Kinds of stabilizers added to improve long-term stability of nanoemulsions.
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\r\n\tThis book intends to provide the reader with a comprehensive overview of the current epidemiology, valuable information in relation to the management of specific poisoning agents, and important evidence-based developments in the toxicology field, with special focus on children, who are a more vulnerable population for severe poisonings. Its aim is to be a practical handbook to aid health care professionals involved in individual care of patients poisoning.
The human organism is constantly exposed to many microbes, most of them being pathogenic microorganisms that can cause life‐threatening infections. The host tissues are a good target for colonization and growth of pathogens; however, the immune system developed during the course of evolution, specialized and responsible for protecting against pathogens, effectively prevents infections. Among cells of the immune system, polymorphonuclear cells—neutrophils—deserve a special attention. These cells form the first line of defense against pathogens and their components effectively combat the intruders [1]. Neutrophils are phagocytic cells capable of active migration from blood vessels to the site of infection. Their high efficiency in pathogen killing is possible due to a number of factors with microbicidal activity [2]. The main task of neutrophils is capturing pathogens, i.e., reducing the area of infection and inflammation by effective elimination of microorganisms. To fulfill this task, neutrophils use a number of mechanisms. The best‐known one is the phagocytosis that involves capturing pathogenic cells, their internalization and killing in special compartments of neutrophil cells—phagosomes [3]. This mechanism, despite its high efficacy and minimal side‐effects for the host, can be insufficient to combat massive bacterial infections or attack of other large‐size pathogenic cells. An alternative to phagocytosis is a mechanism described in 2004 by Brinkmann et al., involving web‐like structures released into the extracellular space, called neutrophil extracellular traps (NETs) [4]. Morphological changes of neutrophils associated with NET formation (“netosis”) involve a number of complex intracellular events. The initial process is a decondensation of nuclear chromatin, released into the extracellular space and forming a backbone of vast NETs. These DNA fibers are decorated with associated nuclear proteins—histones—and proteins released from neutrophil granules such as elastase, myeloperoxidase, lactoferrin, and azurocidin [5, 6].
\nThe netosis is classified as a unique type of cell death, different from apoptosis and necrosis. The mechanism of this process is complex and still incompletely understood although the main processes involved have been identified [7, 8]. NETs can be released in response to many different stimuli, including selected chemical compounds, components of pathogen cells, and whole bacteria, fungi, viruses, and parasites [9]. Released structures are able to capture all of these factors and, in consequence, to reduce the pathogen spreading over the host organism. The NET proteinaceous components, often enzymes, are responsible for killing trapped microorganisms, thus restoring the proper functioning of the host body [10]. However, the same components may also destroy surrounding host cells and tissues or trigger some autoimmune diseases [11].
\nThe activation of netosis causes dramatic changes in neutrophil morphology involving the decondensation of chromatin, lysis of granules, and cell membrane rupture and leading to neutrophil death called “programmed suicide” which is a third type of neutrophil defensive action, besides phagocytosis and degranulation [4, 6]. However, the newest studies have shown that in some cases neutrophils use exocytosis to release a part of DNA without any rupture of cell membrane, in a process called “vital netosis.” However, this term is still under debate because it is not clear, if neutrophils actually remain alive thereafter [12, 13]. Some reports have suggested that in this fast NET‐releasing process it is rather the mitochondrial DNA that is excreted, supporting observations of significantly lower efficiency of NET production in comparison with regular netosis [13]. The classical NET‐forming pathway is triggered with massive generation of reactive oxygen species (ROS), resulting from the activity of NADPH oxidase. This ROS‐dependent netosis pathway lasts for up to 4 hours, starting from neutrophil activation, and leading to the release of whole nuclear DNA mixed with granular proteins. In contrast, the fast netosis pathway does not require ROS production, leading to a rapid release of NETs within minutes after activation [12].
\nNetosis can be activated by many compounds, mostly those exposed on the pathogen cell surface. This initial step of NET formation determines the form of released NETs and pathways involved, as well as the intensity and time span of neutrophil response.
\nThe largest group of NET activators are pathogenic Gram‐positive and Gram‐negative bacteria, but also some fungi (Aspergillus spp., Candida spp.), as well as viruses (HIV‐1, Hantaan virus) and parasites such as Toxoplasma gondii and Leishmania. Besides microorganisms, numerous chemical factors, including phorbol ester (PMA), hydrogen peroxide, nitric oxide, ionomycin, calcium ions, glucans, mannans, and lipopolysaccharide (LPS), as well as mediators of inflammation such as granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), some interleukins and immune complexes have been identified as potential netosis-triggering factors [9, 11]. Most of them are recognized by neutrophil surface receptors (pattern recognizing receptors, PRRs) that trigger cell signaling for cytokine or chemokine production in order to launch a pathogen‐tailored response [14]. Diverse pathogens may be recognized by neutrophils with very similar and overlapping mechanisms.
\nThe main PRRs involved in the recognition of pathogens and pathogen‐associated molecules are Toll‐like receptors (TLRs). Among several TLRs, only TLR2, TLR4, TLR7, and TLR8 have been identified as participating in NET‐dependent phenomena. The role of TLR4 in the activation of netosis was confirmed in Staphylococcus aureus infection. This receptor plays a great role in the activation of “vital netosis” in vivo, cooperating with complement receptor 3 (CR3) [15]. During bacterial sepsis, neutrophils and platelets cooperate in pathogenesis, but the mutual relationship between these cells is still under debate. TLR4, a lipopolysaccharide receptor, seems to mediate the activation of neutrophils by platelets induced by LPS [16].
\nThe other molecule involved in NET triggering via TLRs is high‐mobility group box 1 protein (HMGB1). This protein released from dying cells or activated macrophages enhances inflammatory reactions. HMGB1 is a TLR4 agonist, but does not induce the production of ROS by NADPH oxidase, suggesting its involvement in an ROS‐independent mechanism of NET formation [17]. On the other hand, an oxidized low density lipoprotein (oxLDL) is able to induce netosis via ROS‐dependent pathway, activated by TLR4 and TLR6 receptors [18]. TLR4 was also identified as an important surface recognizing molecule in viruses‐activated netosis detected in the lungs of infected hosts. Respiratory syncytial virus (RSV) is responsible for acute bronchiolitis in children under 3 years. This RNA virus exposes a fusion protein (F‐protein) on its surface that mediates a fusion of viral envelope with the target cell membrane and also activates NET release using TLR4 mediation [19]. Moreover, F‐protein is also recognized by CD14 receptor, which cooperates with TLR4 [20, 21]. A human immunodeficiency virus HIV‐1 is captured and killed in NETs formed by neutrophils using TLR7 and TLR8 to recognize viral nucleic acids. Activation of these receptors leads to production of ROS and activation of ROS‐dependent netosis pathway [22].
\nThe most commonly identified receptor of complement system that contributes to neutrophil responses is CR3 complex (Mac‐1; CD11b/CD18). It has been identified to be involved in NET triggering by different types of pathogenic microorganisms. The role of Mac‐1 in NET formation is best known in fungal life‐threatening, systemic infections, especially those caused by Candida albicans. On the cell wall, C. albicans exposes well‐characterized compounds, such as β‐glucans or mannans, important for activation of netosis [23–25]. The β‐glucan particles are bound by Mac‐1 allowing to recognize C. albicans at early stage of infection, without preliminary opsonization [26]. Some studies have suggested that for in vitro activation of netosis by fungal compounds the presence of fibronectin is required [27]. The activation of Mac‐1 causes a rapid formation of NETs via the ROS‐independent pathway [26, 27]. However, glucans are also able to induce ROS formation through the activation of NADPH oxidase [28].
\nMannheimia haemolytica is a bacterium that causes a severe respiratory disease. One of the virulence factors of this pathogen is leukotoxin (LKT), which can lead to the death of many host cells. LKT was also identified as a M. haemolytica factor that triggers NET formation via CD18 receptor, but the complete model of this interaction and the regulation of netosis by this toxin are still not fully understood [29].
\nAggregatibacter actinomycetemcomitans, as well as Actinomyces viscosus and S. aureus, also induce NET release by human neutrophils. However, analysis of the complement receptors involved in netosis activated by these bacteria showed that complement receptor 1 (CR1; CD35) rather than CR3 takes part in recognizing the pathogens [30]. However, CR3 seems to be important for the activation of “vital netosis” induced by S. aureus [15].
\nMoreover, some viruses seem to be recognized by neutrophils via complement receptors. Hantaan virus (HTNV), a member of hantaviruses family, causes severe renal and pulmonary pathologies in humans. This virus is known as a potential NET triggering factor that stimulates neutrophils much stronger than Vaccinia virus or LPS. Detailed analysis of mechanisms of neutrophil activation by HTNV indicated that CR3 and CR4 receptors are necessary for activation of netosis using the ROS‐dependent pathway [31].
\nAnother microorganism able to induce netosis is a parasite Eimeria bovis. Although this pathogen does not cause diseases in humans but causes diseases in animals, e.g., a severe hemorrhagic diarrhea, especially in calves, it is a good example of activation of netosis via CR3 by parasites. The interaction of Mac‐1 with E. bovis causes a rapid Ca2+‐mobilization and activation of the ROS‐dependent netosis pathway with intensive NET expulsion [32].
\nComplement receptors are also involved in triggering netosis by immune complexes (ICs) that play an important role in many pathogen‐associated diseases, as well as noninfectious, autoimmunological diseases. ICs are bound to neutrophil surface by many different receptors, causing activation of the cells. Mac‐1 takes part in these interactions leading to NET release. The overall mechanism is still unclear, but it has been confirmed that IC activation of CR3 receptors leads to the increase of NADPH oxidase activity and, thus, to the initiation of ROS‐dependent netosis pathway [33].
\nThe recognition of opsonized pathogens or antibody‐associated foreign molecules is one of key functionalities of the cells of immune system. In the activation of these cells, antibody receptors of the Fc-receptor family are involved. Neutrophil cells express only two types of surface Fc‐receptors for IgG molecules, namely, FcγRIIa (CD32a) and FcγRIIIb (CD16b) [34]. Some microorganisms induce NETs only in the presence of autologous serum [15], suggesting a role of Fc‐receptors in the activation of netosis, but it has not yet been resolved which receptors, CD32 or CD16, have greater impact. The best‐known NET inducers via Fc‐receptors are ICs. Some studies showed that FcγRIIa mediates activation of netosis by endocytosis of ICs [35]. However, other authors suggested that FcγRIIa rather promoted phagocytosis and only FcγRIIIb was involved in the induction of netosis [33]. The activation of netosis by CD16 takes about 3 hours with efficient production of ROS, suggesting a similarity to induction of netosis by PMA.
\nFc‐receptors also seem to participate in NET formation during bacterial infections. The results presented for neutrophils in contact with opsonized S. aureus suggest that activation of Fc‐receptors modulates netosis [30]. Moreover, coating of bacteria by IgA also enhances NET formation via FcαIR [36].
\nC‐type lectin receptors (CLRs), such as dectin‐1, are responsible for recognition of surface exposed β‐glucans of pathogens [37, 38]. The role of glucans in activation of netosis as well as the role of dectin‐1 receptor in activation of NET formation are still under debate [26]. The involvement of dectin‐1 in this process was confirmed for several fungal pathogens, such as Paracoccidioides brasiliensis [39]. However, the role of this receptor in the activation of netosis during C. albicans infection is still unclear. Some studies seem to support this hypothesis [40], but, on the other hand, Gazendam et al. suggested that unopsonized C. albicans cells do not induce netosis via dectin‐1 receptor [26]. The role of dectin‐1 was also proposed by Li et al. who showed that upon ligand binding a dectin‐1 receptor activates Mac‐1, and this receptor induces downstream NET formation [41]. Additional evidence presented that dectin‐1 may indirectly mediate netosis depending on microbial size. Neutrophils in contact with C. albicans hyphae or Mycobacterium bovis aggregates were able to release NETs. It was proposed that phagocytosis of microbes mediated by dectin‐1 plays the function of microbial size sensor and prevents netosis by downregulation of elastase translocation from granules to the nucleus [42]. The number of Candida cells and the level of infection were also proposed to be factors responsible for NET formation [43].
\nInterestingly, the regulation of NET excretion by PMA, used in in vitro models of netosis, occurs without activation of any receptors, but directly by the action on protein kinase C (PKC) [44], an important signal mediator of ROS‐dependent netosis pathway [45].
\nBecause many of receptors exposed on neutrophil surface are involved and cause cross‐activation in NET triggering processes [46–49], the complete pathway of netosis is still under debate. However, some key steps as well as mediating compounds were proposed to be involved in NET formation and are summarized below; however, the specific processes may vary depending on the trigger type.
\nThe first important mediators of netosis, identified in fungal infections associated with NET release, seem to be Src family kinases and spleen tyrosine kinase (Syk) [31, 40]. Src cooperates with plasma membrane‐associated receptors, such as CD11b, CD16, or dectin‐1, and causes an activation of Syk. Further, Syk devolves the activation signal downstream to next mediators—phosphoinositide 3‐kinase (PI3K)/protein kinase B (Akt), p38 MAPK (mitogen‐activated protein kinase), and extracellular signal‐regulated kinases (ERK1/2) pathways [33, 50, 51]. Syk is also involved in the activation of protein kinase C (PKC) by PMA [33, 52, 53], without participation of Src, confirming observed bypassing of the receptors by PMA.
\nMany of the natural NET inducers, activating the receptors mentioned above, lead to the release of calcium ions from endoplasmic reticulum storage into the cytoplasm, increasing PKC activity [54]. PKC is responsible for phosphorylation of gp91phox that can form the functional complex of NADPH oxidase with subsequent ROS generation [55, 56]. ROS are crucial for classical suicidal netosis (ROS‐dependent pathway).
\nNetosis is a different type of neutrophil death in comparison to apoptosis. Although both mechanisms are mutually exclusive, they could be activated by the same receptors. Indeed, neutrophils are able to block apoptosis, to allow for the formation of NETs. A key molecular switch between apoptosis and netosis seems to be protein kinase B. Activation of Akt allows to induce netosis, but inhibition of this enzyme leads to apoptotic cell death. A key role in apoptosis is played by caspases, whose activities are inhibited in netosis [57]. Moreover, ROS may alternatively inactivate caspases favoring autophagy [58].
\nThe role of PI3K in NET formation is still unclear. Some research showed that phosphorylation of PI3K is not important and has no effect on NET formation via activation of CD16 [59]. On the other hand, an activation of netosis by ICs seems to require active PI3K [33]. Moreover, PI3K interplays with Akt [60], as well as influences a nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) regulation by production of phosphatidylinositol (3,4,5)‐trisphosphate [61]. NF‐κB has been identified as a regulatory molecule in netosis [62]. PI3K also regulates the autophagy, an important process in PMA‐ and oxLDL‐induced netosis [18, 58, 63].
\nThe role of ERK1/2 in netosis pathway has also been confirmed [19, 32, 33, 59, 64, 65]. ERK1/2 can be induced by Src/Syk, as well as by TLR receptors via interleukin‐1 receptor‐associated kinase (IRAK) [66]. These mediators seem to be involved in the ROS‐dependent netosis pathway, but the relationship between activation of ERK1/2 and generation of ROS by NADPH oxidase is still unsolved. More probably, ERK1/2 can downstream‐activate NADPH oxidase [33, 65] or is itself controlled by ROS [45]. The role of p38 MAPK is also not clear, because some studies showed that inhibition of these kinases has no impact on ROS production and ROS‐dependent netosis [33, 67, 68], but other presented an opposite effect [32]. The summary of netosis pathways is schematically presented in Figure 1.
\nMolecular mechanisms of NET formation. CLRs, C‐type lectin receptors; CR, complement receptors; ERK1/2, extracellular signal‐regulated kinases; HTNV, Hantaan virus; ICS, immune complexes; IRAK, interleukin‐1 receptor‐associated kinase; LPS, lipopolysaccharide; PI3K, phosphoinositide 3‐kinase; PIP3, phosphatidylinositol (3,4,5)‐trisphosphate; PKC, protein kinase C; PMA, phorbol myristate acetate; RSV, respiratory syncytial virus; Src, Src kinase; Syk, spleen tyrosine kinase; TLRs, toll‐like receptors.
The first described, classical mechanism of netosis assumed that ROS species play an essential role in netosis (the ROS‐dependent pathway) [56]. Indeed, several findings have proven that ROS are key netosis mediators. Patients with chronic granulomatous disease (CGD), caused by a point mutation in gp91‐phox subunit of NADPH oxidase, making the enzyme nonfunctional, were more susceptible to infections. Additionally, CGD patients experienced hyper‐inflammatory states and sterile inflammations [69, 70]. Moreover, providing ROS from external sources, as well as application to CGD patients a gene therapy, restored the ability of neutrophils to release NETs [8, 46, 71]. Similarly, inhibition of NADPH oxidase by diphenyliodide (DPI) turns off the ability to release NETs [72].
\nLittle is known about the ROS‐independent netosis pathway. NET release without ROS contribution is much faster than the classical netosis. The pathway in which neutrophils remained structurally intact was named as “vital netosis.” It can be induced by the same pathogens as those acting in the ROS‐dependent manner, e.g., during Leishmania parasite infection [12]. Similarly, the induction of NET release in response to glucans of C. albicans usually occurs through the ROS‐dependent pathway, but in infants, neutrophils release NETs without ROS involvement [73]. Upon contact with S. aureus neutrophils release NETs but the web of DNA is released in the exocytosis pathway, without cell membrane rupture. Moreover, NET production was also observed in patients with inactive NADPH oxidase [74]. It was also documented that this type of netosis exploited a release of mitochondrial DNA and an oxidative activity of mitochondrion [13], as well as a small conductance calcium‐activated potassium channel 3 (SK3) [75].
\nThe process of DNA release in the ROS‐dependent pathway takes about 1–4 hours and is quite complex. After NADPH oxidase activation, produced ROS probably influence the stability of granules and nuclear envelope. The proteins stored in neutrophil granules—elastase and myeloperoxidase—are moved to the nucleus but the mechanism of their translocation is unknown. In the nucleus, these enzymes contribute to the degradation of linker histones responsible for maintenance of the nuclear structure [55]. They cooperate with next enzyme transferred into the nucleus—peptidyl arginine deiminase 4 (PAD4)—that catalyzes the citrullination of histones, especially H3 and H4. The modification and cleavage of histones lead to the relaxation and decondensation of chromatin, changing the shape and structure of nucleus, and finally causing the disappearance of nuclear membrane [76–78]. DNA is moved into the cytoplasm and mixed with granular proteins such as cathepsin G, proteinase 3, lactoferrin, azurocidin, or with cytoplasmic proteins such as calprotectin [79]. Some research suggests that cytoskeleton also plays an important role in the process of NET formation [46]. At the end of the process, this mixture is released outside the cell. Figure 2 summarizes all morphological changes during netosis.
\nMechanism of NET formation. ALI, acute lung injury; ARDS, acute respiratory distress syndrome; ANCA, antineutrophil cytoplasmic antibodies; MPO, myeloperoxidase; NE, neutrophil elastase; PAD4, protein arginine deiminase 4; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SVV, small vessel vasculitis.
The primary role of NETs is the antimicrobial activity, due to the cooperation of several mechanisms and components exposed at the high local concentrations in the NET fibers [55]. The pathogen spreading is limited by entrapment inside NET structure due to electrostatic interactions between the negatively charged DNA backbone and positively charged bacterial compounds localized on their cell surface [6]. Proteinaceous components of NETs are responsible for different types of NET antimicrobial activities. Proteases such as elastase, cathepsin G, and proteinase 3 are able to cleave virulence factors of Yersinia enterocolitica, Shigella flexneri, Salmonella Typhimurium, and other pathogens [4, 80]. The oxidative mechanisms of defense, e.g., the production of aggressive hypochlorous acid by myeloperoxidase, cause massive damages of NET‐entrapped pathogens with their membrane and protein oxidation [81, 82]. Histones, as well as antimicrobial peptides such as LL‐37 and BPI, also play an important role in pathogen elimination. Peptides derived from histones and LL‐37 take part in cell membrane permeabilization or bacterial cell lysis [83–85]. Moreover, NET‐associated factors can restrict nutrient supply for microbes, e.g., lactoferrin chelates iron and calprotectin sequesters zinc ions [79, 84].
\nMicroorganisms that constantly compete with the host defense mechanisms for survival, elaborated also evasion strategies against toxic effects of NETs. The strategies can be divided into three groups, including: (1) an inactivation of NET components responsible for trapping and killing pathogens, (2) a suppression of NET formation and (3) development of resistance mechanisms against antimicrobial components of NETs.
\nThe main NET component, DNA backbone is degraded by bacterial endonucleases, membrane‐bound or released into the surrounding milieu. The group of microorganisms that produce such enzymes to avoid the killing activity of NETs includes S. aureus whose nuclease influences the bacterial survival and enhances its infectivity in a mouse respiratory tract infection model [86]. The same strategy, leading to decline NET integrity, is also adopted by other bacteria such as Aeromonas hydrophila [87], Escherichia coli [88], Leptospira sp. [89], Neisseria gonorhoeae [90], Streptococcus agalactiae [91], Streptococcus pyogenes [92, 93], Streptococcus synguinis [94], Streptococcus suis [95], Vibrio cholerae [96], and Yersinia enterocolitica [88]. Streptococcus pneumoniae uses cell‐associated endonuclease (EndA) to escape from local entrapment and promote bacterial spreading from lower airways to bloodstream during pneumonia [97]. Also, parasites such as Leishmania infantum use nuclease activity to resist the NET activity [98].
\nMoreover, the production of ROS involved in the initiation and progression of the main netosis pathway can be regulated by bacterial catalase activity in a self‐protection process [99].
\nOther interesting NET evasion strategies were proposed for meningococci [100], which apply the release of outer membrane vesicles for protection of bacteria from binding to NETs and express a high‐affinity zinc uptake receptor (ZnuD) to overcome possible ion sequestration by calprotectin, the NET component also known to be involved in C. albicans killing during netosis [101]. Moreover, a modification of meningococcal LPS with phosphoethanolamine protects bacteria from bactericidal activity of cathepsin G embedded into NET structures.
\nThe bactericidal activity of another NET component, cathelicidin LL‐37, can be abolished by its binding to the surface‐expressed M1 protein in S. pyogenes [102] or to surface exposed D‐alanylated lipoteichoic acid in S. pyogenes and S. pneumoniae, promoting bacteria survival within NETs [103, 104].
\nMoreover, C. albicans aspartic proteases, secreted during NET formation in response to fungal infection, are able to degrade and inactivate LL‐37 [105].
\nMany bacterial toxins are involved in induction of NETs but some of them are used by bacteria to regulate, in particular to inhibit NET formation [106]. Bordetella pertussis causing coughing syndrome adopts adenylate cyclase toxin (ACT) to suppress NET shaping [107]. ACT, after translocation into the host phagocyte, may influence the conversion of ATP to cyclic AMP, that in consequence prolongs neutrophil life span by inhibiting the oxidative burst, being one of the initial signals in NET production. This part of NET formation mechanism is also blocked by streptolysin O (SLO) produced by S. pyogenes [108].
\nIn the defense against NET formation, microorganisms can also exploit host signaling as in the case of interleukine‐8 (IL‐8) production by epithelial cells in response to infection. This chemokine is responsible for neutrophil recruiting and amplification of NET release but S. pyogenes can produce a peptidase (SpyCEP) which inactivates IL‐8 and reduces NET formation [109].
\nA more complex strategy, used by Pseudomonas aeruginosa [110] or S. agalactiae [111], employs molecular mimicry with the acquisition of sialic acid motifs presented on the host cell surface which attenuate NET formation. A comparable, indirect mechanism suppressing NET release has been adopted by Mycobacterium tuberculosis. This microorganism that triggers NET release during the first stage of infection activates the production of anti‐inflammatory cytokine IL‐10 that inhibits TLR‐induced ROS production and suppresses further NET generation [112].
\nAlso, viruses can apply this strategy of NET suppression, as demonstrated for HIV‐1 envelope glycoprotein [22]. Moreover, Dengue virus serotype‐2 can negatively affect NET formation by inhibiting glucose uptake in the ROS‐independent mechanism of netosis [113].
\nOn the other hand, conidia of Aspergillus fumigatus expose hydrophobin (RodA) that suppresses the formation of NETs [114]. This process is also supported by the production of a positively charged exopolysaccharide—galactosaminogalactan that protects the microorganism from binding by NET components [115]. The polysaccharide capsule negatively modulating NET production that contributes to fungal disease severity was also observed in Cryptococcus neoformans infections [116].
\nAnother way to subsist the antimicrobial activity of NETs is applied by P. aeruginosa in patients with chronic fibrosis where bacteria during its long‐term adaptation can form the resistant biofilm that protects the pathogen [117]. Moreover, S. pneumoniae and Haemophilus influenzae are even able to embed NETs into biofilm for self‐protection [118, 119]. Also, the extracellular matrix components of C. albicans biofilm alter its recognition by neutrophils and inhibit release of NETs [43].
\nAll the above mechanisms developed by microorganisms to avoid killing by NETs confirm their ongoing adaptation to the sophisticated processes of host defense.
\nNetosis is a process being under control of many mechanisms of activation, but NET fibers seem not to be a target or location specific, and in some cases, their release get out of the control. So, the process can be a double‐edged sword, acting also against the host cells. Therefore, NETs seem to play a significant role in several autoimmune disease and disorders, described in detail in others reviews [54, 120].
\nA chronic inflammatory state of the lungs leads to the development of acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) [121–123]. The increased permeability of alveoli due to a mechanical ventilation or infection causes an activation of signaling involved in the release of proinflammatory factors by epithelial cells, and in consequence the massive migration and activation of neutrophils.
\nNET release can be also the trigger of sterile inflammatory state in the lung. Moreover, a lack of surfactant proteins makes a NET clearance difficult. The proteolytic enzymes contained in NETs damage epithelial cells, in consequence releasing more proinflammatory factors. This generates a self‐perpetuating mechanism of netosis activation [11, 124, 125].
\nA similar mechanism was observed in patients with cystic fibrosis (CF), a disease consisting in an increase in mucus viscosity, therefore hindering the clearance of mucus from the airways [126]. The presence of DNA in CF patient sputum increases a mucus viscosity, which correlates with the development of inflammation state and higher migration of neutrophils. The high viscosity of mucus makes it difficult to remove, generating good conditions for bacterial invasion [126, 127].
\nAutoimmune diseases including small vessel vasculitis (SVV), systemic lupus erythematosus (SLE), or rheumatoid arthritis (RA) seem to be also associated with uncontrolled release and ineffective clearance of NETs [128–130]. The high amount of NETs and free‐circulating DNA causes a production of antineutrophil cytoplasmic antibodies (ANCAs) against DNA and NET‐associated proteins such as MPO, cathepsin G, elastase, etc. Autoantibodies to citrullinated proteins (ACPA) seem to be a key pathologic factor in RA. The circulating complexes of antibodies‐DNA or antibodies‐NET proteins induce multiorgan inflammatory states, as well as inflammations of vessels [11, 13, 131, 132].
\nDeep vein thrombosis (DVT) is a next pathological state mediated by NETs. Neutrophils can be activated in veins by many different factors, including activated platelets, interleukins, proinflammatory cytokines, as well as von Willebrand factor (vWF), released by NET‐damaged endothelial cells. NETs, released inside veins, promote the formation of thrombi by binding of necessary blood cells and supporting of clot formation. The uncontrolled netosis can lead to massive DVT and consequently to multiple ischemia [11, 13, 133].
\nThe progress in investigation of the fundamental processes leading to activation of netosis during pathogenic infection allows us to better understand the main causes of microbial infections and to consider the consequences of neutrophil responses to the host. All of them pointed out on the possible targets for novel therapeutic approaches regulating immunity responses during microbial infection and counteracting the detrimental NET formation and inflammatory diseases.
\nThis work was supported in part by the National Science Center of Poland (grant UMO‐2012/05/B/NZ1/00003 awarded to M.R.‐K.) and Jagiellonian University (grant K/DSC/003704 awarded to M.Z.).
\nSerious health-related problems contribute to the worldwide distribution of healthier, safer, and cost-effective food products. Additionally, functional foods were introduced as a tool to give an additional function to food. This can be achieved by increasing the production of existing biologically active molecules or adding new bioactive ingredients. Therefore, food products in addition to their nutritional value, they usually have health-promotion or disease prevention values. Nevertheless, it has become evident that the low bioavailability or inefficient long-term stability of these health-promoting products may not sustain their benefits. Subsequently, a great attention has been received in the last few years for nanotechnology in food applications. Nanoemulsions are one of the most interesting delivery systems in food industry. Nanoemulsion-based delivery systems improve the bioavailability of the encapsulated bioactive components and increase food stability [1].
Nanoemulsions are emulsions that have very small particle size [2]. They have some unique characteristics such as small size, increased surface area and less sensitivity to physical and chemical changes, making them ideal formulas in food industry [3, 4].
Food grade nanoemulsions are being increasingly used in for improving digestibility, efficient encapsulation, increasing bioavailability and targeted delivery [3, 4, 5]. The aforementioned advantages of nanoemulsions over the conventional emulsions increased the utility of nanoemulsions in food industry. The kinetic stability of nanoemulsions can be improved by incorporating stabilizers such as emulsifiers, ripening retarders, weighting agents or texture modifiers [3]. Emulsifiers such as small molecule surfactants (Tweens or Spans), amphiphilic polysaccharides (gum Arabic or modified starch), phospholipids (soy, egg or dairy lecithin) and amphiphilic proteins (caseinate or whey protein isolate) can be used in food industry to formulate nanoemulsions. Texture modifiers, substances that increase the viscosity such as proteins (whey protein isolate, gelatin or soy protein isolate), sugars (high-fructose corn syrup or sucrose), polysaccharides (carrageenan, xanthan, pectin, alginate) and polyols (sorbitol or glycerol) can be also used as stabilizers. Dense lipophilic materials such as brominated vegetable oil, sucrose acetate isobutyrate, ester gums can be used as a weighting agent to balance the densities of the liquids nanoemulsions [1, 3, 5, 6, 7, 8, 9].
In this chapter, we provide an overview on the terminology used in emulsions, formulation of nanoemulsions and diverse approaches for production of nanoemulsions. Additionally, we summarize the recent applications of nanoemulsions in food industry.
Emulsions are defined by International Union of Pure and Applied Chemistry (IUPAC) as “a fluid colloidal system in which liquid droplets and/or liquid crystals are dispersed in a liquid” [10]. If the continuous phase of the emulsion is an aqueous solution, the emulsion is oil-in-water and denoted by the symbol O/W, whereas, if the continuous phase is oil, the emulsion is referred to W/O (Figure 1) [10]. An emulsifier is a surfactant or surface-active agent, a substance that lowers the surface tension and/or the interfacial tension [10].
Schematic representation of oil in water (O/W, A) and water in oil (W/O, B) emulsions.
Nanoemulsions are emulsions that have a particle size at the nanometer range (20–500 nm) [2, 5, 6, 11]. Nanoemulsions have major differences in size, shape and stability from the classical macroemulsions and microemulsions [5]. While microemulsions are thermodynamically stable, both macroemulsions and nanoemulsions are thermodynamically unstable [5, 11].
A typical nanoemulsion consists of a water phase, an oil phase and an emulsifier [5]. When present in small amounts, an emulsifier facilitates the formation of emulsions by decreasing the interfacial tension between the oil and water phases [5]. Additionally, emulsifiers aid the stabilization of nanoemulsions [11]. Formation and stabilization of nanoemulsions depend largely on the physico-chemical properties of the three aforementioned constituents.
O/W nanoemulsions have the greatest application in commercial products [9]. The particles in O/W nanoemulsion have a core-shell-type structure with a shell of surface-active amphiphilic material covers a core made of lipophilic material.
The oil phase used to prepare food-grade nanoemulsions can be formulated from a variety of nonpolar molecules, such as free fatty acids (FFA), monoacylglycerols (MAG), diacylglycerols (DAG), triacylglycerols (TAG), waxes, mineral oils or various lipophilic nutraceuticals [9]. TAG oils extracted from soybean, safflower, corn, flaxseed, sunflower, olive, algae or fish are the most commonly used in nanoemulsions primarily due to their low cost and nutritional value [9]. Physical and chemical characteristics of the oil phase such as viscosity, water solubility, density, polarity, refractive index and interfacial tension and chemical stability greatly influence the properties of nanoemulsions [1, 3, 5, 6, 7, 8].
The aqueous phase used to prepare food-grade nanoemulsions can be formulated from water with a variety of polar molecules, carbohydrates, proteins, acids, minerals or alcoholic cosolvents [9]. The selection of the aqueous phase has a great impact on the physicochemical properties of the produced nanoemulsion.
Stabilizers influence the long-term stability of nanoemulsions; therefore, the selection of the appropriate stabilizer is one of the most important factors to consider for the proper production of nanoemulsions. Various kinds of stabilizers are added to improve the long-term stability of nanoemulsions, and they are summarized in Table 1 [1, 3, 5, 6, 7, 8, 9]. Stabilizers can be emulsifiers, ripening retarders, texture modifiers and weighting agents. Emulsifiers are the most common stabilizers added in nanoemulsions. Emulsifiers of different kinds may be added such as phospholipids, small molecule surfactants, polysaccharides, and proteins. Examples of small molecule surfactants are listed in Table 2.
Stabilizers | Function | Examples |
---|---|---|
Emulsifiers | Single emulsifier or combination of emulsifiers are added to stabilize emulsions by increasing their kinetic stability |
|
Ripening retarders | Hydrophobic substances that stabilize nanoemulsions by retarding or inhibiting Ostwald ripening |
|
Texture modifiers | Substances that increase the viscosity of nanoemulsions |
|
Weighting agents | Substances that balance the densities of the liquids nanoemulsions |
|
Kinds of stabilizers added to improve long-term stability of nanoemulsions.
Small molecule surfactants | Type | Examples | Remarks |
---|---|---|---|
Ionic surfactants | Negatively charged | Sodium lauryl sulfate (SLS) Diacetyl tartaric acid ester of mono- and diglycerides (DATEM) Citric acid esters of mono and diglycerides (CITREM) |
|
Positively charged | Lauric arginate | ||
Nonionic surfactants | Sugar esters | Sucrose monopalmitate Sorbitan monooleate |
|
Polyoxyethylene alkyl ethers (POE) | Brij-97 | ||
Ethoxylated sorbitan esters | Tweens 20 and 80 Spans 20, 40, 60 and 80 | ||
Zwitterionic surfactants | Positively and negatively charged groups | Phospholipids (lecithin) | pH influences the net positive, negative or neutral charge |
Examples of small molecule surfactants added to nanoemulsions.
Nanoemulsion is a nonequilibrium system which needs external or internal energy source to be successfully formed [12]. Nanoemulsions can be fabricated using many approaches that can be classified as high-energy or low-energy approaches.
The used techniques for the production of nanoemulsion has a great effect on the droplet size and consequently affect the stability mechanisms of the emulsion system through operating conditions and composition. Generally, preparation of nanoemulsions applies lower concentrations of surfactant (5–10%) than the microemulsion (20% and higher) [13].
Mechanical devices which can produce strong disruptive forces are used in high-energy approaches to mix and disrupt oil and water phases allowing the formation of tiny oil droplets [2, 14, 15, 16]. On the other hand, low energy approaches depend on the spontaneous formation of tiny oil droplets in the oil-water-emulsifier mixed systems when either the solution or the environmental conditions such as temperature and composition are changed [14, 17, 18, 19, 20, 21]. The used approach in nanoemulsion formation, together with the operating conditions, and the composition of the system affect the size of the formed droplets. In this section, we have a brief overview on the most commonly used high-energy and low-energy approaches for nanoemulsion formation.
The preparation of nanoemulsions by high-energy methods is strongly dependent on the surfactants used as well as the functional compounds in addition to the quantity of energy applied [1]. Accordingly, the nanoemulsions formed by high-energy approaches constitute a natural method for the preservation of the nanoemulsions against formulation modification such as addition of monomer, surfactant, cosurfactants [17].
High-energy methods employ mechanical devices to produce disruptive forces that can mix and disrupt oil and water phases leading to the formation of the tiny oil droplets, such devices as high-pressure valve homogenizers, microfluidizers, and sonication methods [14, 16]. To keep the droplets in spherical shapes, intense energies are applied in order to generate disruptive forces that exceed the restoring forces, and these restoring forces could be calculated by the Laplace Pressure: ΔP = γ /2r, which increases by reducing droplet radius (r) and increasing interfacial tension (γ) [22]. Generally, the droplet size produced by high-energy approaches is controlled by a balance between two opposing processes that occur within the homogenizer, which are the droplet disruption and droplet coalescence [23]. Smaller droplets can be obtained by increasing the homogenization intensity or duration, increasing the concentration of the used emulsifier or by controlling the viscosity ratio [14, 22, 24]. The smallest droplet size that can be obtained using certain high-energy device is governed by the flow and force profiles of the homogenizer, the operating conditions such as the energy intensity and duration of the process, the environmental conditions meaning the applied temperature, the sample composition which includes the oil type, emulsifier type and concentrations, and the physicochemical properties of the phases which means the interfacial tension and viscosity [14, 25, 26]. In more clear words, the droplet size decreases as the intensity or duration of energy increases, the interfacial tension decreases, the emulsifier adsorption rate increases, and the disperse-to-continuous phase viscosity ratio falls within a certain range (0.05 < ηD/ηC < 5) [12, 13, 27]. Production of small droplets depends on the extent of the ηD/ηC range and the nature of the disruptive forces produced by the particular homogenizer used, that is, simple shear versus extensional flow. Thus, the smaller the droplet radius, the more difficult is to break them up further.
High-energy approaches are the most suitable methods for the production of food-grade nanoemulsions as they can be applied to various types of oils such as triacylglycerol oils, flavor oils, and essentials oils as the oil phase as well as different emulsifier types such as proteins, polysaccharides, phospholipids, and surfactants. Even so, the size of the formed particles is strongly dependent on the oil characteristics and the used emulsifier. For instance, it is easier to produce very small droplets when flavor oils, essential oils or alkanes are used as the oil phase because they have low viscosity and/or interfacial tension [9]. Now we present the most commonly used devices in high-energy approaches.
In high-pressure valve homogenization, first a very high pressure is applied on the mixture and then it is pumped through a restrictive valve (Figure 2). The very fine emulsion droplets are generated by the very high shear stress [28, 29]. High-pressure and multiple passes are necessary to produce the required droplet size [9]. The combination of intensive disruptive forces such as shear stress, cavitation, and turbulent flow conditions can break the large droplets into smaller ones [30]. Production of conventional emulsions with small droplet sizes in food industry is commonly done using high-pressure valve homogenizers [22, 31]. Some of the food nanoemulsions prepared by high-pressure valve homogenization technique is β-carotene, thyme oil, and curcumin nanoemulsions [32, 33, 34].
Schematic representation of three devices utilized in high-energy approach for production of food-grade nanoemulsions: A. high-pressure valve homogenization; B. ultrasonic homogenization; C. microfluidizer; and D.D. droplet disruption.
These devices are more suitable for reducing the size of the droplets in preexisting coarse emulsions than in making emulsions directly from two separate liquids [9]. To describe the operation in the high-pressure valve homogenizer, the coarse emulsion is produced by the high shear mixer and is then passed into a chamber by the pump through the inlet of the high-pressure valve homogenizer and then forced through a narrow valve at the end of the chamber on its forward stroke. The coarse emulsion particles are broken down into smaller ones by a combination of intense disruptive forces when it passes through the valve. Different nozzle designs are available to increase the efficiency of droplet disruption [9].
The droplet size produced using a high-pressure valve homogenizer usually decreases as the number of passes and/or the homogenization pressure increases. It also depends on the viscosity ratio of the two phases (usually oil and water) being homogenized. As mentioned before, small droplets can only usually be produced when the disperse-to-continuous phase viscosity ratio falls within a certain range (0.05 < ηD/ηC < 5) [12, 13, 27]. Moreover, sufficient emulsifier is required to cover the surfaces of the new droplet formed during homogenization, and the emulsifier should be rapidly adsorbed on the droplet surfaces to prevent re-coalescence [23].
As a summary, to obtain the required droplet size in nanoemulsions, we need to operate at extremely high pressures and to use multiple passes through the homogenizer. Even then, high emulsifier levels, low interfacial tensions, and appropriate viscosity ratios are required to obtain droplets less than 100 nm in radius [9].
This device is similar in design to high-pressure valve homogenizer in that it employs high pressure to force the premix of emulsion through a narrow orifice to facilitate the disruption of droplet but differs only in the channels in which the emulsion flows (Figure 2). The emulsion flowing in a microfluidizer is divided through a channel into two streams, each passes through a separate fine channel, and then both streams are redirected into interaction chamber, in which they are exposed to intense disruptive forces leading to highly efficient droplet disruption [3]. Increasing the homogenization pressure, number of passes, and emulsifier concentration can efficiently reduce the droplet size formed. McClements and Rao have practically proved that the logarithm of the mean droplet diameter decreased linearly as the logarithm of the homogenization pressure increased for both ionic surfactant and a globular protein (β-lactoglobulin). But it could be noticed that this relation was appreciably steeper for the surfactant than for the protein, and this could be explained by the slow rate of the protein to adsorption to the droplet surfaces, with the formation of a viscoelastic coating which inhibits further droplet disruption [9].
In addition, there is an optimum range of disperse-to-continuous phase viscosity ratio, which facilitates the formation of small droplets [14]. But this relation is highly affected by the surfactant used, for the ionic surfactant mean droplet diameter decreases when the viscosity ratio decreases. On the other hand, the mean droplet size is hardly affected by viscosity ratio when a globular protein was used as an emulsifier, which may be also attributed to the relatively slow adsorption of the protein and its ability to form a coating that inhibits further droplet disruption [9].
Microfluidizers have been extensively used for the preparation of pharmaceutical products as nutraceutical emulsions, food and beverages such as homogenized milk in addition to the production of flavor emulsion [9]. Nanoemulsions of various bioactive compounds such as β-carotene and lemon grass essential oil were prepared using microfluidization technique [35, 36, 37].
When two immiscible liquids in the presence of a surfactant are subjected to high-frequency sound waves (frequency > 20 kHz) using sonicator probes that contain piezoelectric quartz crystals that expand and contract in response to an alternating electrical voltage, this causes strong shock waves produced in the surrounding liquid by the tip of the sonicator placed within the liquid (Figure 2). The mechanical vibrations lead to the formation of liquid jets at high speed, the collapse of the micro-bubbles formed by cavitation generates intense disruptive forces that lead to droplet disruption and the formation of emulsion droplets of nano size (70 nm). The emulsion should spend sufficient time within the region where droplet disruption occurs to ensure efficient and uniform homogenization [9, 16, 25, 38]. Practically, the droplet size decreases when the intensity of ultrasonic waves, sonication time, power level, and emulsifier concentration increase [25, 39, 40]. The type and amount of the emulsifier used, as well as the viscosity of the oil and aqueous phases affect the homogenization efficiency [16, 23, 25, 40]. All the above parameters should be first optimized to produce nanoemulsions of the right droplet size. It is noteworthy to mention that sonication methods may lead to protein denaturation, polysaccharide depolymerization, or lipid oxidation during homogenization. Thus, this technology has not yet been proved as efficient for industrial-scale applications [3].
Rotor/stator devices (such as Ultra-Turrax) do not provide a good dispersion in terms of droplet sizes when compared to other high-energy techniques. The efficiency of such devices when calculated was 0.1%, where 99.9% is dissipated as heat during the homogenization process, so the energy provided mostly being dissipated, generating heat [12, 13, 17].
The low-energy methods are dependent on the internal chemical energy of the system [13, 41]. The nanoemulsions here are formed as a result of phase transitions that occur during the emulsification process due to the change in the environmental conditions such as temperature or composition [20], applying constant temperature and changing the composition or using constant composition and changing the temperature [42, 43, 44]. The composition of the emulsion such as surfactant-oil-water ratio, surfactant type and ionic strength in addition to the environmental conditions temperature, time history and stirring speeds greatly affect the droplet size [17, 44].
Low-energy approaches can produce smaller droplet sizes than high-energy approaches; however, low-energy approaches can be applied to limited types of oils and emulsifiers. For example, proteins or polysaccharides cannot be used as emulsifiers; alternatively, high concentrations of synthetic surfactants should be used to form nanoemulsions by low-energy approaches. This factor limits the use of such approaches in many food applications [4, 9]. The low-energy approaches are listed in the next section and represented in Figure 3.
Schematic representation of four devices utilized in low-energy approach for production of food-grade nanoemulsions: A. membrane emulsification method; B. spontaneous emulsification method; C. phase inversion temperature method; D. emulsion inversion point method; a, rotating membrane; b, disperse phase; stabilized droplets of colloidal particles; d, surfactant and oil phase, e, aqueous phase; f, surfactant moves to water phase; g, oil in water emulsion; H. W/O emulsion; I. O/W emulsion; and J. O/W nanoemulsion.
This technique involves the formation of a dispersed phase (droplets) through a membrane into a continuous phase (Figure 3). It requires less surfactant and produces emulsions with a narrow size distribution range than the high-energy techniques. Unfortunately, the low flux of the dispersed phase through the membrane is a strong limitation during scale-up of this method [29].
This technique involves spontaneous formation of nanoemulsion as a result of the movement of a water miscible component from the organic phase into the aqueous phase when the two phases are mixed together (Figure 3) [17]. The organic phase is usually a homogeneous solution of oil, lipophilic surfactant and water-miscible solvent, and the aqueous phase consists of water and hydrophilic surfactant [19]. The spontaneous characteristic of this technique results from the initial nonequilibrium states when the two liquids are mixed without stirring. Accordingly, spontaneous emulsification is brought about by various methods such as diffusion of solutes between two phases, interfacial turbulence, surface tension gradient, dispersion mechanism or condensation mechanism. These mechanisms are highly influenced by the systems’ compositions and their physicochemical features such as the physical properties of the oily phase and nature of the surfactants [19]. The size of the droplets produced can be controlled by varying the compositions of the two initial phases, as well as the mixing conditions [9].
There are many physicochemical mechanisms that can be utilized for spontaneous emulsification [45]. When two immiscible phases like water and oil are brought into contact with each other, and one of the phases contains a component that is partially miscible with both phases such as amphiphilic alcohol or surfactant. In this case, some of the components that are partially miscible with both phases will move from its original phase into the other one causing an increase in oil-water interfacial area, interfacial turbulence, and spontaneous formation of droplets. In this method, the variation in the compositions of the two initial phases, and the mixing conditions can control the size of the droplets produced.
McClements and Rao [9] compared the spontaneous emulsification method of producing nanoemulsions with the high-energy method named the microfluidizer. The surfactant-oil-water system used consisted of 15.4 wt% nonionic surfactant, 23.1 wt% medium-chain triglycerides (MCT), and 61.5% water, with the surfactant containing a 50:50 mixture of a hydrophilic (Tween 80) and lipophilic (Tween 85) surfactant. The microfluidization method produced droplets with a diameter of about 110 nm, whereas the spontaneous emulsification method could produce droplets with diameters around 140 nm. This simple experiment demonstrated that nanoemulsions could be produced using the spontaneous emulsification method, provided that the system composition was optimized, that is, surfactant, oil, and water contents.
This process itself increases entropy and thus decreases the Gibbs free energy of the system [17]. In pharmaceutical industry, the systems prepared by spontaneous emulsification method are referred to either as self-emulsifying drug-delivery systems (SEDDS) or as self-nano-emulsifying drug delivery systems (SNEDDS).
This method depends on the rapid diffusion of a water-miscible organic solvent that contains a lipophilic functional compound in the aqueous phase promoting the formation of nanoemulsions. This rapid diffusion enables the one-step preparation of nanoemulsion at low-energy input with high yield of encapsulation. At the end, the organic solvent is evaporated from the nanodispersion under vacuum [20, 21]. However, the use of this technique is limited to water-miscible solvents [21].
Another low-energy approaches are the phase inversion methods that use the chemical energy released as a result of phase transitions that occur during the emulsification. Nanoemulsions have been formed by inducing phase inversion in emulsion from a W/O to O/W form or vice versa by either changing the temperature in the phase-inversion temperature (PIT), the composition in phase-inversion composition (PIC) or emulsion-inversion point (EIP) [6].
This method depends on that at a fixed composition and by changing temperature, the nonionic surfactants changes their affinities to water and oil through the changes in the optimum curvature (molecular geometry) or relative solubility of nonionic surfactants [46, 47]. Using the PIT method, nanoemulsions are spontaneously formed by varying the temperature-time profile of certain mixtures of oil, water, and nonionic surfactant, thus nanoemulsions are formed by suddenly breaking-up the microemulsions maintained at the phase inversion point by a rapid cooling [48] or by a dilution in water or oil [17] the formed nanoemulsions are kinetically stable and can be considered as irreversible [3]. PIT also involves the controlled transformation of W/O emulsion to O/W emulsion or vice versa through an intermediate liquid crystalline or bicontinuous microemulsion phase [9].
The key for this phase inversion is the temperature-induced changes in the physicochemical properties of the surfactant (Figure 3). Here the molecular geometry of a surfactant is dependent on the packing parameter, p = aT/ aH, where, aT is the cross-sectional area of the lipophilic tail-group and aH is the cross-sectional areas of the hydrophilic head-group [49].
In water, the surfactant molecules tend to associate with each other forming a monolayer due to the hydrophobic effects, and these monolayers have an optimum curvature that causes the most efficient packing of the molecules [49]. The packing parameter p determines the optimum curvature of the surfactant monolayer, when p < 1, the optimum curvature is convex and the surfactant favors the formation of O/W emulsions, for p > 1 the optimum curvature is concave favoring W/O emulsions, while for p = 1, monolayers have zero curvature, where surfactants do not favor either O/W or W/O systems and instead lead to the formation of form liquid crystalline or bicontinuous systems (Figure 3).
The relative solubility of surfactants in oil and water phases usually changes with temperature due to the physicochemical properties and packing parameter (p) of nonionic surfactants [50, 51]. At a particular temperature, the solubility of the surfactant in the oil and water phases is approximately equal, and this is known as phase inversion temperature or PIT at which an oil-water-surfactant system changes from an O/W emulsion to a W/O emulsion as the packing parameter equals unity (p = 1). At temperatures greater than the PIT (≈ T > PIT +20°C), the head group becomes progressively dehydrated and the solubility of the surfactant in water decreases, it becomes more soluble in oil, its p > 1, and the formation of a W/O emulsion is favored. When the temperature is decreased (≈T < PIT-30°C), the head group of a nonionic surfactant becomes highly hydrated and tends to be more water soluble (p < 1), favoring the formation of O/W emulsions [9].
Above PIT, the surfactant molecules are being present predominantly within the oil droplets as they are more oil-soluble at this temperature. When this system is quench-cooled below the PIT, the surfactant molecules rapidly move from the oil phase into the aqueous phase just like the movement of water-miscible solvent in the spontaneous-emulsification method, which leads to the spontaneous formation of small oil droplets because of the increase in interfacial area and interfacial turbulent flow generated. For this reason, Anton et al. [51] proposed that he formation of nanoemulsions by the PIT method has a similar physicochemical basis to the spontaneous emulsification method.
This process is characterized by being simple, prevents the encapsulated drug being degraded during processing, consumes low amounts of energy, and allows an easy industrial scale-up [17].
PIC method is very close to PIT method, but here the optimum curvature of the surfactant is altered by changing the formulation of the system, rather than the temperature [51]. For example, an O/W emulsion can be phase inverted to a W/O emulsion by adding salt as in this case the packing parameter increased and becomes greater than unity (p > 1) due to the ability of the salt ions to screen the electrical charge on the surfactant head groups [52]. Alternatively, a W/O emulsion containing a high salt concentration can be phase inverted to O/W emulsion by dilution with water in order to reduce the ionic strength below some critical level. Another PIC method for preparation of nanoemulsions is to change the electrical charge and stability of emulsions by changing the pH. The carboxyl groups of fatty acids are uncharged at low pH (pH < pKa) and have a relatively high oil solubility (p > 1), so they could stabilize W/O emulsions, but at high pH, they become ionized so they become more water-soluble (p < 1) and stabilize O/W emulsions. Consequently, nanoemulsions can be formed by increasing the pH of a fatty acid-oil-water mixture from below to above the pKa value of the carboxyl groups [41, 52].
This method involves changing the composition of the system at a constant temperature. In order to create kinetically stable nanoemulsions, the structures are formed through a progressive dilution with water or oil [17]. In EIP methods, the change from W/O to O/W or vice versa needs a catastrophic-phase inversion, rather than a transitional-phase inversion as with the PIC or PIT methods [53]. A transitional-phase inversion occurs when the characteristics of a surfactant are changed through adjusting one of the formulation variables, such as the temperature, pH, or ionic strength. A catastrophic-phase inversion occurs by changing the ratio of the oil-to-water phases while the surfactant properties remain constant. The emulsifiers used in catastrophic-phase inversion are usually limited to small molecule surfactants that can stabilize both W/O emulsions (at least over the short term) and O/W emulsions (over the long term) [9].
McClements and Rao [9] showed practically that increasing the amount of water in a W/O emulsion consisting of water droplets dispersed in oil with continuous stirring can cause the formation of additional water droplets within the oil phase at low amounts of added water; however, once a critical water content is exceeded, the coalescence rate of water droplets exceeds the coalescence rate of oil droplets, and so phase inversion occurs from a W/O to an O/W system (Figure 3). Thus, the catastrophic-phase inversion is usually induced by either increasing (or decreasing) the volume fraction of the dispersed phase in an emulsion above (or below) some critical level.
The value of the critical concentration where phase inversion occurs, as well as the size of the oil droplets produced, depends on process variables, such as the stirring speed, the rate of water addition, and the emulsifier concentration [53].
Nanoemulsions have diverse applications such as drug delivery, pharmaceuticals, cosmetics, and food [5]. In this section, we focus on the applications of nanoemulsions in food industry. Nanoemulsions have been used as a suitable form to improve the digestibility of food, bioavailability of active components, pharmacological activities of certain compounds, and solubilization of drugs. Some applications are listed below.
One of the most important applications of nanoemulsions in food industries is the encapsulation of lipophilic components such as vitamins, flavors, and nutraceuticals [9]. Encapsulation is a useful tool to entrap a bioactive ingredient in a core or a fill within a carrier (coating, matrix, membrane, capsule, or shell) for improving the delivery of bioactive molecules within living cells [54].
This technology has many applications in food industry for masking the unpleasant taste or smell of some bioactive materials, increasing the bioavailability of some components, improving the stability of food ingredients, decreasing air-induced food degradation or decreasing the evaporation of food aroma [54]. One of the most interesting applications of encapsulation in food industry is probiotics. Probiotics are defined as microorganisms that provide health benefits when consumed in adequate amounts [55, 56]. Encapsulation of bioactive compounds in nanoemulsion-based delivery system was achieved for resveratrol (Figure 4) [57].
Applications of nanoemulsions-based delivery systems in food industry.
Nanoemulsions from food-grade ingredients are being increasingly utilized to encapsulate biologically active lipids such as Omega-3 fatty acids, polyunsaturated fatty acids (PUFAs) [9]. Omega-3 fatty acid supplementation may be protective effect against cancer, cardiac death, sudden death, cognitive aging, asthma, inflammation and myocardial infarction. α-Linolenic acid (ALA), an Omega−3 fatty acid, is one of two essential fatty acids together with linoleic acid (Figure 4). ALA is necessary for health and cannot be synthesized within the human body.
Low bioavailability of some naturally occurring active compounds hinders their efficient pharmacological activities. Nanoemulsions have been used as a suitable form to increase bioavailability of natural extracts. Curcumin, 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (Figure 4), is a yellow-colored polyphenolic compound isolated from the rhizomes of turmeric (Curcuma longa, family Zingiberaceae) [58]. Curcumin has been used as a natural coloring agent health benefits such as anticarcinogenic, antioxidant, anti-inflammatory, and antimicrobial [59]. Curcumin nanoemulsions showed significant inhibition of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation [60]. However, low bioavailability hinders the efficiency of orally administrated curcumin. Flavored nanoemulsions have been prepared with improved curcumin digestibility compared to directly taken curcumin [60, 61].
Additionally, nanoemulsion formulation of oil-soluble vitamins such as alpha-tocopherol enhanced their oral bioavailability and pharmacological effects [62, 63]. α-Tocopherol, a type of vitamin E, is mainly present in olive and sunflower oils (Figure 4). Vitamin E supplements have important antioxidant, anticancer as well as cardiovascular protective activities.
Moreover, nanoemulsion preparations improved the bioavailability quercetin or methylquercetin [64]. Quercetin, a polyphenol from the flavonoid group of, has been found in many fruits, vegetables, leaves, and grains (Figure 4). Quercetin supplements have been promoted as antioxidant and anticancer.
Food digestibility is a measure of how much of food is absorbed by the gastro-intestinal tract into the bloodstream. Nanoemulsions have been used as a suitable form to improve digestibility characters of food and natural extracts.
β-Carotene is a red-orange pigment that is found in plants such as carrots and colorful vegetables. β-Carotene is a member of the carotenes, which are terpenoids (isoprenoids), biosynthesized from geranylgeranyl pyrophosphate (Figure 4). β-Carotene is the best-known provitamin A carotenoid. β-Carotene flavored nanoemulsion with improved digestibility has been applied [20, 33, 65].
Nanoemulsion formulation has been applied to increase the solubilization of phytosterols [66]. Phytosterols have been shown to lower the blood cholesterol, and therefore, they reduce the risk of coronary heart diseases. Among phytosterols, β-sitosterol has been isolated from many vegetables and fruits (Figure 4). Moreover, nanoemulsions formulas increased also the solubilization of lycopene [66]. Lycopene, a carotenoid pigment and phytochemical, has been found in tomatoes, other red fruits and vegetables (Figure 4). Lycopene has potential effects on prostate cancer and cardiovascular diseases.
Nanoemulsions have gained great attention and popularity during the last decade due to their exceptional properties such as high surface area, transparent appearance, robust stability, and tunable rheology. The most commonly known preparation approaches for nanoemulsions include high-energy approaches such as high-pressure valve homogenization, microfluidizers and ultrasonic homogenization, and low energy methods such as spontaneous emulsification, phase inversion composition, phase inversion temperature and emulsion inversion point. There is little understanding of the possible industrial relevance of many of these approaches as the physics of nanoemulsion formation is still semi-empirical and rational scale-up procedure have not been widely explored. The interest in nano-emulsion preparation and application is growing, but few of the numerous ideas reported become commercial final applications. Nanoemulsions are considered one of the most promising systems to improve solubility, bioavailability, and functionality of nonpolar active compounds. Food industry seeks to use these systems for the incorporation of the lipophilic functional compounds for the development of innovative food products. The application of nanoemulsions to food systems still poses challenges that need to be addressed both in terms of the production process, especially their cost, and of the characterization of both the resulting nanoemulsions and the food systems to which they will be applied in terms of product safety and acceptance.
Although nanoemulsions have potential advantages over conventional emulsions such as the preparation of transparent foods and beverages, their improved bioavailability, and physical stability. However, there are a number of regulatory aspects that should be overcome first to allow the wide applications of nanoemulsions.
First of all, most of the components used in formulation of nanoemulsions either in low-energy or high-energy approaches are unsuitable for widespread utilization within the food industry such as synthetic surfactants, synthetic polymers, synthetic oils, or organic solvents. Thus, food-grade ingredients such as flavor oils, triglyceride oils, proteins, and polysaccharides must be utilized in the formulation of food nanoemulsions as these ingredients are legally accepted, label-friendly and economically viable.
Second, in order to fabricate food-grade nanoemulsions on the industrial scale, suitable processing operations should be employed to obtain economic and robust products. Accordingly, many of the identified approaches which were developed in the research laboratories are not suitable for industrial production especially the low-intensity approaches, which could not be yet investigated in industrial scale production. At present, the high-intensity approaches only are utilized for production of nanoemulsions in the food industry.
Finally, there are certain safety concerns associated with the utilization of very small lipid droplets in foods. For example, the route of absorption, the bioavailability or potential toxicity of a lipophilic component encapsulated within nanometer-sized lipid droplets are considerably different from those dispersed within a bulk lipid phase. For these reasons, extensive studies are strongly needed in the area of nanoemulsion safety.
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