Maillard conjugate-based delivery systems for the encapsulation, protection, and controlled release of nutraceuticals and food bioactive ingredients: A review

Food Hydrocolloids 100 (2020) 105389

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Maillard conjugate-based delivery systems for the encapsulation, protection, and controlled release of nutraceuticals and food bioactive ingredients: A review

T

Majid Nooshkam, Mehdi Varidi∗ Department of Food Science and Technology, Faculty of Agriculture, Ferdowsi University of Mashhad (FUM), Mashhad, Iran

A R T I C LE I N FO

A B S T R A C T

Keywords: Delivery system Maillard reaction Protein-polysaccharide conjugate Emulsion Nanoparticle Bioactive compound

Bioactive compounds are mostly prone to decomposition during the production process, storage, and severe gastrointestinal conditions. Therefore, their potential application as functional ingredients in many food products has opened a new horizon in designing novel food-grade delivery systems. Protein-based delivery vehicles have been extensively applied for this purpose. The stability of such systems is substantially affected by destabilizing conditions such as pH change and high ionic strength, thereby affecting bioavailability and stability of the encapsulated bioactive compound. Protein-polysaccharide Maillard-type conjugates are one of the latest food-applicable carriers and promising attractive methods of delivering nutraceuticals. Recently, these types of carriers have been introduced to improve the bioavailability and stability of nutraceuticals and nutrients and to create novel functional foods. The present paper reviews the most recent potential applications of Maillard conjugates for designing delivery systems; i.e., oil-in-water (O/W) emulsion, nanoemulsion, double emulsions, nanoparticles, nanogels, and microencapsulation. It also highlights the structures/compositions of Maillard conjugates used for delivery in food. Moreover, the gastrointestinal fate of Maillard conjugate-based bioactiveloaded delivery systems has been discussed.

1. Introduction In recent years, in the light of the significant advances in food science, novel approaches have been designed in the area of food-grade delivery systems in order to boost bioavailability, stability, and controlled release of bioactive drugs or nutrients (Augustin, Sanguansri, & Bode, 2006; Feng, Wu, Wang, & Liu, 2016; Lesmes & McClements, 2012; Li & Gu, 2014). These delivery systems include emulsions, hydrogels (nanogels and microgels), nanoparticles, and liposomes, which have manifold advantages and disadvantages related to the stability, bioavailability, biodegradability, biocompatibility, and cost (Fan, Yi, Zhang, & Yokoyama, 2018). Among biopolymers, proteins are major materials that have been extensively used for delivery systems. However, these carriers have several drawbacks due to the impacts of pH value and ionic strength on protein structures, which can lead to precipitation (at isoelectric point, pI) and aggregation. In addition, protein in the protein-based delivery system can be readily hydrolyzed to lower molecular weight peptides and amino acids by digestive enzymes in the gastrointestinal tract (GIT), which in turn leads to burst release of biologically active

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compound followed by degradation and poor absorption (Li & Gu, 2014). On the other hand, the use of some methods, e.g., coacervation, anti-solvent precipitation, and emulsifying-cross-linking to design protein-based nanoparticles, has increased. However, the use of chemical cross-linkers residues such as glutaraldehyde and organic solvents in the above-mentioned methods causes health concerns and may reduce the application of these carriers in the targeted release of nutraceuticals (Fan et al., 2018). Recently, protein-polysaccharide conjugates based on the Maillard reaction have received a great deal of attention for the encapsulation of volatile oils, flavors, and other bioactive compounds in food and pharmaceutical sectors owing to their unique characteristics including excellent solubility and emulsifying capacity (higher surface activity and emulsion stabilization), antioxidant properties, stability over a wide range of pH values, temperature and ionic strength, and providing a thicker, continuous, viscoelastic, and shear-resistant layer around oil particles and other oil-soluble bioactive components (Lesmes & McClements, 2012; Nooshkam & Madadlou, 2016a; Nooshkam & Madadlou, 2016b; Vhangani & Van Wyk, 2013; Vhangani & Van Wyk, 2016). All these characteristics make the Maillard conjugates good

Corresponding author. E-mail addresses: [email protected] (M. Nooshkam), [email protected] (M. Varidi).

https://doi.org/10.1016/j.foodhyd.2019.105389 Received 18 June 2019; Received in revised form 17 September 2019; Accepted 18 September 2019 Available online 25 September 2019 0268-005X/ © 2019 Elsevier Ltd. All rights reserved.

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sugars or 2-amino-2-deoxyaldose from ketose sugars as Amadori (ARPs) or Heyns (HRPs) rearrangement products, respectively (Troise & Fogliano, 2013). This step increases the reducing capacity and decreases the proteins' biological value. It is worth noting that the flavor, color, metal chelation, and toxicity of the obtained products are not changed at the early stage (Nursten, 2005). Moreover, the instability at high temperatures and the presence of oxidation and nucleophilic agents, are the main drawbacks regarding ARPs quantification; ARPs with high hydrophilic nature poorly absorb in the ultraviolet and visible regions, and the modification procedures to form easily active derivatives are not always effective nor practicable (Troise, 2018).

candidates for the development of a new class of encapsulants and drug delivery systems (Livney, 2008). In protein-polysaccharide conjugates, the polysaccharide moiety renders strong steric and sometimes electrostatic repulsion, and the protein in the conjugate can be attached to hydrophobic surfaces (Feng et al., 2016). However, it is necessary to control the Maillard reaction, and stop it in its early stages to prevent the formation of brown melanoidin polymers and undesired advanced glycation products, such as acrylamide (Spivey, 2010). This review paper highlights the potential applications of Maillardbased conjugates in designing food-grade delivery systems to tailor their efficiencies in the case of encapsulation, protection, and delivery of biologically active compounds. It also highlights the structures/ compositions of Maillard conjugates used for delivery in food along with the gastrointestinal fate of nutraceutical-loaded Maillard conjugate-based delivery systems.

2.2. Intermediate stage The intermediate stage is characterized by the degradation of ARPs and probably HRPs to the intermediate compounds through 1, 2-enolization and 2, 3-enolization routes based on the initial pH value. At pHs ≤7.0, the early compounds mainly undergo the 1,2-enolization pathway and form hydroxymethylfurfural from hexoses or furfural from pentoses. The 2,3-enolization route is mainly dominant at pH > 7.0 and leads to the formation of reductones, such as 4-hydroxy-5-methyl2,3-dihydrofuran-3-one and fission products like acetol, diacetyl, and pyruvaldehyde from ARPs. These dicarbonyl compounds can react with amino acids and form aldehydes and aminoketones through Strecker degradation pathway (de Oliveira, Coimbra, de Oliveira, Zuñiga, & Rojas, 2016). Some documented characteristics of this stage are the production of yellow color, strong absorption in the near-ultraviolet region, reducing activity, and the generation of flavor or off-flavor and carbon dioxide (Nursten, 2005; Wu et al., 2014).

2. A brief overview of the Maillard reaction The Maillard reaction happens between free amino group of amino acids/peptides/proteins and carbonyl group of reducing sugars during heating/storage of many food products (Vhangani & Van Wyk, 2013). It comprises three main stages (Fig. 1), which are briefly summarized hereunder. 2.1. Early stage The early stage of the reaction begins with the formation of covalent bond between the carbonyl group of a reducing sugar and the free amino group of an amino acid, peptide or protein to produce a Schiff base along with the release of one water molecule. Afterwards, the Schiff base undergoes the cyclization process to form a low stable condensation product N-substituted glycosylamine (O'Brien, Morrissey, & Ames, 1989). The reaction is followed by the rearrangement of glycosylamine to more stable 1-amino-1-deoxy-2-ketose from aldose

2.3. Final stage At the final stage, reductones and fission products as well as Strecker degradation products undergo aldol and aldehyde-amine

Fig. 1. The Maillard reaction pathways; designed with respect to Arena, Renzone, D'Ambrosio, Salzano, and Scaloni (2017). 2

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Table 1 Applications of protein-polysaccharide Maillard conjugates in stabilizing O/W emulsions. Maillard-based conjugate systems

Conjugate formation method

Physical stability

Thermal stability

Freeze/thaw stability

Reference

β-lactoglobulin-maltose/maltodextrin Acid soluble soy protein-dextran Caseinate-maltodextrin WPI-dextran Deamidated wheat protein-dextran Soy whey protein isolate (WPI)-fenugreek gum SPI-soy soluble polysaccharide (SSPS)

Dry-heating Dry-heating Dry-heating Dry-heating Dry-heating Dry-heating Dry-heating

↑ ↑ ↑ ↑ ↑ ↑ ↑

↑ ↑ ↑ – – – ↑

– – ↑ ↑ – – –

Soy protein isolate (SPI)-dextran SPI/SPI hydrolyzate-dextran

Wet-heating Wet-heating

↑ ↑

– –

↑ ↑

Wooster and Augustin (2007) Xu and Yao (2009) O'Regan and Mulvihill (2010) Xu et al. (2010) Wong et al. (2011) Kasran et al. (2013) Yang et al. (2015a) and Yang et al. (2015b) Zhang et al. (2017) Yu et al. (2018)

properties (de Oliveira et al., 2016). The Maillard reaction under controlled conditions could be harnessed to fabricate protein-polysaccharide conjugates with appreciable functionality which can be used as novel carriers for food-grade delivery systems to encapsulate, protect, and control the release of many bioactive compounds (Livney, 2012).

condensations, resulting in brown nitrogenous polymers, melanoidins (Peng, Ma, Chen, & Wang, 2011). Although food melanoidins are found in daily diet and have some documented bio-functionalities, such as antioxidant, antihypertensive, and antimicrobial activities (Nooshkam, Babazadeh, & Jooyandeh, 2018; Nooshkam et al., 2019b; Nooshkam, Varidi, & Bashash, 2019a; Wang, Qian, & Yao, 2011), it was reported that the Maillard reaction at the final and advanced stages can lead to several diseases like diabetes and Alzheimer (Silván, Assar, Srey, del Castillo, & Ames, 2011). The Maillard reaction under controlled conditions may prevent the reaction progression to the more advanced stages and subsequently reduce the formation of harmful compounds. For example, the degradation of ARPs is retarded when the Maillard reaction is performed at high pressure (400 MPa) and pHs lower that 8.0 at which the progress of the intermediate and advanced stages is inhibited (Moreno, Molina, Olano, & López-Fandiño, 2003). In this regard, the Maillard glycation can be applied as a facile method to improve the protein functionality, such as solubility and thermal stability, and the resultant protein-based conjugates can be used as functional ingredient in many food products (de Oliveira et al., 2016). It should also be pointed out that the further rearrangement, reduction, and oxidation of the Maillard reaction products (MRPs) lead to the production of advanced glycation end products (AGEs) such as pyrraline, pentosidine, Nε-(carboxymethyl)lysine (CML), and imidazolones. It is unclear whether the AGEs which are responsible for the oxidative stress and inflammation arrive from food, or formed in the body (Goldin, Beckman, Schmidt, & Creager, 2006; Van Nguyen, 2006). The formation of AGEs can be reduced or inhibited by applying synthetic carbonyl scavengers including pyridoxamine and aminoguanidine as well as natural AGE inhibitors, such as plant extracts and phenolic compounds (Peng et al., 2011). Despite the fact that the oxidative circumstances and high temperatures under basic pHs resulted in an increase in AGEs formation through the wet-heating mode of the Maillard reaction, it was reported that the use of ferulic acid (a phenolic phytochemical) led to a significant reduction in the amounts of CML and fluorescent AGEs by 90% (Silván et al., 2011). Uribarri et al. (2010) stated that the production of AGEs in dry heating version of the Maillard reaction is 10–100 fold higher than that of the uncooked state. In addition, carbohydrate-based foods (e.g., whole grains, vegetables, fruits, and low-fat milk) contain a relatively low level of AGEs after storage and cooking, while animal-born foods are rich in AGEs due to their high fat and protein contents. This is because the lipid oxidation reaction could generate lipid oxidation products (such as, aldehyde and ketones), which are precursors of the Maillard reaction (Nooshkam et al., 2019a). It was also claimed that the use of acidic ingredients (such as, lemon juice or vinegar), cooking through wet-heating under mild temperatures and short times, and AGE inhibitors can suppress the AGEs formation (Uribarri et al., 2010). It is necessary to mention that the Maillard reaction-assisted protein modification is safer than the other chemical modifications and the glycated proteins can be added to foods as potentially food-derived ingredients to ameliorate gelation and alter texture and organoleptic

3. Types of delivery systems based on the Maillard conjugates 3.1. Emulsions Oil-in-water (O/W) emulsions and nanoemulsions are useful platforms for designing delivery systems to encapsulate hydrophobic bioactives in the emulsion oil droplets to elevate their stability and solubility in aqueous solutions (Wang, Liu, Xu, Yin, & Yao, 2016a). O/ W emulsions stabilized by proteins have been introduced and extensively applied for delivery of water-insoluble biologically active compounds. However, such protein-stabilized emulsions are prone to coalescence, creaming, and phase separation triggered by acidic pH, temperature, ionic strength, and digestive enzymes as well as other surfactants (Yang et al., 2015a). In addition, some lipid-based delivery systems, especially nanoemulsions are sometimes thermodynamically unstable and the use of some approaches seems to be mandatory to improve the performance of such emulsions (Gumus, Davidov-Pardo, & McClements, 2016). These problems can be solved through anchoring polysaccharides onto oil droplet surfaces by the application of proteinpolysaccharide Maillard-derived conjugates as emulsifiers, which in the light of their safety and stability, they are currently applied as promising delivery systems for bioactive compounds (Wang et al., 2016a). The chemical and physical stabilities of O/W emulsions have been improved by applying protein-polysaccharide conjugates obtained through the Maillard reaction (Table 1) (Wooster & Augustin, 2006; Wong, Day, & Augustin, 2011; Dong, Wei, Chen, Mcclements, & Decker, 2011; Kasran, Cui, & Goff, 2013; Li, Woo, Patel, & Selomulya, 2017; Nasrollahzadeh, Varidi, Koocheki, & Hadizadeh, 2017). As mentioned above, the protein moiety provides rapid adsorption of the conjugate to the surface of oil droplets and the polysaccharide moiety prevents the aggregation of oil droplets via strong steric and sometimes electrostatic repulsion (Fig. 2) (Gumus et al., 2016). It was also reported that Maillard-based conjugates obtained between whey protein and polysaccharides (gellan gum and sodium alginate) decreased the surfactanttriggered competitive displacement of whey protein from the interface in the presence of low molecular weight (LMW) surfactants due to the self-assembled network of the polysaccharide at the interface (Cai & Ikeda, 2016; Cai, Saito, & Ikeda, 2018). Moreover, the high stability of Maillard conjugate-stabilized emulsions is mostly due to greater film thickness around the droplets of such emulsions (5–10 nm), while proteins and LMW surfactants provide film thickness of 1–5 nm and 0.5–1 nm, respectively, when used as stabilizing agents (Li et al., 2017). Studying the oxidative stability of β-carotene in O/W emulsions stabilized by applying whey protein isolate (WPI)-beet pectin (BP) 3

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delivery of curcumin in O/W emulsions was investigated (Wang et al., 2016a). The emulsion and curcumin stabilities depended on the loaded amount of curcumin (LAC) and oil volume fraction (OVF). At higher OVC or LAC, the emulsion presented lower stability. As well, curcumin in CUR@BD-1 (12 mg mL−1 LAC and 20% OVF) was significantly less degraded in neutral and acidic conditions followed by storage at 4 °C and 37 °C in comparison to other emulsions probably because of its more integrated and cohesive interfacial film that could prevent curcumin degradation, precipitation, and diffusion to aqueous phase. It was also found that BSA-dextran conjugates in curcumin-loaded emulsions could increase the oral bioavailability of curcumin in mice (4.8 fold) and also enhance its absorption in GIT (Wang et al., 2016a). In another research, lutein-enriched O/W emulsions stabilized by either casein or casein-dextran conjugates as emulsifiers, showed a slight increase in particle aggregation at temperatures exceeding 37 °C, and became more prone to color fading at high temperature. The luteinloaded conjugate-stabilized emulsions were stable to droplet aggregation at acidic conditions (pH 3.0–7.0), due to the ability of the dextran moiety to produce a steric repulsion that was strong enough to overcome any attractive interactions between the droplets. The Maillard conjugate-stabilized emulsion was also stable at the gastric phase. This resistance in the gastric phase could be attributed to the steric repulsion rendered by the dextran moieties on the droplet surfaces. The steric hindrance prohibits the pepsin from reaching the droplet surfaces and therefore hampers the caseinate proteolysis (Gumus et al., 2016). This would help to rationally design functional foods to combat obesity. In this way, an appreciable part of the delivery system cannot be digested in the stomach, which can retard the gastric emptying and energy uptake. MRPs have also demonstrated outstanding ability to stabilize essential oils such as citral in O/W emulsions. Citral is an antibiotic alternative with strong lemon flavor, which is used traditionally as flavoring agent. However, it has limited physical and chemical stability during processing, storage, and passage through the GIT. As a consequence, Yang et al. (2015a, b) conducted two separated studies to evaluate the potential of soy protein isolate (SPI)–soy soluble polysaccharide (SSPS) MRPs in stabilizing citral in an O/W emulsion system (Yang et al., 2015a, b). The citral-loaded O/W emulsions stabilized by SPI-SSPS conjugates showed outstanding physical stability compared to those stabilized by SPI or SPSS solely after thermal process, prolonged storage period, and under in-vitro digestion conditions mainly due to the good emulsifying feature of protein and the steric stabilizing role of polysaccharide moiety of the conjugate which might prevent droplets coalescence. A lower amount of hydrophobic citral was released from stable emulsions and about 70% of citral remained in the emulsion droplets after 2 h in simulated gastric condition; whilst, the bioactive citral released completely after 4 h under in-vitro intestinal digestion. The authors claimed that the superb propensity of SPI-SSPS conjugate to tune citral release in digestive conditions could be ascribed to the covalent linkage of SSPS to SPI (inhibiting SPI digestion by pancreatin) and the stabilizing effect of SSPS-SPI conjugates (preventing droplet destabilization in emulsion). Double emulsions are another type of emulsion-based delivery systems that provide opportunities to protect and control the releasing profile of sensitive nutraceuticals. Stability and release properties of vitamin B12 in water-in-oil-in-water (W/O/W) emulsions stabilized by caseinate-dextran conjugates were studied by Fechner, Knoth, Scherze, and Muschiolik (2007). The double emulsions coated with Maillard conjugates had smaller droplets with narrower droplet distribution than those obtained by pure protein because the former can provide an additional bulky layer around oil droplets, resulting in better steric stabilization and preventing oil droplets from aggregation and coalescence. The Maillard conjugates at the interfacial layer resulted in an increase in the stability of double emulsions to acidification to pH 4.0. This could be ascribed to the increased protein solubility at acidic conditions and the masking effect of the polysaccharide on protein layer

Fig. 2. The schematic representation of emulsion droplets coated by native protein and conjugates.

Maillard conjugates, Xu, Wang, Jiang, Yuan, and Gao (2012) showed that β-carotene-loaded emulsions stabilized by WPI-BP conjugates had higher physical stability in the terms of lower droplet sizes with more homogenous distribution and augmented freeze-thaw stability. This could be derived from the strong steric and electrostatic repulsion between oil droplets in the emulsion rendered by the pectin moiety of the conjugate at interface. It was also observed that β-carotene degradation in conjugated WPI-BP stabilized emulsions was significantly retarded thanks to the denser and thicker viscoelastic layer around emulsion droplets provided by the Maillard conjugates (Xu et al., 2012). It is noteworthy that the molecular environment and interactions of β-carotene with antioxidant and prooxidative compounds may influence its stability in emulsions. In this regard, it was reported that WPIBP conjugates improved oxidative stability of β-carotene in O/W emulsions (Xu, Yuan, Gao, McClements, & Decker, 2013). The improved β-carotene stability in emulsions containing conjugates at interface might be ascribed to the thick layer provided by the conjugate, which could function as a physical barrier between oxidizable β-carotene in the droplet core and prooxidants in continuous phase (i.e. metals). Moreover, the Maillard conjugate could create a more cohesive, denser, and impermeable interfacial membrane to LMW prooxidants such as iron (Xu et al., 2013). Additionally, the Maillard conjugates have appreciably high antioxidant property, which could protect the encapsulated bioactive compound against oxidative degradation. Furthermore, it is possible to gain an additional protective effect against oxidation of the lipophilic core by incorporating a metal chelator (e.g. desferoxamine) and antioxidants (e.g. α-tocopherol) in the conjugatestabilized O/W emulsions (Xu et al., 2013). Likewise, the properties and digestibility of β-carotene loaded emulsion stabilized by WPI-BP conjugate were studied by Xu et al. (2014). During digestion, the flocculation and coalescence of emulsion droplets decreased in emulsions stabilized by WPI-BP conjugates, likely due to the ability of conjugates to form a comparatively thick interfacial film around oil droplets, which could lower the enzymatic degradation and competitive displacement by bile salts. However, in such emulsions, the release of β-carotene did not differ considerably from other unconjugated WPI-BP stabilized emulsions but was lower than those obtained by WPI. This could be attributed to the negative charge of BP-containing emulsions (lowering the binding of pancreatic lipase with negative charge; the isoelectric pH of lipase is about 5.0 (Ünlüer, Özcan, & Uzun, 2014) and therefore it is negatively charged at intestinal pH), thicker interfacial layer formed by BP (decreasing lipid accessibility to lipase), and changes in physical features of the emulsion such as viscosity induced by BP (lowering lipase migration to lipid phase). Recently, the potential application of bovine serum albumin (BSA) and dextran conjugate (obtained by dry heating of BSA-dextran powder at 60 °C and 79% relative humidity for 48 h) for the protection and 4

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Fig. 3. The schematic illustration of gelatin-dextran conjugate preparation and the photographs of gelatin-TPP physical mixture, gelatin-dextran-TPP physical mixture, and gelatin-dextran conjugate-TPP C3Ms; designed with respect to Zhou et al. (2012).

industrial scale (Ifeduba & Akoh, 2015). Recently, Maillard conjugates have gained more attention as potential encapsulants to create stable complex coacervates. In a study, stearidonic acid soybean oil (SDASO) was encapsulated through complex coacervation based on gelatin-gum Arabic Maillard conjugates (Ifeduba & Akoh, 2015). The gelatin-gum Arabic mixture was firstly prepared, but the authors did not report the pH of mixing the two polymers. In their study, however, the gelatin type A (with a pI of 7.0–9.0; Wang, Wang, & Heuzey, 2016b) was dissolved in deionized water having a pH value below neutral (Hoehl, Schoenberger, & BuschStockfisch, 2010). Therefore, it seems that the polymer gelatin has a positive charge in deionized water and could electrostatically bond to the negatively charged gum Arabic to form a complex coacervate. The resultant complex coacervate was freeze-dried and then dry-heated at 80 °C for 5 h, under 79% relative humidity, followed by dissolving the conjugates in deionized water. Afterwards, the SDASO was homogenized with the Maillard conjugates to form SDASO-loaded conjugatestabilized complex coacervates. The resultant SDASO-loaded complex coacervates (microcapsules) showed higher colloidal stability, antioxidative capacity, and oxidative stability during storage (28 days at 4 °C) than control coacervate. As well, the microcapsules were incorporated into yoghurt and surprisingly they exhibited the highest thermal stability when heated at 80 °C for 30 min and also showed the best oxidative stability during refrigeration period (14 days). This could be attributed to the secondary polysaccharide layer at interface achieved by the conjugation that enhanced colloidal stability via steric repulsion between particles. It was hypothesized that improved oxidative stability in Maillard-based coacervates might be due to (i) hydroperoxide reduction, oxygen scavenging, and fatty-acyl free-radical inactivation at interface, (ii) forming a rigid and integrated capsular wall which functions as a physical barrier against oxygen and other factors promoting lipid oxidation, and (iii) chelating prooxidants such as metal ions (Ifeduba & Akoh, 2015). Other type of coacervates (such as protein-polyphenol based) have also been reported. Zhou et al. (2012) developed a novel complex coacervation core micelle (C3Ms) based on gelatin-dextran Maillardtype conjugate for the delivery of tea polyphenols (TPP) (Fig. 3). Gelatin-dextran mixtures were dry heated at 60 °C under 79% relative humidity for 24 h to produce the Maillard conjugates. Then, TPP solution was mixed with the gelatin-dextran conjugates at ambient temperature and at desired pH values to form C3Ms. In contrast to the gelatin or non-heated gelatin-dextran mixture, which showed obvious precipitates in the presence of TPP, the solution of gelatin-dextran

moiety yielding an extra barrier (steric stabilization) against aggregation and coalescence. However, vitamin B12 release was significantly decreased after acidification, heating, and storage period when the conjugate was used as an emulsifier instead of pure protein probably due to a more stable interfacial layer provided by the former (Fechner et al., 2007). It can be concluded that food emulsions stabilized by proteinpolysaccharide conjugates generally have high stability towards gastric digestion mainly due to the polysaccharide segment which hampers the proteolysis of proteins at the interface by pepsin. This can be exploited at the formation of niche functional foods for the treatment of obesity through lowering stomach emptying rate and energy uptake. Moreover, the high stability of Maillard conjugates against enzymatic digestion in the upper part of the GIT (i.e., stomach and small intestine) make them an ideal candidate for designing colon-specific delivery systems to prevent or possibly to treat bowel diseases. 3.2. Complex coacervates containing Maillard conjugates Some microencapsulation techniques such as complex coacervation, spray drying, and extrusion are commonly used for the encapsulation of polyunsaturated fatty acids (PUFAs) to make their stable form and delay oxidative deterioration when incorporated into foods. Among these methods, complex coacervation has received a great deal of research interest mainly due to its high encapsulation efficiency and controlled release (Yuan, Kong, Sun, Zeng, & Yang, 2017). It is a phase separation phenomenon in which neutral complex is formed when two biopolymers with opposite charges are brought together (Eratte, Wang, Dowling, Barrow, & Adhikari, 2014). Complex coacervation can be performed under mild conditions without the use of any toxic solvents and the obtained coacervates have higher surface activities than protein and polysaccharide alone. Therefore, complex coacervates are applied as effective emulsifying and stabilizing agents in food emulsions (Timilsena, Wang, Adhikari, & Adhikari, 2017). It is noteworthy that this technique is triggered by non-covalent interactions and the use of some cross-linking agents such as glutaraldehyde or formaldehyde (hardening agents) has been practiced to stabilize the complex wall and enhance its thermal and mechanical stabilities (Ifeduba & Akoh, 2016). However, these cross-linkers have toxicity issues and there is a great demand in the food industry to replace them with safer ones including genipin, tannic acid, iridoids, and transglutaminase, the latter of which requires long treatment time and is not an appropriate choice for the production in an 5

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improve its heat stability, solubility, and bioavailability (Yi, Lam, Yokoyama, Cheng, & Zhong, 2014). β-carotene loaded nanoparticles exhibited considerable release rate and permeability coefficient on Caco-2 cells and were more stable against pH-induced aggregation under in-vitro gastric condition. Trans-resveratrol protection from isomerization induced by UV-light and its bioavailability were successfully increased when it was encapsulated in zein nanoparticles coated by caseinate-dextran Maillard conjugates (Davidov-Pardo, Pérez-Ciordia, Marı́n-Arroyo, & McClements, 2015). Recently, Fan et al. (2018) fabricated curcumin-loaded BSA-dextran Maillard-based conjugate nanoparticles. The green and facile approach led to the formation of nanoparticles with spherical structure and boosted stability at pHs 2.0–7.0. In addition, the stability of curcumin in the BSA-dextran nanoparticles was higher than that of free curcumin, and the nanoparticles improved the antioxidant ability of curcumin in Caco-2 cells. It is worth noting that the superb stability of protein-dextran nanoparticles is mainly due to the steric stabilizing effect of the hydrophilic polysaccharide dextran conjugated to the protein, suggesting a dextran shell-protein core structure. The polysaccharide shell could resist the proteolysis in the stomach and small intestine, and increase the chemical stability of the entrapped bioactive during GIT digestion.

conjugate and TPP at pH 5.0 formed a homogenous dispersion with narrow size distribution, indicating micelle formation with gelatin/TPP core and dextran shell structure. The authors hypothesized that dextran moiety in the conjugate due to its stabilizing ability (steric hindrance effect) led to a lower aggregation of the insoluble core of gelatin-TPP complex. It was also reported that the C3Ms formed via hydrogen bonding and hydrophobic interaction in contrast to electrostatic interactions, and TPP encapsulation into C3Ms was pH-independent, as well. The Maillard conjugate stabilized coacervates could therefore successfully encapsulate and protect a wide range of nutraceuticals against destabilization stresses applied during food processing. In addition, the bioactive-loaded Maillard-based coacervates can be spray or freeze dried to obtain powdered forms to be used as functional ingredients in many food products. 3.3. Nanoparticles Nanoparticle-based drug delivery systems have been extensively used to improve the absorption of biologically active compounds in oral administration due to the penetration of nanoparticles in small intestinal epithelium through paracellular and/or endocytotic pathways (Li & Gu, 2014). A Therapeutic agent in a drug delivery system should be compatible with the polymer and the obtained nanoparticles should have the abilities to evade uptake by the reticuloendothelial system and target tumor tissues. The exposure of the particles to acidic pH values, high temperature of tumor tissues, and their disruption in intracellular compartments including endosome and lysosome lead to the drug release (Deng, Li, Yao, He, & Huang, 2010). Protein-based colloidal vehicles are often stabilized by electrostatic repulsive interactions between nanoparticles. However, the particles undergo aggregation and precipitation at high ionic strengths and pHs near the pI of the nanoparticles. Therefore, some techniques, especially the use of Maillard reaction to obtain protein-polysaccharide conjugates, are introduced to design more stable protein-type colloidal delivery systems (Davidov-Pardo, Pérez-Ciordia, Marı́; n-Arroyo, & McClements, 2015). Ovalbumin-dextran conjugates were used to encapsulate and increase the bioavailability of (−)-epigallocatechin gallate (EGCG) (Fig. 4) (Li & Gu, 2014). The conjugates were mixed with EGCG and after adjusting the pH value to 5.2, the solution was heated at 80 °C for 60 min. EGCG-loaded ovalbumin-dextran conjugate nanoparticles had a spherical morphology with particle size of 285 nm and loading efficiency of 23.4%. As well, the apparent permeability coefficient of the EGCG on Caco-2 monolayers was significantly increased when the EGCG was encapsulated in the nanoparticles. Other bioactive compounds have also been encapsulated in proteinpolysaccharide conjugate stabilized nanoparticles. For example, β-carotene was encapsulated in β-lactoglobulin-dextran conjugates nanoparticles through a homogenization-evaporation approach in order to

3.4. Nanogels In the light of some key features such as biodegradability, nontoxicity, and nanoscale sizes with a high ability for multivalent bioconjugation in a large internal network, protein-based nano-hydrogels (nanogels) are distinctive polymer-based nanoparticulate systems with many potential applications in the food sector for the delivery of biologically active compounds (Abaee, Mohammadian, & Jafari, 2017). The three-dimensional network of nanogels is formed through crosslinking of natural or synthetic polymers. The nanogels are able to entrap a large amount of water without being dissolved in aqueous solution (Soni, Desale, & Bronich, 2016). Although heat-induced gelation approach has been frequently used for preparing nanogels from proteins, the obtained nanoparticulate entities are prone to aggregation at considerably high salt concentrations and certain pH values close to the nanoparticle pI. In this regard, the development of a new green method is particularly welcomed by the food industry to produce proteinpolysaccharide nanogels with high dispersibility and stability at vast pH ranges and ionic strengths (Li, Yu, Yao, & Jiang, 2008). In a study conducted by Li et al. (2008), lysozyme-dextran core-shell spherical shape nanogels were obtained by the Maillard reaction followed by heating above the denaturation temperature of lysozyme (heat gelation process), and the nanogels showed high long-term storage stability at different pH values and ionic strengths. Likewise, Feng et al. (2015) fabricated soy β-conglycinin-dextran Maillard-based conjugate nanogels. Soy β-conglycinin was glycated with dextran via the Maillard dry heating reaction for 4 days (at 60 °C and 79% relative

Fig. 4. The schematic representation for ovalbumin-dextran conjugate-EGCG nanoparticles formation; designed with respect to Li and Gu (2014). 6

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Fig. 5. Emulsion-evaporation technique used for the preparation of powdered capsules containing lipophilic compounds and subsequent nanodispersion formation; designed with respect to Shah et al. (2012b).

(glucose, dried glucose syrup, and Raftilose P95) sources were used for the encapsulation of different oils (fish oil, evening primrose oil, and milk fat) through emulsion preparation followed by spray drying approach to obtain microcapsules. The oxidation of microencapsulated oils was effectively decreased when the MRPs were used as encapsulants, but the mechanism of this key feature was not clarified (Augustin et al., 2006). A study was carried out by Drusch et al. (2009) to elucidate the mechanism of MRPs as encapsulants for protecting encapsulated lipophilic compounds. Glycated caseinate with glucose, glucose syrup and dextran through both dry and wet heating Maillard reaction were produced for the microencapsulation of fish oils, through the emulsionevaporation technique. Although, the oxidative stability of the oil encapsulated in caseinate-glucose syrup-Maillard-based encapsulant obtained via wet heating was enhanced likely due to the production of redox active compounds, the dry-heated caseinate-glucose syrup conjugates did not improve the oxidative stability in comparison with unheated mixture when used as carrier matrix for the microencapsulation process. The caseinate-glucose conjugate encapsulant led to a significant decrease in the content of hydroperoxide and propanal of the encapsulated oils compared to the caseinate-glucose syrup one. The authors claimed that the improved oxidative stability of encapsulated oils is due to either an antioxidant ability or boosted emulsification capacity of the MRPs and this parameter is mainly affected by the molecular weight profile of the encapsulant agent (Drusch et al., 2009). Choi, Ryu, Kwak, and Ko (2010) noticed that the microcapsules containing conjugated linoleic acid (CLA) obtained via emulsion-evaporation method exhibited smaller particle size with better water solubility and encapsulation efficiency when WPI-maltodextrin conjugates were used as wall materials. Beside their above-mentioned excellent potential applications, the Maillard protein-polysaccharide conjugates have been successfully employed for the encapsulation of essential oils to create heat stable and transparent dispersions when used as bioactive ingredients in functional beverages. Eugenol was encapsulated in WPI-maltodextrin Maillard conjugates via a low cost and simple emulsion-evaporation approach (Fig. 5) (Shah et al., 2012a). This technique resulted in an encapsulation efficiency of 35.7 g eugenol in product per 100 g eugenol in the feed, and a mass yield of 82.7 g collected product per 100 g of non-solvent mass in feed. After dissolving the spray-dried powders in deionized water followed by heating at 80 °C for 15 min at pH 3.0 and 7.0, the obtained nanodispersions were transparent even above the solubility limit of eugenol. Surprisingly, one treatment based on the WPI-maltodextrin conjugate as encapsulant had transparent nanodispersion when heated at pH 5.0 in contrast to control sample made from non-heated WPI-maltodextrin mixture, which formed gel at pH value near the pI of WPI. Analogously, the authors encapsulated lipophilic

humidity) and then the obtained conjugates were heated at 95 °C for 50 min (above the denaturation temperature of the protein) and pH 4.8 to assemble nanogels. The nano-scale spherical core-shell nanogels were sufficiently stable against pH change, long-term storage, dilution, and lyophilization mainly due to the steric hindrance at the shell provided by dextran moiety. It was also reported that the nanogels with hydrophobic compartments in the core can be applied for the delivery of hydrophobic components. Analogously, ovalbumin-dextran nanogels were developed through the Maillard reaction followed by a heat-gelation process to enhance the oral bioavailability of curcumin (Feng et al., 2016). This green procedure improved storage stability, pH stability, and redispersibility of the nanogels. As well, the authors claimed that the nanogels could ameliorate the oral bioavailability of curcumin. Generally, the protein moiety in Maillard conjugate-based nanogels acts as a cargo space for hydrophobic bioactive components, while the shells originated from hydrophilic polysaccharide protect the protein from gastric digestion (i.e. enzymatic hydrolysis) and ensure the controlled release of the encapsulated compound in the intestinal phase or the colon for specific purposes (see the gastrointestinal fate section). 3.5. Encapsulation via emulsion-evaporation/freeze drying method Encapsulation, an effective approach to disperse water-insoluble components, has been vastly applied in the food industry to inhibit the degradation of sensitive compounds, mask unpleasant flavors, decrease evaporation losses, prevent interaction with other compounds, and expedite controlled release (Shah, Davidson, & Zhong, 2012a). Spray drying is known as the most convenient procedure employed for the encapsulation of sensitive functional ingredients (Augustin et al., 2006). Food proteins and polysaccharides are commonly used as bioencapsulants. Thermal treatment is necessary in many beverage products to inactivate pathogenic and spoilage microorganisms, however; the heat stability of protein-based encapsulation vehicles, especially whey protein, is also a key factor because the high ionic strength and acidic conditions (pH ~ pI) lead to whey protein aggregation upon heating (Bryant & McClements, 1998). It is important to keep in mind that, although, polysaccharides and proteins can be applied separately as bioencapsulant agents, some studies have emphasized that their mixtures led to an increase in encapsulation efficiency and oxidative stability of the encapsulated compound (Li et al., 2017). It is also reported that protein-carbohydrate conjugates based on the non-enzymatic Maillard glycosylation exhibit superb emulsifying and antioxidant abilities as well as stability over a wide range of pH values period. They are excellent encapsulants for the microencapsulation process, and carbohydrate moieties can improve the drying properties of the particles (Augustin et al., 2006). On this point, MRPs between protein (sodium caseinate, WPI, SPI, and skim milk powder) and carbohydrate 7

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Therefore, L. rhamnosus showed good pH tolerance. The authors noticed that the WPC-IMO physical mixture and WPC-IMO MRPs microspheres could provide a good protection against the damage of the bile salt solution. However, the encapsulated probiotics were released quickly. In another study, the authors investigated the viability of L. rhamnosus microencapsulated in WPC-IMO MRPs through an emulsificationcold gelation procedure during cheese storage and under in-vitro digestion conditions (Liu et al., 2017a). White-brined cheese incorporated with microencapsulated L. rhamnosus showed significantly higher number of viable bacteria than in the cheese containing non-encapsulated bacteria. Under simulated GIT conditions, the number of microencapsulated L. rhamnosus in cheese samples was found to be more than 7.3 log cfu g−1 higher than the reported minimum therapeutic level. These findings proved the ability of encapsulation to improve the resistance of probiotics to acidic pHs and high bile salt levels. The carbohydrate part may also provide additional protection for the probiotic organisms under GIT conditions. Highly stable MRPsbased microcapsules towards acidic pHs, high bile salt levels, and enzymatic digestion may make them superb carriers to protect probiotic bacteria during the GIT transit.

antimicrobial thymol in WPI-maltodextrin conjugate via a similar method (Shah, Ikeda, Davidson, & Zhong, 2012b). The use of WPImaltodextrin conjugates as carrier for the encapsulation of thymol increased the dispersibility, transparency, and thermal stability of the nanodispersions even at pH values close to pI of WPI as well as at high concentrations of thymol (> its solubility limit). As described earlier, this might be due to the improved solubility and heat stability of proteins upon glycation as the polysaccharide moiety of the obtained conjugate can enhance colloidal stability of the nanodispersions via steric stabilization. The emulsion-evaporation procedure may be used as a simple and low cost nanoscale system for the encapsulation and delivery of lipophilic components like fat-soluble vitamins, flavor oils, antimicrobials, and pigments in transparent liquid products to produce functional beverages. In another study, hydrolyzed SPI (HSPI)-maltodextrin conjugates obtained via wet heating Maillard glycation were used to ameliorate emulsion features and oxidative stability of microencapsulated fish oil (Zhang et al., 2015). The conjugates had outstanding amphiphilic activity and resulted in fish oil emulsions with smaller droplet size and polydispersity index and superior stability during storage time of up to 8 weeks. As well, the emulsions that were coated with HSPI-maltodextrin conjugates showed higher encapsulation efficiency and lower amount of hydroperoxide and propanal as the indicators of lipid oxidation products in comparison with those coated by hydrolyzed SPI or native SPI solely. In addition, the application of conjugates as encapsulants prior to freeze drying led to the formation of microcapsules with porous and even surface structure and increased thermal stability. Authors hypothesized that high encapsulation efficiency (lower surface oil) obtained by the Maillard conjugates is mainly responsible for the improved oxidative stability of the microencapsulated fish oil. Furthermore, the polysaccharide moiety of the conjugate has a tendency to form films around the microcapsules, which act as an oxygen barrier and reduces the oxidation process of the microencapsulated oil (Zhang et al., 2015). The Maillard conjugate stabilized microcapsules, due to their high stability to pH changes, ionic strength, storage stability, and high temperature could be used as functional supplements in food products to ensure the chemical stability of the entrapped bioactive compound or nutraceuticals for a longer periods of time.

4. Gastrointestinal fate of nutraceutical-loaded Maillard conjugate-based carriers In practice, the potential health-promoting effects of many hydrophobic nutraceuticals are not realized mainly due to their low chemical stability, low water-solubility, and low oral bioavailability. The careful design of the structure and composition of food matrices can often tackle these challenges; the structurally designed food matrices, therefore, have the ability to improve the bioavailability of nutraceuticals in the GIT through enhancing bioaccessibility, lowering degradation, and improving absorption (Chen et al., 2018). Several delivery systems have been designed to improve the oral uptake of biologically active compounds by (i) increasing the retention time, (ii) protect the entrapped compound in the stomach and achieve controlled release under intestinal pH, and (iii) colon-specific release (Taheri & Jafari, 2019). During the past years, there has been a great deal of research and industrial interest to develop O/W emulsion-based delivery systems to encapsulate lipophilic components because of the remarkable flexibility in controlling/tuning their structures and compositions (Singh & Sarkar, 2011). The composition, structure, and integrity of the interfacial layer may impact the interaction of digestive enzymes with lipids in the emulsion droplet cores (Maldonado-Valderrama, Terriza, Torcello-Gomez, & Cabrerizo-Vilchez, 2013; McClements & Li, 2010). Encapsulated compounds can be readily released from unstable emulsions and subsequently degraded before absorption by the small intestine (Hou, Liu, Lei, & Gao, 2014). The stable O/W emulsions can significantly enhance the stability of entrapped lipophilic compounds during the GIT transit (Liu, Ma, Zhang, Gao, & McClements, 2017b). Maillard conjugate-stabilized colloidal systems could likely successfully control the release of lipophilic nutraceuticals at specific locations of the GIT. Although the effect of environmental conditions, such as heat treatment, ionic strength, and pH, on the stability of Maillard conjugate-stabilized emulsions have been vastly evaluated during the two past decades, there is very little information about the behavior of such colloidal systems during and after oral consumption. Therefore, it is critical to understand the gastrointestinal fate of nutraceutical-loaded emulsions stabilized by different types of Maillard conjugates to manipulate the sensorial and physicochemical properties of colloidal food systems developed to enhance human health and wellbeing. It is noteworthy that the following sections are mainly focused on the gastrointestinal fate of emulsions stabilized by Maillard conjugates due to the fact that the emulsifying and stabilizing effects of the Maillard conjugates have been strongly investigated in food emulsions rather than other colloidal systems. However, the gastrointestinal fate of other

3.6. Encapsulation via gelation method Probiotics are living microorganisms with the potential to positively affect human health. However, they are sensitive to adverse conditions applied during the production process and passage through the human stomach. In recent years, researchers have attempted to increase their bioavailability through various methods, especially microencapsulation technology. Probiotic microencapsulation through MRPs has currently acquired much attention in the food industry due to their remarkably high thermal, colloidal, and oxidative stabilities in conjugation with protein gelation behavior (Liu et al., 2016a, 2017a). In this context, Liu et al. (2016a) evaluated the effect of MRPs between whey protein concentrate (WPC) and isomaltooligosaccharide (IMO) on the resistance of Lactobacillus rhamnosus during the encapsulation process and under the simulated digestive system. In their study, two groups of treatments were produced. The first microcapsules produced with the mixture of WPC and IMO (WPC-IMO MIX) and the second group prepared with MRPs of WPC and IMO (WPC-IMO MRPs) through cold gelation within an emulsification system. The microspheres produced from WPC-IMO MRPs after cold gelation within emulsification system showed higher encapsulation efficiency (88.88%). This high encapsulation yield was attributed to the hydrophilic-hydrophobic balanced glycoprotein within WPC-IMO MRPs which is able to lower interfacial tension. Furthermore, the firm network created by MPRs could reduce the diffusion rate of acid into the microspheres. This could also be due to buffer capacity of the proteins. 8

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in the artificial saliva. The lower susceptibility of the Maillard conjugate-based nanogels to aggregation under mouth condition compared to ovalbumin nanoparticles was also attributed to the steric hindrance provided by the dextran attached to nanogel exterior (Feng et al., 2016). From our point of view, protein-polysaccharide conjugates have the ability to improve the stability of emulsions/colloidal systems to salivatriggered flocculation through steric repulsion and electro-steric repulsion when anionic polysaccharides are used to fabricate Maillard conjugates. Furthermore, protein-polysaccharide conjugates provide a shear-resistant interfacial layer around oil droplets or other colloidal particles, which can resist the high shears applied in the mouth and subsequently lower the possible changes in physicochemical attributes and microstructure of food emulsions or colloidal systems.

Maillard conjugate-based delivery systems has also been reviewed in less detail. 4.1. Oral conditions Emulsions or other colloidal particles undergo a wide range of changes upon ingestion, such as dilution with saliva, interaction with various electrolytes in saliva, a moderate change in temperature (~37 °C) and pH, exposing to salivary enzymes like amylases and different biopolymers like mucins, and friction between the oral mucosa and the tongue which induces complex forces/flow profiles (Singh & Sarkar, 2011). Saliva molecules are able to trigger flocculation of colloidal particles or oil droplets through depletion or bridging flocculation, which is dependent on their size and interfacial characteristics (McClements, 2015). There is a limited information regarding the changes in physicochemical properties and interactions of Maillard conjugate-stabilized emulsions with various saliva components. This may be due to the fact that most liquids do not need an oral phase because of the significantly short residence times of 5–60 s in the oral cavity (Minekus et al., 2014). β-carotene-loaded emulsions formed with WPI, WPI-BP mixture, and WPI-BP conjugate showed no significant changes in droplet size (flocculation) and zeta-potential when mixed with simulated saliva solution for 5 min, which contained 0.02% mucin, 0.1594% NaCl, and 0.0202% KCl. This was attributed to the lack of saliva enzymes in the simulated solution to digest the emulsifiers, and it also did not contain significant amounts of mucin and surface active compounds capable of displacing the emulsifiers (Xu et al., 2014). Indeed, WPI-stabilized emulsions have negative charge at neutral pH used in simulated mouth fluid and therefore they do not interact with negatively charged mucin due to the strong repulsive electrostatic forces between anionic WPI interfacial layer and anionic mucin, however; the high concentrations of mucin could induce depletion flocculation at neutral conditions. In addition, the human saliva contains various electrolytes which could promote bridging flocculation in protein-stabilized emulsions. The addition of higher mucin concentrations (3% w/v) into simulated oral fluid led to a small-scale droplet aggregation and significant increase in mean particle size in β-carotene emulsions stabilized by oat protein isolate (OPI) and OPI-Pleurotus ostreatus β-glucan (POG) mixture. In contrast, OPI-POG conjugate stabilized emulsions did not undergo significant changes in mean particle size and microstructure after oral ingestion. This was ascribed to the higher concentrations of anionic carboxyl groups on the droplet surfaces provided by the glycated POG, which were able to counteract the binding of negatively charged mucin through electrostatic repulsion as the conjugate stabilized O/W emulsion had more negative zeta-potential (−35.321 mv) compared to that of OPI-POG mixture (−25.091 mv) and SPI (−17.231 mv) (Zhong et al., 2019). Additionally, β-carotene loaded chlorogenic acid-lactoferrin-polydextrose ternary conjugate stabilized emulsion and lactoferrin-based emulsion underwent a significant increase in the mean particle diameter after exposure to simulated mouth conditions containing 3% mucin (Liu et al., 2017b). This could be explained by the fact that anionic mucin in human saliva could attach to positively charged proteins (such as lactoferrin) on the oil droplet surfaces of protein-stabilized emulsions and induce bridging flocculation in such systems, which are mainly stabilized by the electrostatic interactions (Sarkar, Goh, & Singh, 2009). In general, saliva-induced flocculation in emulsions is regulated by depletion, electrostatic, and/or van der Waals interactions, and is strongly dependent on the initial emulsion droplet charge (Singh & Sarkar, 2011). Curcumin-loaded ovalbumin nanoparticles and ovalbumin-dextran conjugate-based nanogels underwent extensive and moderate (nearly doubled) aggregation, respectively, after exposure to simulated mouth fluid containing 0.3% mucin and various salts. The aggregation in these delivery systems was ascribed to the mucin-induced bridging and depletion flocculation and the salt-induced electrostatic screening effects

4.2. Stomach conditions The emulsion or colloidal particle (named as the “bolus”) is then swallowed and passed through the esophagus to enter the stomach (McClements, 2015). It is mixed with gastric juice containing highly acidic conditions (pH 1–3), relatively high ionic strength (~150 mM), mineral ions, and both proteolytic and lipolytic enzymes. Also, it undergoes mechanical agitation by the peristalsis in the stomach (Singh, 2011). Protein-stabilized emulsions undergo significant changes during passing through the stomach due to the effects of highly acidic pH and ionic strength on the droplet charge, the possible action of gastric lipase and the proteolytic enzyme pepsin on the interfacial layers, and mucin interaction with interfacial protein (Singh & Sarkar, 2011). Bioactiveloaded O/W emulsions stabilized by protein-polysaccharide Maillard conjugates generally have higher stability to droplet flocculation and coalescence (smaller droplet size) during gastric digestion (in response to acidic pH and pepsinolysis) compared to those stabilized by native proteins (Gumus et al., 2016; Lesmes & McClements, 2012; Xu et al., 2014; Zhong et al., 2019). This is mainly attributed to the thick and integrate interfacial layer surrounding oil droplets provided by the conjugates, which prevents the flocculation of oil droplets through strong steric repulsions. It has been reported that electrostatically stabilized protein-coated oil droplets undergo extensive aggregations in comparison to sterically stabilized Tween-coated counterparts (Van Aken, Bomhof, Zoet, Verbeek, & Oosterveld, 2011). Pepsinolysis of interfacial protein layer is considered as the most important destabilization factor in protein-based emulsions during stomach digestion. The adsorbed layer hydrolysis by pepsin generally leads to positive charge losses in conjugation with decrease in the thickness of the adsorbed protein layer on the droplet surface. The formed LMW peptides are not able to fabricate a cohesive film around oil droplets and in turn provide sufficient steric effects and/or electrostatic repulsions. These emulsion are therefore strongly sensitive to flocculation and coalescence (McClements, 2015; Nooshkam & Madadlou, 2016b; Singh, 2011). The Maillard conjugate-based cohesive and thick interfacial layer could inhibit pepsin interaction with emulsion droplets and, in turn, prevent the proteolysis of interfacial protein layer (Davidov-Pardo et al., 2015). A similar effect (i.e., strong steric repulsion between the particles provided by the polysaccharide moiety of the conjugate) has been also found in other colloidal systems stabilized by protein-polysaccharide conjugates, such as nanogels, nanoparticles, and microcapsules (Feng et al., 2016; Liu et al., 2017a; Yi et al., 2014; Davidov-Pardo et al., 2015). Surprisingly, the casein-maltodextrin Maillard conjugate-based core-shell co-assembles did not release the entrapped hydrophobic nutraceutical during simulated gastric digestion in the virtue of steric hindrance by the maltodextrin, inhibiting pepsinolysis (Markman & Livney, 2012). It is also worthwhile to note that gastric lipases have remarkable impacts on the protein-stabilized food emulsions through acting on the oil molecules to produce surface active fatty acids and monoacylglycerols (about 10–30% of the ingested triacylglycerols) capable of 9

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such as protein/polysaccharide type and concentration, pH, temperature, and time are different in those studies, which would lead to various conjugates with different functionality and molecular weights. In addition, the used simulated gastrointestinal fluids did not contain the same amount of proteolytic and lipolytic enzymes as well as mineral salts and bile salts. The increased droplet size after intestinal digestion could be due to the enzymatic degradation and the displacement of the initial interfacial layer by FFA and bile salts, resulting in droplet aggregation or coalescence. However, it seems that the conjugate-based thick interfacial film is more stable towards enzymatic hydrolysis (Liu et al., 2017b; Xu et al., 2014) and LMW surfactant-induced competitive displacement from the interface (Cai et al., 2018; Cai & Ikeda, 2016). A decrease in protein proteolysis in Maillard conjugate-based nanoparticles has also been reported by Li and Gu (2014) and Yi et al. (2014). A fairly lower particle sizes in conjugate stabilized nanoparticles compared to non-conjugate-based ones was also indicated in some studies (Davidov-Pardo et al., 2015). It is worth noting that the digesta contained different types of colloidal particles, such as mixed micelles, vesicles, liposomes, undigested samples, and insoluble matters (e.g., calcium soaps), and the light scattering procedure applied to measure particle size cannot distinguish between them (Davidov-Pardo et al., 2015). This explains why the curcumin-loaded ovalbumin nanoparticles and ovalbumin-dextran conjugate-based nanogels adopted fairly similar particle sizes after intestinal digestion (Feng et al., 2016). The composition and structure of the interfacial layer have an appreciable effect on the lipid digestion products, the formation of mixed micelles, and finally the bioaccessibility and bioavailability of the bioactive compounds. It is necessary to point out that bioaccessibility and bioavailability are different terms. Bioaccessibility is considered as the concentration or level of each component released from the food matrix into digestive fluids and therefore, available for absorption; whilst, bioavailability gives information about the portion of the digested component that is absorbed and metabolized through normal pathways (Žugčić et al., 2018). It has been demonstrated that lowering the emulsion droplet size (larger surface area) could increase the access of lipolytic enzymes to the interface more easily and lead to faster lipid digestion (more FFA and monoacylglycerols) followed by increasing the amount of mixed micelles and bioactive bioavailability (Gumus et al., 2016; Salvia-Trujillo et al., 2013). Maillard conjugates usually fabricate homogenous emulsions with smaller droplet size (larger surface area) in comparison to native proteins (Xu et al., 2012, 2013), which resulted in a faster lipid digestion and mixed micelle formation, and consequently higher nutraceutical bio-accessibility/availability (Liu et al., 2016b; Zhong et al., 2019). βcarotene-loaded conjugate stabilized emulsions could readily pass through the mucus layers in the virtue of their lower particle sizes, resulting in an effective β-carotene absorption (Zhong et al., 2019). However, Xu et al. (2014) reported that although the WPI-BP conjugate coated emulsion had lower particle size than that of WPI-based one, the formation of FFA and β-carotene content in the micellar fraction were significantly lower in WPI-BP conjugate-based system. This was related to the repulsive interaction between anionic interfacial BP and negatively charged lipase, and the thick interfacial layer around oil droplets that inhibit the access of lipase to the lipid phase, and the viscosity increment effect of BP that lowers the migration rate of lipase to the oil molecules. In addition, Gumus et al. (2016) reported that the sodium caseinate-dextran conjugate did not affect the fate of digestion and bioaccessibility of lutein in O/W emulsions, likely due to the similar size and charge of sodium caseinate and conjugate-stabilized emulsions after the small intestine phase. Protein-polysaccharide conjugated nanoparticles, nanogels, and microcapsules could protect nutraceuticals and improve their bioavailability during the simulated digestion (Feng et al., 2016; Li et al., 2015; Markman & Livney, 2012; Davidov-Pardo et al., 2015). It is noteworthy that the presence of triacylglycerols molecules in food systems

displacing intact or hydrolyzed protein from the interfacial layer, affecting droplet size and stability of such emulsions (Singh & Sarkar, 2011). The lipid accessibility to gastric lipases is reduced in Maillard conjugate-stabilized emulsions mainly because of the thicker and impermeable interfacial layer surrounding oil droplets compared to the thinner layer in protein-stabilized ones. In addition, the human gastric juice contains negatively charged mucin which could form an additional layer on the cationic oil droplets (due to pH < pI of the protein) and consequently lower the migration of pepsin and lipase to the interfacial layer and lipid phase. The lower amounts of protein and lipid digestion products in emulsions stabilized by protein-polysaccharide conjugates would affect the bioavailability of the entrapped bioactive compound in the small intestine. Furthermore, lower oil droplet aggregation and gravitational separation of the Maillard conjugate-based emulsions could play a crucial role in the biological response to the ingested foods in terms of satiety and satiation. It has been suggested that gastric-stable emulsions that underwent manifestly lower destabilization and remained evenly distributed during gastric digestion, generally resulted in a slower gastric emptying rate and consequently a higher satiety feeling, in comparison to gastric-unstable ones (Marciani et al., 2009). Due to their significantly high stability to gastric digestion, the protein-polysaccharide Maillard conjugate stabilized food emulsions and other colloidal systems could therefore slow down the gastric emptying and increase the satiety feeling, suggesting a possibility to design functional foods for obesity treatment. 4.3. Intestinal conditions The partially digested foods (the “chyme”) exit the stomach to enter the small intestine which contains a complex mixture of phospholipids, surface active bile salts, bicarbonate and other inorganic salts, digestive enzymes, and co-enzymes (proteases, phospholipases, amylases, pancreatic lipases, and co-lipases) under close-to-neutral pH (McClements, 2015). The enzymes trypsin and chymotrypsin have the potential to hydrolyze the adsorbed protein layer in protein-stabilized emulsions and lead to the system instability through coalescence phenomenon (Agboola & Dalgleish, 1996). Small intestinal fluids also contain surface active bile salts which could likely displace protein/peptide from oil interfaces due to their remarkably high surface activities, thereby increasing the accessibility of the lipid core of the emulsion droplets to the active site of the lipases (Mun, Decker, & McClements, 2005, 2007). It is also necessary to note that the final state of oil droplets and their digestion in the small intestine is importantly determined by the pancreatic lipases, which digest triacylglycerols to surface active free fatty acids (FFA) and monoacylglycerols with the ability to displace the initial interfacial layer from the droplet surface (Singh, 2011; Singh & Sarkar, 2011). These lipid digestion products (resulting from the action of both gastric and pancreatic lipases on the lipid core of the emulsion droplets) usually move into the surrounding aqueous phase to form colloidal structures “mixed micelles” with phospholipids and bile salts, which have the potential to solubilize lipophilic molecules and transport them to the intestinal cells to be absorbed (Hou et al., 2014; Qian, Decker, Xiao, & McClements, 2012; Salvia-Trujillo, Qian, MartínBelloso, & McClements, 2013). Thus, the structure and composition of the emulsion interface strongly influence the lipid digestion rate and consequently the content of mixed micelles. Despite the fact that Maillard conjugate-stabilized emulsion experienced an increase in the droplet size after passing through the small intestine, the loss of the small droplets and the generation of large droplets are usually more evidenced in protein-based emulsions (Liu et al., 2017b; Liu, Ma, McClements, & Gao, 2016b; Xu et al., 2014). Nonetheless, the higher particle sizes in Maillard conjugate-based emulsions have also been reported in the literature, compared to protein-based pairs (Gumus et al., 2016). These controversial findings could be explained by the fact that the Maillard reaction conditions, 10

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influences the bioavailability of hydrophobic bioactive compounds through fascinating mixed micelle formation and consequently bioactive solubilization (Colle, Van Buggenhout, Lemmens, Van Loey, & Hendrickx, 2012; Huo, Ferruzzi, Schwarts, & Failla, 2007). Protein digestion products resulting from the protein-based nanogels and nanoparticles could not be well incorporated into the mixed micelles to increase their solubilization effect (Feng et al., 2016). Mixed micelles in such systems are mainly composed of bile salts and phospholipids in the gastrointestinal fluids (Davidov-Pardo et al., 2015), which would affect the nutraceutical bio-accessibility/availability. An ideal delivery system should be designed to protect biologically active compounds from hydrolysis during GIT digestion and fully transport and solubilize them into the mixed micelles to be absorbed in the small intestine. Maillard conjugate-based delivery systems are more efficient in increasing chemical stability of lipophilic nutraceuticals without affecting their bioavailabilities.

Maillard conjugate-based CODES™ could be therefore highly desirable to the local treatment of various bowel diseases, such as colonic cancer, pathologies, amebiosis, Crohn's disease, ulcerative colitis, and systemic delivery of peptide and protein drugs that are strongly sensitive to proteolysis in the upper part of the GIT (Kosaraju, 2005; Philip & Philip, 2010). In general, Maillard conjugate-based delivery systems can be used to control the releasing profile of hydrophobic drugs and other nutraceuticals at specific locations of the GIT. These carriers can also be specifically useful to develop functional foods to combat obesity through retarding lipid digestion and gastric emptying. More importantly, the protein-saccharide Maillard conjugates could be used to design novel CODES™ for efficient treatment of different bowel disorders.

4.4. Colonic conditions

The Maillard protein-polysaccharide conjugate based delivery systems are effective vehicles to encapsulate, protect, and deliver a wide range of bioactive compounds in the food, medical, and pharmaceutical industries due to their outstanding properties. This review paper has provided an overview of most types of Maillard conjugate-stabilized delivery systems, such as oil-in-water emulsions, nanoparticles, nanogels, and coacervates. In these systems, the conjugate provides a thick and continuous layer around the encapsulated compound, which lowers its degradation rate when the system is exposed to certain environmental stresses during processing, storage, utilization, and gastric transition. Hence, the Maillard conjugates could be used as promising carriers to improve stability and bioavailability of lipophilic nutraceuticals and other biologically active compounds and to design multi-functional products for the food and medicinal applications. However, more studies are needed to characterize the Maillard reaction products and to select a conjugated fraction with high functionality for designing a Maillard-based delivery system. It is also worthwhile to mention that lower digestibility of the protein-based Maillard conjugates could lead to the fabrication of niche foods to treat obesity by lowering gastric emptying rate and energy uptake. Moreover, it seems that more in vitro and in vivo studies are needed in the future to reliably test the performance of the protein-polysaccharide Maillard conjugate based delivery systems.

5. Conclusions

Typically, the passage of food emulsions through the stomach and small intestine prepares them to be digested and absorbed; however, a remarkable fraction of specific systems could reach the colon. It is worth to state that fully digestible constitutions, such as proteins, triacylglycerols, and starches are used to fabricate most food emulsions. In contrast, if an indigestible compound used to stabilize or fabricate an emulsion, it is not fully digested and absorbed in the stomach and small intestine, and it consequently enters the colon for subsequent digestion (McClements, 2015). To the best of the authors' knowledge, there is no report in the literature regarding the colonic fate of Maillard conjugate stabilized bioactive-loaded delivery systems. According to the previous sections, the fate of Maillard conjugates of proteins and polysaccharides strongly depends on the type of polysaccharide used; if it is fully digestible, the conjugate would be digested and absorbed in the small intestine. However, if the poly- or oligo-saccharide is indigestible the conjugates may reach the colon. This means that the protein-polysaccharide Maillard-based conjugates have the ability to fabricate novel colontargeted delivery systems (CODES™), particularly microbially-triggered ones. It was reported that the gut microbiota are able to ferment lactulose/galactooligosaccharides (GOS)-caseinomacropeptide Maillard conjugates (Hernandez-Hernandez, Sanz, Kolida, Rastall, & Moreno, 2011). Lactulose and GOS are known as potent prebiotic saccharides with a wide range of functionality. Prebiotics can pass the stomach and small intestine without being degraded or absorbed, and then reach to the colon to be preferentially degraded by health-promoting bacteria, i.e. Lactobacillus and Bifidobacterium strains to short chain fatty acids and other products having potentially benefit effects for human health (Nooshkam et al., 2018). In a recent study, the Maillard conjugates of lactoferrin hydrolysate and GOS have been designed to selectively deliver peptides of the hydrolysate to the probiotic bacteria in the colon to give them a competitive advantage against undesired bacteria. The conjugates have endured simulated gastric and intestinal digestion, i.e. they would reach the colon. It was also found that Lactobacillus casei grew twice as fast on the conjugates compared to the unconjugated components (Seifert, Freilich, Kashi, & Livney, 2019). Protein-prebiotic sugar conjugates could be therefore applied to design novel CODES™; the prebiotic saccharide could act as an outer acid/enzyme-stable material layer to pass the system through the stomach and small intestine without it being significantly destabilized and degraded. In the colon, the probiotic bacteria Lactobacillus and Bifidobacterium strains could enzymatically degrade the prebiotic sugar to organic acids, lowering the pH value of the colon environment and in turn suppressing the growth of pathogenic bacteria. It is noteworthy that the probiotics are able to consume both carbohydrate and protein as carbon and nitrogen sources. The barrier (conjugate) degradation ability of gut microbiota could finally lead to drug release in the colon.

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