i.e., head and tail group geometry, polarity, and charge),
the properties of the solvent (e.g., pH, ionic strength, and di-
electric constant), the presence of co-surfactants, the overall
surfactant (and co-surfactant) concentration, and the tempera-
ture. For example, a particular surfactant solution may undergo
a transition from spherical micelles to wormlike micelles to
bilayers as the temperature is increased. Temperature plays a
critical role in the formation and properties of association col-
loids due to the fact that the interaction forces that drive their
formation are temperature dependent and the magnitude of these
interactions is typically of the order of the thermal energy. Sur-
factant aggregates are highly dynamic structures that not only
rapidly diffuse but that are also undergoing constant molecu-
lar rearrangements. Their interaction with other compounds in
the bulk phase is to a large extent determined by the nature of
the hydrophilic head group that determines the surface proper-
ties of the micelle. For example, the head group may be pos-
itively (cationic) or negatively charged (anionic) or may carry
no charge at all (nonionic). For charged surfactant micelles,
the colloidal stability of surfactant aggregates depends on pH
and the presence of electrolytes that alter electrostatic interac-
tions between other colloidal particles, or charged components
that may be present in the bulk phase (e.g., charged proteins or
polysaccharides).
Micelles can serve as delivery systems for a variety of func-
tional compounds due to their ability to incorporate lipophilic
molecules within their structures (Rosen, 2004). The resulting
surfactant-lipophilic molecule system is usually referred to as
a “swollen micelle” or a “microemulsion.” Solubilization of
lipophilic components is closely associated with the phase be-
havior of the surfactant (and co-surfactant) used to form the
association colloids. Due to the fact that the mechanism is
based on an uptake and inclusion of the normally insoluble
material in a colloidal structure, the form and shape as well
as the temperature-concentration dependence of the colloidal
structures are a major factor for solubilization. Knowledge of
micelle structure is therefore necessary to relate the molecular
properties of a surfactant to its mechanism and efficiency of
solubilization. Encapsulated lipophilic materials may become
part of the surfactant layer (the palisade layer) or may be lo-
cated within the interior of the micelle (Fig. 12). Micelle size
and shape usually changes upon incorporation of a solubilized
material. In nonionic micelles, micelle size typically increases
as the amount of the compound being solubilized is increased,
up to a particular level when all the micelles present are satu-
rated with material. If the functional compound becomes part of
the palisade layer, its presence can affect the overall properties
of the micelle e.g. surface charge and/or hydrophilicity. In this
case, the compound may also be exposed to the solvent phase
and thus be more accessible for reactions with reactive species
present in the solvent. In ionic micelles, size can sometimes
decrease as repulsive interactions between the charged head
groups are reduced because of the inclusion of the functional
compound in the palisade layer. Alternatively, very hydropho-
bic molecules may preferentially be solubilized and located in
the interior of the micelles. Finally, incorporation of lipophilic
materials in micelles may also result in changes in shape. For
example, if the initial colloid is a wormlike micelle, the en-
capsulation may result in a transition to a spherical micelle.
The solubilization may thus alter the interaction with light and a
transition from an opaque system to a transparent system may be
observed.
Micelles can be formulated with either a single surfactant or
a mixture of surfactants. The combination of two different sur-
factants results in the formation of mixed micelles. Rather than
producing two separate species of single-surfactant micelles,
the association colloids formed are composed of a mixture of
both surfactants. Such mixed micelles have become increasingly
Figure 12 Non-polar substances can be solubilized within the hydrophobic
core of a micelle or between the surfactant molecules in the palisade layer.
 DESIGN AND FABRICATION OF STRUCTURED DELIVERY SYSTEMS
important since they have been shown to exhibit significantly
improved performance in terms of their solublization capacity
and physical stability when compared to their single surfac-
tant counterparts (Rosen, 2004). This synergistic behavior is the
direct result of the molecular interactions between the two or
more surfactant species with their environment including the
solvent phase and the solubilized internal phase. High syner-
gistic effects have been particularly found if ionic and nonionic
surfactants or two ionic species carrying opposite charges are
mixed (Rosen, 2004). The latter however may be difficult to
formulate without causing formation of large macromolecular
aggregates. For example, stability of ionic micelles at pH values
where the micelle typically loses its charge or in the presence of
salts that shield the electrostatic charges of the surfactant momo-
mers may be greatly improved with the addition of a nonionic
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surfactant. Solubilization capacity has been reported to greatly
increase, sometimes by an order of a magnitude. The involved
driving forces are more complex in the case of mixed surfactant
systems. In the case of nonionic surfactants, the formation of sin-
gle surfactant micelles, and nonionic-nonionic mixed micellar
systems is mainly driven by hydrophobic interactions between
the tail groups and steric interactions between the head group.
However, in ionic micelles and nonionic-ionic and ionic-ionic
mixed micellar systems, electrostatic interactions, van der Waals
forces, and the formation of hydrogen bonds among the differ-
ent surfactant head groups play an increasingly important role.
Thus, mixed micelles may exhibit very complex phase tran-
sition behavior as influenced by surfactant concentration and
temperature.
Solid Lipid Particle Microemulsions
In recent years, surfactant micelles have not only been used as
a simple carrier system for functional compounds in the food,
chemical, and pharmaceutical industries but as reaction and
containment chamber to furnish the crystallization of lipophilic
compounds to produce solid lipid particles. A preparation tech-
nique for solid lipid particles using surfactant micelles was
first published by Gasco and co-authors (Gasco, 1993; 1997).
Solid lipid particles may be made from surfactant aggregates
by first formulating a warm or hot oil-in-water microemulsion
(a micelle containing the solubilized lipophilic functional com-
pound). The warm microemulsions form spontaneously, and are
clear, and thermodynamically stable systems. For very lipophilic
compounds, complex mixtures of surfactants such as lecithin,
polysorbate 20, polysorbate 60, and co-emulsifiers such as bile
salts and butanol may be required to form the warm microemul-
sion. The co-surfactants have the effect of further reducing the
interfacial tension and simultaneously increasing the fluidity of
the interface (Flanagan and Singh, 2006). Solid lipid particles
are then produced by dispersing the warm microemulsion in a
cold aqueous medium (Gasco, 1993; 1997; Fueredi-Milhofer
et al., 1999; Marengo et al., 2000; Ugazio et al., 2002). The
critical step in the production of SLP from microemulsions
is the dilution-cooling step and microemulsions are typically
597
diluted into 2–3◦ C water under mechanical stirring with dilu-
tion ratios of microemulsions in water of 1:25 to 1:50 (Constan-
tinides, 1995). SLPs from microemulsions can be freeze-dried
to improve handling, reduce shipping costs, and increase shelf
life. The freeze-dried powders can be easily re-dispersed in an
aqueous media prior to use. The properties of SLP made from
microemulsions are determined by the properties of the parent
microemulsion, i.e., the size and composition of the surfactant
aggregates containing the encapsulated functional component.
Depending on the composition of the microemulsions, the loca-
tion of the functional compound with respect to the surfactant
layer may vary and the obtained structures of the crystallized
functional compound may thus be considerably different. Pro-
cess equipment for scale-up of SLP production has recently
been developed by a group in Italy and consists of an auto-
mated, thermostatted injection system to control the dispersion
of microemulsions in cold water followed by filter sterilization
to obtain a shelf stable SLP preparation (Marengo et al., 2000).
Process parameters for the automated systems include applied
pneumatic pressure, temperature, needle gauge, and volume of
water in the dispersion chamber.
Biopolymer-Based Delivery Systems
Proteins and polysaccharides used either individually or in
combination can be used to create a variety of delivery sys-
tems that may be suitable for encapsulating nutraceutical and
functional food components (Benichou et al., 2002; Dickinson,
2003; Tolstoguzov, 2002; 2003; McClements, 2006). Typically,
one starts with a biopolymer solution and then changes the en-
vironmental conditions to promote the formation of biopolymer
“particles,” which may be soluble complexes, fluid droplets or
hydrogel particles. The ability of these particles to encapsulate
and deliver functional food components depends on molecular
and physicochemical factors, such as their composition, internal
structure, polarity, electrical charge, and physical dimensions.
It is therefore important to establish the relationship between
the characteristics of the molecules present, the nature of the
assembly conditions, and the final properties of the biopoly-
mer particles formed. In this section we highlight some of the
most important methods used to prepare biopolymer particles,
and discuss how these particles can be utilized to encapsulate
functional components.
Single Biopolymer Systems
Biopolymer particles can often be prepared using a single
type of biopolymer, e.g., a particular protein or polysaccha-
ride (Norton and Frith, 2001). The formation of these particles
usually relies on adjusting system conditions so that the self-
assembly of the biopolymer molecules is promoted and can be
directed to form a particular structure. Some of the system con-
ditions that can be utilized to promote self-assembly are outlined
below:
 598 D. J. McCLEMENTS ET AL.
Thermal Transitions. Many biopolymer molecules undergo
alternations in their conformation at a particular temperature,
which promotes a change in their tendency to interact and as-
semble with themselves or with other molecules. Examples of
systems where thermal transitions of biopolymers are important
in structure formation are given below:
•
Globular Proteins: Many globular proteins (e.g., whey, soy,
and egg proteins) partially or fully unfold upon heating,
which causes an increase in their surface hydrophobicity and
chemical reactivity (disulfide bond formation) (Chen et al.,
2006; Graveland-Bikker and de Kruif, 2006; 2005; Graveland-
Bikker et al., 2006; Foegeding, 2006; Totosaus et al., 2002).
These thermally denatured globular proteins can often be
made to form particular structures (e.g., filaments, particu-
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lates, or tubes) by carefully controlling the heating conditions,
shearing conditions, pressure, pH, and/or ionic strength.
• Flexible Biopolymers: Many flexible “random coil” proteins
and polysaccharides undergo a coil-to-helix transition upon
cooling, which promotes the formation of intramolecular
and intermolecular hydrogen bonds between helical regions
(Ross-Murphy, 1997; Wybor and Zaborski, 2000; Djabourov,
1991; Braudo et al., 1998). The formation of junctions be-
tween different biopolymers in solution can be used to cre-
ate macroscopic hydrogels or hydrogel particles. In some
cases, oppositely charged counter-ions are needed in so-
lution to screen electrostatic interactions or to act as salt
bridges between charged helical regions, e.g., carrageenan,
low methoxyl pectin, and alginate (Cui, 2005).
Consequently, controlled changes in temperature can be used
to promote the association of biopolymers with each other,
which can be used to build specific structures, such as hydrogel
particles.
pH and Ionic Strength. Electrostatic interactions play a major
role in determining the association of many types of biopolymer
molecules in aqueous solution, and their careful manipulation
can often be used to direct the formation of specific assembled
structures. The most common ways of varying the sign, strength,
and range of electrostatic interactions is to control the pH (which
determines the charge density of food components), the overall
ionic strength (which determines the range of the interactions),
and the type of ions used (since this may affect specific salt-
bridging interactions). Examples of the role of pH and ionic
strength in forming assembled structures using biopolymers are
given below:
• The milk protein casein forms specific nanometer-sized struc-
tures (micelles or sub-micelles) under particular pH and ionic
strength combinations (Farrell et al., 2006).
• Globular proteins can be induced to form specific structures
(tubes, filaments or particulates) by heating them at a con-
trolled pH or ionic strength, e.g., ovalbumin, BSA, and β-
lactoglobulin.
• Some polysaccharides can be induced to form hydrogels when
they are cooled in the presence of sufficiently high concentra-
tions of mineral ions, e.g., alginate, carrageenan, and pectin
(Cui, 2005).
• Some polysaccharides can be induced to form hydrogel parti-
cles by cross-linking them using multivalent ions (Cui, 2005),
e.g., cationic chitosan can be cross-linked using multivalent
anions (TPP), whereas anionic carrageenan can be cross-
linked using multivalent cations (Ca2+ ).
Covalent Cross-Linking. It is often possible to form spe-
cific structures using biopolymers and then covalently cross-
link them, which can be achieved through a variety of physical,
chemical, or enzymatic means.
• The Maillard reaction can be used to covalently link proteins
to carbohydrates
• The enzyme Laccase can be used to covalently cross-link
phenolic groups in some polysaccharides (beet pectin) and
proteins (β-lactogloblin).
• The enzyme transglutaminase can be used to covalently cross-
link proteins via a reaction between a free amine group on one
protein and a gamma-carboxamid group on another protein.
• Gluteraldehyde can be used to covalently cross-link protein
molecules by forming a bridge between nitrogen groups on
different protein molecules.
• Disulfide bond formation can be induced between many pro-
teins by heating.
Ideally, one would like to control the structural and physic-
ochemical properties of the particles produced, e.g., their di-
mensions, electrical charge, loading capacity, stability, and en-
vironmental responsiveness. This can usually be done through a
combination of controlling the system composition and process-
ing conditions. A macroscopic hydrogel is usually formed by
inducing biopolymer association in an aqueous solution where
the biopolymer concentration exceeds the critical level required
to form a three-dimensional space filling object. On the other
hand, nanoscopic or microscopic hydrogel particles can often be
formed by inducing biopolymer association in an aqueous so-
lution where the biopolymer concentration is sufficiently below
this critical value. The size, structure, and charge of these hydro-
gel particles can be controlled by altering solution composition
(e.g., pH, I) or processing conditions (e.g., temperature, hold-
ing time, shear rate). Alternatively, hydrogel particles can be
formed using specific processing operations, such as injection,
extrusion, templating, or molding. For example, hydrogel beads
could be formed from a liquid biopolymer solution by inject-
ing it into a solution where biopolymer association is favored,
e.g., by controlling its temperature, pH, or ionic composition.
The material to be encapsulated could be mixed with the initial
biopolymer solution prior to induction of biopolymer associa-
tion. It should be noted that many of the methods used for single
biopolymer systems can also be applied to mixed biopolymer
 DESIGN AND FABRICATION OF STRUCTURED DELIVERY SYSTEMS
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Figure 13 Proteins and polysaccharides may form a variety of different phases in aqueous solutions due to segregative or associative separation.
systems in order to design and fabricate more complex struc-
tures.
Mixed Biopolymer Systems
A variety of assembled structures that can be used as deliv-
ery systems can be formed when two or more biopolymers are
combined together (Benichou et al., 2002; Tolstoguzov, 2002;
2003; McClements, 2006). When two different biopolymers are
mixed they may either form a one-phase or a two-phase system
depending on the nature of the biopolymers involved, the solu-
tion composition, and the prevailing environmental conditions
(Fig. 13). In a one-phase system, the two biopolymers can exist
either as individual molecules or as soluble complexes that are
evenly distributed throughout the entire system. In a two-phase
system, the solution separates into two distinct phases that have
different biopolymer compositions. Phase separation can occur
through two different physicochemical mechanisms: associative
and segregative separation.
In associative separation, there is a relatively strong attraction II. pH ≈ pI: When the pH is reduced close to the isoelectric
between the two different kinds of biopolymers which causes
them to associate with each other. The most common example
of this type of interaction for food biopolymers is the elec-
trostatic attraction between molecules with opposite electrical
charges. The resulting two-phase system consists of a phase that
is rich in both biopolymers and a phase that is depleted in both
biopolymers (Fig. 13). The biopolymer-rich phase may either
by a coacervate or a precipitate, depending on the strength of the
electrostatic attraction and the charge densities of the biopoly-
mers involved. Coacervates are formed when the biopolymers
have opposite net charges, and the complexes themselves have a III. pH ≤ pI: When the pH is reduced just below the isoelectric
net charge that does not oppose higher-order association. They
tend to have fairly open structures that are rich in water (>70%).
Precipitates are also formed when the biopolymers have oppo-
site net charges, but are favored when the biopolymer inter-
599
actions are strong enough to release appreciable amounts of
counter-ions and water, e.g., under low ionic strength and high
biopolymer charge density.
Associative separation can be used to form a range of as-
sembled structures by varying the pH and ionic strength of the
solution. For example, consider a mixed biopolymer system that
contains a protein and an anionic polysaccharide. The associa-
tion of the protein and polysaccharide in the system is strongly
dependent on pH and can be conveniently divided into four
regions:
I. pH  pI: At pH values appreciably above the isoelectric
point of the protein, both the protein and polysaccharide
have relatively strong net negative charges, and so there is
an electrostatic repulsion between the two types of molecule
which prevents their assembly. Consequently, the system
exists as a molecular dispersion of the individual molecules
(provided segregative separation does not occur – see be-
low).
point of the protein, the protein gains a significant number
of cationic groups (-NH+ 3 ) on its surface which promotes
the formation of soluble complexes. These soluble com-
plexes are believed to consist of individual polysaccharide
molecules that are “decorated” with a number of protein
molecules along their chain (de Kruif et al., 2004). The ra-
dius of gyration of the complexes is therefore fairly similar
to that of the original polysaccharide molecules. The mag-
nitude of the net charge on the soluble complexes is fairly
large, which prevents them from aggregating further.
point of the protein further association of the protein and
polysaccharide molecules occurs, which leads to the forma-
tion of a complex coacervate phase (de Kruif et al., 2004;
Cooper et al., 2005). Initially, the coacervate phase forms
 600 D. J. McCLEMENTS ET AL.
as small spherical “water” droplets (typically 0.2 to 2 µm)
that are rich in the two biopolymers, and are surrounded by
an aqueous solution that is depleted in both biopolymers.
This system is often referred to as a water-in-water (W/W)
emulsion, by analogy to an oil-in-water (O/W) emulsion that
contains oil droplets dispersed in an aqueous solution. With
time coacervate droplets tend to aggregate and sediment,
which leads to the formation of a macroscopic two-phase
system consisting of a layer of aqueous solution on top of
a layer of coacervate phase (de Kruif et al., 2004; Cooper
et al., 2005).
IV. pH < pI: When the pH is further reduced below the iso-
electric point of the protein there is a strong electrostatic at-
traction between the protein and polysaccharide molecules,
resulting in loss of counter-ions and water and the forma-
Downloaded by [University of South Dakota] at 17:51 19 May 2013
tion of a precipitate (de Kruif et al., 2004; Cooper et al.,
2005). The precipitate phase is much denser than the coac-
ervate phase and so it rapidly sediments to the bottom of the
container.
An analogous behavior occurs when a protein and a cationic
polysaccharide are mixed together, but the pH sequence is re-
versed. The utilization of associate separation to form novel
structures that can be used as delivery systems depends on be-
ing able to control the characteristics of the particles formed.
For example, one would like to be able to efficiently encap-
sulate the functional component within the structure, as well
as control the overall size, charge, stability, and environmen-
tal responsiveness of the particles. One of the problems with
assembled soluble complexes or coacervates is that it is of-
ten difficult to stabilize their structures once they have been
formed. For example, they may dissociate when the pH or ionic
strength is changed, or in the case of coacervates they may be
unstable to coalescence (Cooper et al., 2005). Consequently, it
is important to find methods of stabilizing their structures. At
present, coacervates are often held together by covalently cross-
linking the proteins and polysaccharides using gluteraldehyde
(Cooper et al., 2005). Other methods may also prove to be useful,
such as cross-linking the proteins or polysaccharides by heating
(Yu et al., 2006), enzymatic treatment (Flanagan and Singh,
2006) or adding multivalent ions (Chen and Subirade, 2005).
In segregative separation, there is a relatively strong repul-
sion between the two different kinds of biopolymers, i.e., there
is a relatively high positive (unfavorable) free energy of mix-
ing (Tolstoguzov, 2002; 2003). The molecular origin of this
effect is usually the steric exclusion effect mentioned earlier.
This type of phase separation often occurs when one or both
of the biopolymers are uncharged, or when both biopolymers
have similar electrical charges. At sufficiently low biopolymer
concentrations, the two biopolymers are intimately mixed and
form a one-phase solution, but once the biopolymer concen-
tration exceeds a certain level phase separation occurs and a
two-phase solution is formed with one of the phases being rich
in one type of biopolymer and depleted in the other type, and
vice versa (Fig. 13). The behavior of biopolymer blends under
different solution and environmental conditions can be con-
veniently characterized in terms of phase diagrams (Walstra,
2003). These phase diagrams can often be used to optimize the
biopolymer composition required to produce a solution with a
particular microstructure and physicochemical properties. For
example, segregative separation has been used to produce a
variety of structures, such as spherical droplets, non-spherical
droplets, and fibers by controlling preparation conditions such
as pH, ionic strength, temperature, and applied shear.
A variety of different microstructures can be created in phase
separated biopolymer systems by varying the preparation condi-
tions or by shearing the system, e.g., “water-in-water” emulsions
can be formed (Fig. 14) or “oil-in-water-in-water” (Fig. 15).
Once a particular microstructure has been formed by phase sep-
aration of a mixed biopolymer solution it is often possible to trap
the system in a kinetically stable state, and thus create novel food
microstructures and rheological properties (Norton and Frith,
2001). For example, kinetic trapping can be achieved by chang-
ing solution or environmental conditions so that one or both of
the phases thickens or gels, e.g., by changing temperature, pH,
ionic composition or solvent quality. If this process is carried
out in the presence of shear forces it is possible to produce
a wide variety of different microstructures, e.g., spheres, tear-
drops, fibers (Norton and Frith, 2001). Alternatively, it may be
possible to adsorb another biopolymer around the water droplets
that form the dispersed phase in a W/W emulsion, thereby sta-
bilizing them.
Different types of gel microstructure can be created using
biopolymer blends by varying the nature of the biopolymers
involved, the solution composition, and the prevailing environ-
mental conditions, e.g., interpenetrating networks comprised of
different biopolymers, a single network that incorporates both
types of biopolymer, or a “filled gel” consisting of regions rich
in one biopolymer dispersed in regions rich in the other biopoly-
mer. Each of these microstructures will have unique rheological
Figure 14 Schematic representation of production of a water-in-water (W/W)
emulsion from two phase-separated aqueous phases.
 DESIGN AND FABRICATION OF STRUCTURED DELIVERY SYSTEMS
Figure 15 Schematic representation of production of an oil-in-water-in-water
(O/W/W) emulsion from a two-phase system consisting of two aqueous phases
and an O/W emulsion.
Downloaded by [University of South Dakota] at 17:51 19 May 2013
and physicochemical properties, e.g., gel strength, gelation rate,
gelation temperature, water holding capacity, and opacity. Many
food scientists are currently attempting to understand the fun-
damental processes involved in the formation of structured
biopolymer blends and in utilizing these systems to create foods
with novel or improved physicochemical and sensory proper-
ties. In particular, mixed biopolymer systems appear to be an
effective means of creating low-fat products with similar prop-
erties to high-fat products, e.g., deserts, yogurts, dressings, and
spreads (Norton and Frith, 2001).
Applications. The possibility of forming food-grade hydro-
gel particles has been demonstrated in a number of studies uti-
lizing single biopolymer gelation (Chen et al., 2006; Malone
et al., 2003), aggregative phase separation (Desai and Park,
2005; Madene et al., 2006; Benichou et al., 2002; Schmitt et
al., 1998; Weinbreck et al., 2004; Renken and Hunkeler, 1998)
and segregative phase separation (Norton and Frith, 2001; Kim
et al., 2006; Lian et al., 2004; Malone and Appelqvist, 2003).
Filled hydrogel particles based on aggregative phase separation
have been used to encapsulate and protect ω-3 fatty acids (Lam-
precht et al., 2001; Wu et al., 2005) and flavor oils (Weinbreck
et al., 2004), while those based on segregative phase separa-
tion have also been used to encapsulate fish oils (Kim et al.,
2006). It is also possible to encapsulate hydrophilic materials
within hydrogel particles, such as enzymes, peptides, proteins,
and fibers (Chen et al., 2006; Cooper et al., 2005). Careful de-
sign of the biopolymer system can be used to increase the food
matrix compatibility of functional ingredients, to protect labile
functional ingredients, or to release functional ingredients at
particular sites of action.
CONCLUSIONS
A wide variety of structured delivery systems is currently
available for the encapsulation of nutraceutical and functional
food components, each with its own advantages and disadvan-
tages. This review article has provided an overview of some of
601
the major types of structured delivery system that are available
for encapsulating substances in aqueous systems, and has high-
lighted some of the advantages and disadvantages of each one.
Simple oil-in-water emulsions are currently the most widely
used method of encapsulating lipophilic functional components,
such as flavors and bioactive lipids. Nevertheless, they are only
kinetically stable systems that are susceptible to breakdown over
time or when they are exposed to certain environmental stresses
during production, transport, storage, or utilization. In addition,
they have limited ability to encapsulate, protect, and deliver cer-
tain types of functional food components, and they are optically
opaque. Consequently, there is a need for certain applications
to have alternative types of structured delivery systems. Other
types of lipid-based delivery systems, such as multiple emul-
sions, multilayer emulsions, and solid lipid emulsions, have
certain advantages over simple emulsions, but they are often
more complicated to prepare and are sometimes more unstable.
Surfactant based delivery systems have the advantage of being
thermodynamically stable and optically transparent, but they
usually have a relatively low loading capacity and there are of-
ten taste problems associated with the high levels of surfactant
needed. Biopolymer based delivery systems (such as soluble
complexes, coacervates, hydrogel particles) can also be used to
encapsulate certain functional components. The main advantage
of these systems is that the fat and surfactant level can be re-
duced, but again they have to be carefully designed in order to
be robust enough for general application.
ACKNOWLEDGEMENTS
This material is based upon work supported by the Coop-
erative State Research, Extension, Education Service, United
State Department of Agriculture, Massachusetts Agricultural
Experiment Station (Project No. 831), and a United States De-
partment of Agriculture, CREES, NRI Grant (Award Numbers
2005-01357, 2008-02191 and 2008-01368).
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