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Toward a Spatiotemporal Model of Oxidation in Lipid

Dispersions: A Hypothesis-Driven Review
Mickaël Laguerre,* Mathieu Tenon, Antoine Bily, and Simona Birtić

1. Introduction
Unsaturated lipids are prone to get oxidized through a sequence of reactions
known as lipid oxidation. From a phenomenon considered at the beginning as a Contemporary view of lipid oxidation is
largely inherited from its chemical descrip-
mere chemical process and described by the triptych of initiation, propagation,
tion as a sequence of three reaction steps:
and termination, the vision of lipid oxidation has progressively evolved initiation, propagation, and termination.[1]
to further integrate the physical dimension of the phenomenon. Despite It is generally admitted that during ini-
tremendous research efforts, however, this sequence of reactions is not yet well tiation, unsaturated lipids, LH, in the
understood, especially in lipid dispersions where many facts are still inexplica- presence of initiators or catalysts such as
free radicals, heat, light, photosensitiz-
ble and unpredictable under the current paradigm. Here, the aim is to suggest
ers, metal ions, or metalloproteins, lose
that the main reason why a better understanding has not already been achieved a hydrogen atom and produce ab initio
is that the reactional network is not yet organized in a coherent spatiotemporal lipid-derived free radicals, L• (reaction 1).
framework. The novel concepts and hypotheses proposed in this article may
help redirecting a significant part of research efforts toward the establishment initiator
← L ∙ + H∙
LH ←←←←←←←←←←←←→ (reaction 1)
of a spatially and temporally resolved model of oxidation in dispersed lipids.
Practical Application: Predicting how oxidation spreads in lipid dispersions
The rationale behind this process is sim-
represents a goal of crucial importance for academia but also for industry. ple: the loss of hydrogen atom takes place
Such prediction models would indeed greatly help food manufacturers prevent most readily at the site where the energetic
oxidation by using the most adapted antioxidative strategies for their specific cost associated to this hydrogen abstrac-
products. To achieve such an objective, it is proposed that the first thing tion is the lowest. Because the energetic
to do is to go beyond the extremely reductive and narrow framework in which cost to abstract hydrogen atoms decreases
with unsaturation (i.e., number of bis-allylic
this chemical process has been locked in. Indeed, while lipid dispersions
hydrogens), it has long been thought that
are composed of a multitude of lipid colloids, researchers usually consider the more unsaturated a lipid, the more
oxidation at the sole level of an individual droplet or membrane. Instead, lipid oxidizable it was.[2,3] However, when dis-
oxidation is advocated as a dynamic trafficking of chemical species within persing double bond rich lipids, including
large communities of different colloidal objects such as droplets, membranes, omega-3 lipids, in water, they are surpris-
ingly more resistant to oxidation than lipids
or micelles dispersed in water—a system that dubbed “colloidal ecosystem”.
from less unsaturated oils.[4] Such findings
This might represent a scale complementary to the scales of individual shed doubt on the predictive power of a
colloids or molecules that were the sole consideration so far to try to represent model based only on the chemical ability of
lipid oxidation. Only then can one hope to effectively apply modeling lipids to oxidize.
and “omics” approaches, as is explained in more details in this article. Moreover, these relatively recent results
together with others, much older, have
drawn our attention to the fact that the ox-
idative stability of lipids can be modulated
by the physicochemical environment in which they are found.[5–7]
In bulk oils and organic solutions, as long believed and expected,
Dr. M. Laguerre, M. Tenon, Dr. A. Bily, Dr. S. Birtić
Naturex SA, Science and Technology Department omega-3s such as eicosapentaenoic acid (EPA) and docosahex-
Givaudan Flavour Division aenoic acid (DHA) are more sensitive to oxidation than less un-
250 rue Pierre Bayle, BP 81218, F-84911 Avignon Cedex 9, France saturated lipids. However, the opposite may occur when the same
E-mail: mickael.laguerre@givaudan.com lipids are dispersed in water as micellar or emulsified media[8,9]
© 2019 The Authors. European Journal of Lipid Science and Technology
or in a liposome model.[10] Through history, as the theory of lipid
Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. This is oxidation has been mainly developed on lipids in bulk-oil form
an open access article under the terms of the Creative Commons or solubilized in organic solvents, it is not surprising that para-
Attribution License, which permits use, distribution and reproduction in doxes, such as the omega-3 paradox [4] or the polar paradox,[11]
any medium, provided the original work is properly cited. have emerged as researchers were progressively turning their in-
DOI: 10.1002/ejlt.201900209 struments toward the terra incognita of dispersed lipids.

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Our thinking about lipid oxidation has thus changed a lot over
the past two decades. From a phenomenon considered at the be-
ginning as an essentially chemical process and described by the
classical triptych of initiation, propagation, and termination, our
vision has progressively evolved to further integrate the physical
dimension of the phenomenon, especially its spatiality. This ar-
ticle is not intended to oppose the chemical version to the more
physical version of the model, but rather tries to make them co-
exist so that the two models enrich each other. In particular, we
wish to suggest that the main reason why a better understanding
of the oxidation of dispersed lipids has not already been achieved
is that the reactional network is not yet organized in a coherent
spatio-temporal framework.

2. Toward Space-Resolved Models: The Necessary

First Step
To cope with this heterogenous media where lipids form a Figure 1. Effect of initial methyl linoleate hydroperoxide on the oxidation
diverse range of colloidal structures in water such as droplets, of methyl linoleate micelles induced by copper at 37 °C. [MeLH] = 74 mm;
[CuCl] = 100 nm; [SDS] = 0.5 m. Methyl linoleate hydroperoxide prepared
micelles, particles, or membranes—hereinafter refer to as
separately was added to methyl linoleate prior to the preparation of mi-
“colloids”—, efforts were brought to develop a more physically celles. Reproduced with permission.[14] Copyright 1992, Academic Press,
ground model of lipid oxidation with a spatial resolution. Such a Inc.
spatially resolved approach would not make sense in a perfectly
homogeneous system such as organic solutions of lipids where
handling or extraction. For example, the purchase of high-purity
it can be assumed that there are no microdomains or phases
(99.9%) fatty acids is no safeguard, since purity refers to contam-
and that all lipid molecules are solvated by the solvent. But
ination with other fatty acids, not to hydroperoxide content.[13] In
this can become suddenly important in lipid dispersions in
lipids containing hydroperoxides, the contribution of reaction 1
which the molecular species can be distributed in different
to initiation is quickly overshadowed by that of lipid hydroper-
compartments depending on their affinity for a particular phase.
oxide decomposition, especially in the presence of metal cations
Anyone who wants to combine a space-resolved model with
(reactions 2 and 3). Measuring the oxygen consumption in a
the standard chemical description of oxidation as a sequence of
lipid dispersion of methyl linoleate oxidized by copper at 37 °C,
steps (initiation, propagation, and termination) will intuitively
Yoshida and Niki [14] observed that “appreciable oxidation will not
try to assign a particular phase to each reaction step. At first
take place if the lipid is completely free from contaminated hydroperox-
sight, there is probably no reason to assign a precise location for
ide.” They came to this conclusion because plot of Figure 1 fairly
termination reactions, of which the chances of occurrence pre-
goes to the origin.
cisely depend on the chemical environment (e.g., alkoxyradical 𝛼
The type of initiation involving the presence of pre-existing
and 𝛽 scissions are favored near the water phase core,[12] while
LOOHs has been referred to as “hydroperoxide-dependent
radical–radical recombinations are enhanced in the lipid phase).
initiation”[15] (or sometimes “secondary initiation”[16] ), and we
However, relative to initiation and, at a lesser extent, to prop-
subscribe to this hypothesis which has the merit of clearing up
agation, it could be interesting to know if they occur in only
the initial horizon on which the oxidation opens. While the de-
one phase. This could possibly help to design highly effective
composition of lipid hydroperoxides is often viewed as an end, it
antioxidant strategies by precisely adjusting the position of the
is probably by this very end that everything begins.
antioxidant molecules in the most appropriate phase.
The four types of reactions that lead to a decomposition of lipid
hydroperoxides, namely metal catalyzed-oxidation (reaction 2),
metal-catalyzed reduction (reaction 3), heat or UV light-induced
2.1. Where Does Initiation Take Place in Lipid Dispersions? homolytic scission (reaction 4), and bimolecular decomposition
(reaction 5), are all compatible with the hypothesis of an interfa-
We think it is reasonable to suggest that initiation would in most cial initiation (except in one case that will be mentioned below).
cases occur in the interfacial area between lipids and water. To
reach this conclusion, we must assume that the decomposition LOOH + Fe3+ → LOO∙ + H+ + Fe2+ (reaction 2, slow)
of “pre-existing” lipid hydroperoxides (LOOHs) is the chemical
LOOH + Fe2+ → LO∙ + OH− + Fe3+ (reaction 3, fast)
process that provides the first free radicals; hence, this is the
chemical process that serves as a dominant initiation mecha- Heat, UV light
nism. Clearly, lipids (either purchased from commercial sources ← LO∙ + ∙ OH
LOOH ←←←←←←←←←←←←←←←←←←←←←←←→ (reaction 4)
or extracted from biological samples) are never completely free LOOH + LOOH → LOO-H … OOH (H-bonded dimer) →
of LOOHs which can be formed by photo- or enzymatic oxi-
dation in vivo or simply generated by lipid autoxidation during LOO∙ + LO∙ + H2 O (reaction 5)

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Regarding metal-induced decomposition of LOOHs (reactions 2
and 3), it has been shown that metal catalysts distribute rather
heterogeneously in dispersions where lipid colloids are nega-
tively charged on their surface. This is the case in oil-in-water
emulsions stabilized with anionic surfactants[17] or in lecithin-
based liposomes for example.[18] In these systems, metal cations
tend to accumulate at the lipid colloid surface due to coulom-
bic interactions with the charged head groups. Even in the case
of neutral surfaces for which there is no reason to think metal
cations are associated with them, these metals, which are sol-
ubilized in the aqueous continuous phase, can still approach
enough the interface to encounter LOOHs. Lipid/water inter-
faces thus appear as a privileged contact region where LOOHs
can react with metal cations. The only experimental case which
seems to preclude such a metal-induced interfacial initiation, is
when oil-in-water emulsions, micelles, or membranes are deco-
rated with positively charged emulsifiers, surfactants, or surface
charge modifiers (such as stearylamine[19] ) which can repel cation
metals from the colloid surface. This can be an efficient strategy
to design lipid dispersions with an improved oxidative stability.
Previous results have shown that ferric iron/ascorbate-induced
oxidation of corn oil-in-water emulsions was much greater in
sodium dodecyl sulfate (SDS, anionic) emulsions than in dode-
cyltrimethylammonium bromide (cationic) emulsions, suggest-
ing that iron association with the emulsion droplet surface in-
creases lipid oxidation rates.[20]
In micellar system, several authors have found that surface
charge can influence lipid oxidation. Both iron and copper were
capable of oxidizing methyl linoleate in negatively charged SDS
micelles but not in positively charged tetradecyltrimethylammo-
nium bromide (TTAB) micelles, although, for unclear reasons,
inhibition of linoleate oxidation by TTAB could be overcome by
addition of tert-butyl hydroperoxide.[14] Ferrous ions have also
been found to catalyze the formation of alkoxyradicals from
linoleic acid hydroperoxides (reaction 3) and to promote lipid ox-
idation of linoleic acid in SDS but not in TTAB micelles.[21,22] In-
terestingly, oxidation of linoleic acid in TTAB micelles could be
stimulated by iron in the presence of nitrilotriacetic acid, a nega-
tively charged iron chelator.[21]
Likewise, in a membrane system oxidized by ferrous iron and
ascorbic acid, Kunimoto et al.[19] reported that negatively charged
liposomes (phosphatidylcholine:cholesterol) coated with anionic
dicetylphosphate were the most prone to oxidation, followed by
neutral liposomes. Positively charged liposomes decorated with
stearylamine were almost insensitive to oxidation. Almost thirty
years later, this has been confirmed in liposomes stored at 50 °C
in the dark with no artificial inducer of oxidation. After cationic
chitosan was electrostatically deposited onto lecithin liposomes,
a significant delay was observed in LOOH and hexanal genera-
tion compared to negatively charged liposomes.[18] Lipid oxida-
tion was strongly inhibited by EDTA, indicating that transition
metals were major prooxidants in the studied liposome system.
The fact that transition metals were important prooxidants sug-
gests that inhibition of lipid oxidation by the chitosan coating was
due to the formation of a cationic layer on the surface of the lipo-
somes that can electrostatically repel transition metals away from
the lipid-water interface.
Beyond simple man-made systems, naturally occurring parti-
cles, such as LDLs, may constitute another example of dispersed
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lipids on the surface of which catalytically active metal cations are
bound and initiate oxidation. Electron spin resonance measure-
ments showed that Cu2+ binds to the LDL protein.[23] On the other
hand, fluorescence spectroscopy investigations[24] suggested that
the copper ions bind in the vicinity of the lipid phase of LDL.
Taken together, this led Esterbauer et al.[25] to consider that the
initiating radicals are likely to be formed site specifically at—or
near—a tryptophan-copper complex, that is, at the LDL surface,
which is all the more likely that zeta potential of LDL is slightly
negatively charged (−5 to −20 mV).[26,27]
A crucial advantage of considering the hypothesis of a
hydroperoxide-dependent initiation mechanism at the interface
is that LOOH decomposition reactions by aqueous metal cations
do not seem to suffer from the same topological difficulties as
the conventionally proposed bis-allylic H-abstraction reaction be-
tween a hypothetical water-soluble initiator (whose exact chemi-
cal nature is rarely precised, reaction 1) and an unsaturated lipid
LH. In the set of reactions we proposed (metal-induced LOOH
decomposition at the interface), indeed, the hydroperoxy group
OOH can be oriented toward the aqueous phase via H-bonded in-
teractions with water molecules, making the reactional group of
LOOH fairly available to iron or any other metal catalysts present
in the aqueous phase or bound to the colloid surface. Therefore,
we assume that there is no major topological issue for this reac-
tion (O─OH and OO─H cleavages by Fe2+ and Fe3+ , respectively)
to occur at the interface; an assumption already made thirty years
ago by Fukuzawa et al.:[22] “in SDS micelles, ferrous iron can react
with hydrophilic hydroperoxy groups of LOOH in the surface region of
micelles because the positively charged ferrous iron interacts with neg-
atively charged sulfate groups of SDS and localizes near the micellar
surface.”
On the contrary, relative to the latter mechanism often
described in literature (hydroperoxide-independent initiation
mechanism, reaction 1) where a water-soluble initiator—such as
hydroxyradical for example—abstracts a H-atom from an unsat-
urated lipid LH, it is more difficult to envision how this reaction
can occur at lipid/water interfaces. Indeed, in emulsions, mem-
branes or any other colloidal dispersions in water, the acyl chains
stretch in the lipid phase behind the interface which is composed
of polar head groups. Even in highly unsaturated fatty acids that
are capable of folding, their saturated ends are the ones that are
the nearest to the interface. Under such conditions, the bis-allylic
positions susceptible to H-abstraction are buried well within the
oil. To our knowledge, there is no unsaturated acyl chain that can
be looped around so as to position its bisallylic hydrogen atoms
at the interface. How then can initiation targets be reached by
catalysts at the interface? This seems topologically impossible.
In stark contrast, since the LOOH interfacial decomposition in-
duced by metal cations (i) is topologically possible and (ii) gen-
erates free radicals from non-free radical lipids (the definition of
the initiation), it should, in our opinion, be preferred as an ini-
tiation mechanism to other mechanisms described above which
suffer from serious topological mismatches.
Two other putative interfacial initiation mechanisms involving
LOOH decomposition are heat (or UV light)-induced homolytic
scission (reaction 4) and bimolecular decomposition (reaction 5).
At first sight, since these two pathways do not involve water-
soluble metal ions and solely require the presence of LOOHs,
there is no reason to think that the reaction is particularly
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40 37
35
Interfacial tension (mN/m)
30 LH
LOOH
21
20
20
14
10
0
Control Linoleic Methyl
acid linoleate
Figure 2. Surface-activity of some lipids in a hexadecane/water mixture.
After Nuchi et al.[28]
favored at the lipid/water interface. However, when considering
the LOOHs surface-activity, then again, the interface appears to
be a preferred location for their metal-independent decomposi-
tion to occur. In a study related to LOOHs derived from trili-
nolein, linoleic acid, and its methyl ester, Nuchi et al.[28] indeed
showed that all of the different LOOHs reduce more the inter-
facial tension between hexadecane and water than their nonoxi-
dized parents (Figure 2). This means that LOOHs are prone to ac-
cumulate at the lipid–water interface. Likewise, Berton-Carabin
et al.[29] showed that oxidized stripped sunflower oil decreases the
tension at the interface formed with water, while the parent non-
oxidized stripped oil does not. Again, this indicates that oxygen-
bearing surface-active species, presumably LOOHs, accumulate
at the interface with water. In membrane systems, LOOHs float
on the LDL surface.[30] Because reactions 4 and 5 produce lipid
derived free radicals from non-radical molecules (LOOHs), they
can both serve as plausible initiation mechanisms taking place at
the interface (where LOOHs naturally accumulate), similarly to
metal-induced interfacial LOOH decomposition, with which they
can work together or competitively.
The occurrence of an interfacial initiation mediated by LOOH
decomposition reactions may be further complicated as the lipid
phase before being homogenized—to form an oil-in-water emul-
sion for example—, already contains nanoscale compartments
called reverse micelles organized around a water core and that
form lipid/water interfaces with bulk lipids.[31,32] Since these re-
verse micelles are suspected to be the nanoreactors in which lipid
oxidation takes place in bulk oils (the initiation site), the question
remains regarding emulsions. It is unknown whether these re-
verse micelles maintain their structure once the oil is converted
to an oil-in-water emulsion.[33] In such emulsions, reverse mi-
celles could be lost as the surface-active compounds migrate to
the surfaces of the lipid droplets. Conversely, they could persist
and change their structures if the emulsifier used to produce the
emulsion prevents them from migrating to the lipid droplet sur-
faces or if a portion of the emulsifier and water migrate to the
interior of the lipid droplets.
Finally, indirect evidences of the occurrence of initiation at the
interface of multiphase systems may be found in studies report-
ing a cut-off effect in antioxidant activity. So far, more than a
dozen of these studies have shown in media as diverse as oil-
in-water emulsions, liposomes, or cell populations, that within
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a homologous series of antioxidants with increasing hydropho-
bicity, the optimal activity is systematically obtained for the an-
tioxidant which partitions the most at the interface.[34–37] This
26 constitutes an additional argument for the hypothesis of an in-
terfacial initiation. Accordingly, antioxidants which locate at the
17 interface would be able to inhibit lipid oxidation at the initiation
stage, while antioxidants located elsewhere do not. Such an “initi-
ation breaking” mode of action would thus presumably boost the
activity of interfacial antioxidants and would explain, at least par-
tially, the cut-off effect observed in homologous series by many
research groups.
Trilinolein
2.2. Where Does Propagation Take Place in Lipid Dispersions?
Now that we tentatively assigned a location to the initiation stage,
let us try to do the same with the propagation phase. Propagation
is generally described as a fast addition of 3 O2 on the carbon-
centered lipid radical, L• , that is supposed to result from the ini-
tiation step (reaction 1) to form a peroxyradical (reaction 6), fol-
lowed by a slow hydrogen abstraction from a vicinal unsaturated
lipid, L′H, by the formed peroxyradical (reaction 7).
L∙ + 3 O2 → LOO∙ (reaction 6, fast, 109 M−1 s−1 )
∙
LOO∙ + L′ H → LOOH + L′ (reaction 7, slow, <103 M−1 s−1 )
Pushing further this standard propagation mechanism, it is rea-
sonable to ask the question whether the propagation phase would
start at the time when a lipid radical, L• , meets oxygen at the in-
terface, and then spread to the oil interior to oxidize an unsat-
urated lipid, L’H, thus forming a lipid radical, L’• , and a lipid
hydroperoxide, LOOH (reaction 7). In systems in which free rad-
icals are not generated by artificial azo-initiators (i.e., “real life”
oxidative models), we have seen that this exact pathway, which
implies the preliminary formation of L• at the interface, is un-
likely to occur for topological reasons. Indeed, in LH, the bis-
allylic positions susceptible to H-abstraction are buried within
the oil and are inaccessible to most water-soluble oxidative cata-
lysts such as transient metals. Furthermore, since oxygen is more
soluble in oil than in water, it implies that L• has to migrate to the
lipid colloid interior to encounter oxygen and react with it. In-
stead, we propose an alternative initiation/propagation scenario
in which LOOHs directly provide peroxyradicals and alkoxyrad-
icals at the interface (hydroperoxide-dependent initiation mech-
anism). In this case, 3 O2 addition is no longer required at this
stage (i.e., the formation of the first H-abstracting radical) and
the propagation step is entered directly.
That being said, if such a scenario actually occurs during oxi-
dation, the hydrogen abstraction reaction by peroxyradicals and
alkoxyradicals would logically lead to a concomitant accumula-
tion of LOOHs (reaction 7) and hydroxylipids LOH (reaction 8).
LO∙ + LH → LOH + L∙ (reaction 8)
But, as Schaich noted, the hydroxylipids are surprisingly present
in very small proportions in oxidized lipids relative to LOOHs.[38]
At first sight, this suggests either that i) hydroxylipids are
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•O
H Cyclization
HOOC(CH2)7 (CH2)4CH3
O O
H + LH
HOOC(CH2)7 OOH (CH2)4CH3
Figure 3. Formation of a lipid epoxy-hydroperoxide from a linoleate alkoxyradical.
O precluding any role in H-abstraction and the resulting propaga-
O O
or
L1 L2 L1 + L2 L1 + L2
Figure 4. The general scheme of 𝛼- or 𝛽-scissions (C─C cleavages) of
alkoxyradicals.
intermediates quickly converted into hitherto undetected
molecules (unlikely hypothesis), or that ii) alkoxyradicals are
somewhat converted into another radical before they abstract
a hydrogen from a lipid. Regarding this matter, Gardner[39]
suggested that alkoxyradicals rearrange into epoxyallylic rad-
icals. If so, epoxyallylic radicals then adds oxygen to form an
epoxy-peroxyl radical. This peroxyradical with a neighboring
epoxide group can then abstract a H atom from an unsaturated
lipid to form a lipid epoxy-hydroperoxide (Figure 3). This could
explain the minute amounts of hydroxylipids generally found
during lipid oxidation.
An alternative hypothesis that may not have been considered
so far is that the two radicals, LO• and LOO• , do a different job.
Indeed, all hypotheses assume a H-abstraction reaction (reaction
8) for LO• or for any of their putative derived radicals (epoxy-
peroxyradicals). Yet we know that LO• can undergo other reac-
tions called 𝛼- and 𝛽-scissions (Figure 4), in competition with
H-abstraction, to yield a large variety of volatiles known as sec-
ondary oxidation products. Examples of such compounds respon-
sible for rancidity in dispersed lipids are decadienal, heptadi-
enal, propanal, or hexanal. More than fifty years ago, Walling and
Wagner[40] found that the ratio of the rate constants for hydrogen
abstraction (reaction 8) and scission (Figure 4) for LO• strongly
depends on the polarity of the solvent. Pursuing these work, Tsen-
talovich et al.[12] showed that both the solvent polarity and ability
for hydrogen bonding (i.e., proticity) accelerate the scission reac-
tions, with a maximal rate constant for water as solvent. Consid-
ering our hypothesis of a LOOH-mediated interfacial initiation,
alkoxyradicals formed at the lipid–water interface would thus be
in a medium promoting scissions rather than H-abstraction. Ac-
cordingly, LO• could be almost exclusively involved in the gener-
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O
H
•
HOOC(CH2)7 (CH2)4CH3
+ O2
H
HOOC(CH2)7 OO (CH2)4CH3
•
ation of volatile aldehydes, ketones, and alkenes at the interface,
tion due to their location at the interface. The quasi-absence of
hydroxylipids in dispersed lipids could confirm better than any
other experimental proof the hypothesis of an interfacial local-
ization (and thus of an interfacial generation) of LO• . Should
alkoxyradicals predominantly accumulate in the core of a lipid
droplet or membrane, it would follow that reaction 8 is favored
and that hydroxylipids would be formed and detected in high
amounts in the lipid phase. If true, this assumption may be
crucial for future lipid oxidation models because it implies that
LOO• are the dominant propagation radicals (the chain carrier),
while LO• are the dominant radicals for scission-based termina-
tion reactions—the termination type which generates most of the
secondary oxidation products.[41,42] The two radicals formed from
the very same entity could have a different role. To our knowl-
edge, it is also the first time that scission-based termination re-
actions are assigned a specific location, although a putative one.
This could explain why proteins such as those used for stabiliz-
ing oil-in-water emulsions, or those (apoproteins) anchored at the
surface of low density lipoproteins, are so prone to form adduct
with electrophilic aldehydes or ketones derived from lipid oxida-
tion: they may accumulate at the same locus. In the case of low
density lipoproteins, we know that the necessary prerequisite to
generation of epitopes on apoprotein B recognized by the scav-
enger receptor is the decomposition of lipid hydroperoxides, pre-
sumably in aldehydes and ketones.[25]
Finally, disregarding the fate of the alkoxyradicals and of
the hydroxylipids supposed to derive from them, it is nonethe-
less true that the LOOH-derived peroxyradicals will form again
LOOHs during the propagation phase (reaction 7). Because prop-
agation produces nonradical molecules necessary for initiation
(LOOH), it is easy to envision how lipid oxidation can become
an autocatalytic and a geometrically progressive reaction.[15] Spa-
tially speaking, LOOHs would probably migrate from any part of
the particle they are formed on, to the interface, since, as above-
mentioned, they are more surface-active than their non-oxidized
parent lipids.[28] Within this scheme, oxidation would be initiated
at the interface and LOOHs, the major propagation by-products,
would accumulate within the same locus.
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Figure 5. The different scales at which lipid oxidation is/should be considered.
At this point, we are probably nearing the reachable limits set
by a space-resolved model with this image in mind of a LOOH
molecule stuck at the interface of a colloid as a shipwrecked on
a desert island. Hence the question: is such a model sufficient to
really understand the oxidation of dispersed lipids? Something
important may still be missing.
3. Broaden the Picture to Fully Grasp the
Dynamics of Lipid Oxidation
The approach regarding oxidation in lipid dispersions so far is of
concern as theoretical models, when spatially resolved, are usu-
ally based on solely the level of an individual colloid. Most ded-
icated works described in the literature endeavor to understand
lipid oxidation by depicting a single droplet or a single membrane
with its vicinal aqueous environment wherein the abovemen-
tioned reactions are assigned a location (Figure 5). The reason
for that is probably to make the whole process more understand-
able. However, in our opinion, this leads to a cognitive bias. In-
deed, while lipid dispersions are composed from a multitude of
lipid colloids, researchers mainly consider the dynamics of oxi-
dation and the numerous interactions between reactants (such
as lipids, LOOHs, and metal ions) in the narrow and extremely
reductive framework of an individual droplet or membrane. In
other words, data obtained from monitoring lipid oxidation on
systems consisting in a multitude of colloids are then explained
by a model considering only a single colloid, which corresponds
to understanding a multidimensional object in only one or two
dimensions. The question thus arises: are we looking too closely?
It is common belief that our misunderstanding of lipid oxi-
dation comes mainly from our lack of knowledge regarding the
complex network of reactions and interactions occurring between
the many reactants. It follows that when we will have all the
details of this complex chemical circuitry—through an “omics”
approach—, then the model might give better predictions. This is
unsure. Of course, an “omics” approach would be certainly useful
to help measuring many markers of oxidation at the same time,
and not only lipid hydroperoxides or hexanal which can in some
circumstances misrepresent and even distort the real progress of
lipid oxidation.[43] Measuring epoxides, volatiles, polymers, in ad-
dition to the classical peroxide value will be a significant achieve-
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ment. However, it will certainly not be sufficient to fully under-
stand lipid oxidation. Adding more epicycles to the earth-centric
model did not solve the ancient Greek astronomy. In our opin-
ion, this has not so much to do with dealing with many details as
working on the appropriate scale in which this significant level
of chemical information can be integrated. A framework, which
would better represent lipid dispersions encountered in real sys-
tems than a single colloid system, might be required.
We wish to suggest that colloid ecosystems may constitute a
relatively new and relevant scale at which lipid oxidation can be
studied in the future (Figure 5). At this level, order and dynam-
ics, that do not exist at lower scales, spontaneously arise from the
collective organization of colloidal structures. Exactly as in com-
plex patterns encountered in forest fires or in beautiful starling
flights which cannot be inferred from the individual behavior of
one tree or one bird. Important aspects on lipid oxidation may
thus be overlooked when models are reduced at low scales and
focus solely at the level of individual colloids or just at molecules.
Thinking lipid oxidation at the level of colloid ecosystems can
help us understand if the reaction is initiated in a single colloid
from an initial oxidative event, and if it then spreads to all other
colloids by a neighbor-to-neighbor mode of transport, or if it oc-
curs “spontaneously” and independently in different colloids at
a time. Another question arises. How many lipid colloids are ox-
idized during oxidation, which is important considering that in
milk, for instance, oxidation of 0.00002% (molar) of lipids may
lead to rancidity.[44] In other words, is oxidation a process that af-
fects all colloidal objects, meaning that diffusing oxidative species
reach a dynamic equilibrium within the dispersed lipid phase? If
this is not the case, what would be the proportion and the 3D-
spatial distribution of populations of oxidized and non-oxidized
colloids? Obviously, reactants such as LOOHs are not the only
entities which move in a dispersed environment. Lipid colloids
are also in motion with smaller colloids moving faster than large
ones.
Significant progress in our understanding of how oxidation is
organized spatiotemporally could be provided by better know-
ing the mechanisms according to which oxidative species are
transferred between lipid colloids. Unlike free radicals, which
are generally too reactive to migrate over long distances, LOOHs
have a long half-life, which makes them suitable candidates
for “spreading” species moving from their point of formation
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to other regions of the system where they will initiate new
propagation chains. However, how LOOHs would diffuse be-
tween colloids separated by an aqueous phase wherein LOOHs
are poorly soluble remains unclear. Given that the lag phase
(if any) of lipid oxidation in dispersed systems corresponds
to the production of LOOHs in only a few lipid colloids, our
hypothesis is that when a critical concentration is attained,
LOOHs which are surface-active enough would form micelles
alone or co-micelles with surfactants present in the aqueous
phase.[45] Unlike individual LOOH molecules, micelles or co-
micelles of LOOHs can theoretically migrate over long distances
because of their higher solubility in water. The basic idea be-
hind this assumption is that micelles can transport prooxidative
species throughout the colloid ecosystem in a much faster way
than any other transporter (except maybe protein clumps). For
example, fluorescent-labeled N-(7-nitro-2,1,3-benzoxadiazol-4-
yl)phosphatidylethanolamine molecules were shown to transfer
200–6000 times faster between phosphatidylcholine-taurocholate
mixed micelles than between phospholipid vesicles.[46] Likewise,
in a series of experiments using two populations of emulsified
droplets, one with hexadecane, another with octadecane, it has
been shown that complete mixing of oils between the droplets
linearly depends on the surfactant (Tween 20) concentration.[47,48]
The authors assumed that solubilization of oil in aqueous phase
by surfactant micelles was the most probable mechanism for oil
exchange between droplets; the thermodynamic driving force for
this exchange is the free energy of mixing.
Within this scheme, a LOOH micelle approaching a non-
oxidized droplet, membrane, or any other colloidal object, can
meet transition metals and propagate oxidation by in situ
generation of peroxyradicals (reaction 2) and/or alkoxyradicals
(reaction 3). But other scenarios can occur. As LOOH concen-
tration increases in micelles or co-micelles, bimolecular decom-
position (reaction 5) is favored so that, in absence of metal cat-
alyst, LOOH level can fall below the CMC or co-CMC. In such
circumstances, perhaps LOOHs levels would be insufficient to
maintain the supramolecular structure of putative micelles, once
they are far away from their initial point of formation. If LOOH
micelles are disrupted nearby other colloids than the one from
which they originate, then oxidation can still be transferred from
one colloid to another. Such migrations between colloids should
be fast, because rate constants for LOOH self-reactions are in the
range of 10–4 -10–5 m–1 s–1 . In any case, LOOHs may provide “reser-
voirs of potential radicals waiting to be generated,” to use Schaich’s
expression.[43]
Figure 2 shows that among LOOHs, linoleic acid hydroper-
oxides are more surface active than methyl linoleate or trili-
nolein hydroperoxides which results from polarity of the acid
group. If our hypothesis is correct, this suggests that LOOHs
derived from free fatty acids would be the dominant diffusing
species among LOOHs. It is not necessary that all LOOHs spread
through the colloid ecosystem to broadcast lipid oxidation to the
entire system. Even trace amounts of LOOHs would be suffi-
cient to physically “propagate” the oxidation. Indeed, hydrolysis
is negligible in most dispersed lipids and would require acid,
high heat, or lipases to accumulate more than traces of free fatty
acids.
Taken together, this would provide a model in which oxidation
of dispersed lipids is governed by not only the oxidative stability
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of lipids, as generally considered in chemical models, but also
by the surface activity of LOOHs, their assumed ability to mi-
cellize or co-micellize, and their diffusivity from one colloid to
another. Paradoxes as the one observed by Miyashita, for exam-
ple, on the relatively good stability of omega-3 lipid dispersions
containing EPA and DHA compared to less unsaturated lipids
and traditionally explained by configurational arguments[4] could
also be tentatively explained by a differential surface activity of
LOOHs derived from omegas-6 and -3. Indeed, the position of
the OOH group on the acyl chain might influence the poten-
tial of LOOHs to diffuse throughout the system. Little is known
on the surface-activity of lipid hydroperoxides, but some studies
have systematically investigated the effect of hydroxy substituent
of hydroxylipids on their surface activity at gazeous interfaces.
Using a homologous series of hydroxylipid analogs (9, 10, 12,
and 16 hydroxyoctadecanoic acid), it has been shown at the ar-
gon/water interface that when the hydroxyl is at or beyond the
12-position, the molecule lies flatter on the water surface, as the
distal hydrocarbon segment is too short to be excluded from the
water phase.[49] In other words, if the “spacer moiety” between
the COOH and the hydroxyl group is too long, a well-defined hy-
drophobic tail cannot be formed. By analogy with LOOHs, this
result could suggest that the closer the hydroperoxide group is
relative to the terminal methyl of a free fatty acid, the lower the
surface activity of the resulting LOOH is, which is a very testable
hypothesis.
Furthermore, considering the polydispersity/polymodality—
and in some circumstances the fractal nature—of lipid disper-
sions, especially oil-in-water emulsions (Figure 6e), it could also
be possible that prooxidative compounds such as LOOHs are
transported by microemulsion droplets. This mode of transport,
called “collision-exchange-separation transfer,”[45] can be slower
than the micelle-assisted one, but significantly faster than a mass
transport mediated by macroemulsion droplets; the smaller the
transporter, the faster the diffusivity. It has been recently found
on Tween 80-stabilized oil-in-water emulsion, that populations
of small microemulsion droplets (d: 12–22 nm) coexist with na-
noemulsion (d < 200 nm) and macroemulsion (d > 200 nm)
droplets, when the optical properties of the emulsion are those
of a classical macroemulsion (opaque).[50] This raises the ques-
tion of knowing if particular sub-populations of colloids (e.g., mi-
celles, swollen micelles, microemulsion droplets…) are preferred
transporters and, as such, are responsible for speeding up lipid
oxidation to the other colloid sub-populations.[45,51,52]
The mass transfer mechanisms we are discussing, far from
being solely applicable to nonliving systems, might have bio-
logical significance. Since the lipid dispersions encountered in
biological fluids, such as blood, consist in a mixture of sus-
pended cells, lipoproteins (d: 5–500 nm), small and large lipid
droplets, micelles, and protein aggregates, it will be interesting,
although technically difficult, to establish in a not-too-distant
future the complete dynamics of the molecular exchanges that
occur between all these populations of colloidal objects. Low-
density lipoproteins whose oxidation is a central step in the emer-
gence of atherosclerosis have an average diameter of 20 nm[53]
which is in the range of microemulsified droplets. Even intracel-
lularly, lipid droplets (100 nm to 100 µm)—that are ubiquitous to
all eukaryotic cells—have been shown to distribute polar lipids
between membrane-bound organelles such as endoplasmic
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Figure 6. a) A forest fire model using three variables. b,c) Two grids of cells using different variable setup and fire pattern. d) A 2D aerial representation
of a tropical forest (after Anfodillo et al.[67] ). e) An archetypal oil-in-water emulsion.
reticulum, endosomes, peroxisomes, and mitochondria.[54] In-
triguingly, cells that contain higher levels of lipid droplets exhibit
higher levels of oxidative stress.[55] Since they interact with nearly
all organelles in the cell,[56] lipid droplet trafficking can possibly
be responsible for a droplet-conveyed inter-organelle transfer of
LOOHs. Establishing the physical chemistry of intra- and inter-
cellular oxidative cross talk could help treating some diseases as-
sociated with an oxidative stress. Only then can we hope to un-
derstand a little this biological phenomenon that escapes us so
far.
Finally, it should also be mentioned that some oxidation
products that do not necessarily promote oxidation per se can
probably freely diffuse through the intervening aqueous phase
from one droplet to another. Cleavage products resulting from
𝛼 and 𝛽 scissions such as aldehydes or alcohols are indeed
much more soluble in water than their parent LOOHs. On
the contrary, termination products formed through radical re-
combination (a major type of termination) would be blocked
in the droplet, membrane, or any colloid in which they have
been formed, due to their large molecular size and their strong
hydrophobicity. In this case, lipid oxidation would generate
three types of products depending on their diffusion prop-
erties: hydrosoluble cleavage products, amphiphilic LOOHs,
and hydrophobic oligomers. A transport-limited trafficking of
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LOOHs can thus be paralleled by a non-diffusion-limited traf-
ficking of relatively small aldehyde, ketone, alcohol, and car-
boxylic acid molecules. Such different transports may also
explain why, in some cases, primary and secondary oxidation
products are not affected the same way when a given condition is
applied such as the addition of an antioxidant.
4. New Perspectives
Like virtually all sciences, our understanding of the lipid oxida-
tion phenomenon follows from what scientists have sought to
understand, that is, what they choose to study, which is highly de-
pendent upon the available techniques at the momentum. In this
sense, our understanding of the trafficking of the different chem-
ical species within colloid communities in lipid dispersions may
require new experimental tools such as static[57] and dynamic[58]
microfluidics as well as flow cytometry which, in other domains,
is utilized to sort different populations of colloids.[59] The daunt-
ing task of capturing the spatiotemporality of the oxidation of
dispersed lipids can also be greatly facilitated by the develop-
ment of new imaging techniques enabling a dynamic tracking
of lipid droplets[60] or the precise generation of prooxidative
species in a very small and localized area of an emulsion.[61,62] In
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addition, inter-droplet or inter-membrane transfers can be sciences. Indeed, in this field, mathematical modeling of drug
studied using standard fluorescence technique based on transport in emulsion systems is well established since the
concentration-dependent self-quenching of fluorescent-labeled 1990s.[68,69] Perhaps we could reuse and adapt “old” models by
probes[46] or decrease of the excimer peak of pyrene due to simply substituting in the equations the inherent parameters of
inter-droplet transfer and subsequent dilution.[63] Simple UV– the drugs by those of prooxidant species such as LOOHs that
vis spectroscopy techniques can also be employed to probe would diffuse oxidation. In a resolutely optimistic and perhaps
intermicellar transfer of a reducing molecules such as catechin also a little naive way, it is not inconceivable to obtain through
by co-localizing it with the 1,1-diphenyl-2-picrylhydrazyl free this opportunistic approach operational models describing the
radical.[64] Of course, many more methods are yet to be developed propagation of oxidation between different colloidal objects.
and applied to this specific field. That would be a significant progress.
The path of discovery usually consists of first establishing hy-
potheses without necessarily knowing at the moment whether
the tools necessary for their validation are available. It is only the Acknowledgements
second time that the question of the technical means to verify
these hypotheses should concern us. The time of instrumental The authors are grateful to Prof. Claire Berton-Carabin and Dr. Pierre Vil-
developments has now probably come if we sought to broaden leneuve for sharing ideas and discussing some of the concepts described
here.
the lipid oxidation picture at the scale of a colloid ecosystem.
In the near future, we can even imagine that the results gen-
erated by such an experimental approach could provide a learn-
ing dataset for in silico models of lipid oxidation, similarly to the Conflict of Interest
satellite data presently used by forestry scientists that feed cur- The authors declare no conflict of interest.
rent forest fire models. Indeed, being able to predict how oxida-
tion will spread in dispersed lipids is certainly the ultimate goal
of any research dedicated to better understand the phenomenon.
To our knowledge, however, attempts to model oxidation in lipid
Keywords
dispersions have been largely unsuccessful so far. Although it is antioxidants, initiation, interfaces, lipid oxidation, mass transport phe-
hard to imagine at first glance how such models might be more nomena, modeling
effective, perhaps we could be more inspired by phenomena
that, in essence, could resemble lipid oxidation, at least in some Received: May 17, 2019
important points; a trans-disciplinary approach recently encour- Revised: October 28, 2019
Published online: January 16, 2020
aged by two excellent review articles.[65,66] In this way, we wish
to suggest that inspiration can be found from bottom-up predic-
tion models of forest fire such as those based, but not only, on
cellular automata, which are models of physical systems where
[1] J. L. Bolland, Proc. R. Soc. A 1946, 186, 218.
space and time are discrete, and interactions are only local (i.e., [2] J. P. Cosgrove, D. F. Church, W. A. Pryor, Lipids 1987, 22, 299.
neighbor-to-neighbor). Cellular automata consist in regular grids [3] L. Xu, T. A. Davis, N. A. Porter, J. Am. Chem. Soc. 2009, 131, 13037.
of cells (trees) that are at different states (on/off; burnt/unburnt; [4] K. Miyashita, Eur. J. Lipid Sci. Technol. 2014, 116, 1268.
oxidized/nonoxidized). The state of each cell is defined by the [5] C. C. Berton-Carabin, M. H. Ropers, C. Genot, Compr. Rev. Food Sci.
state of its neighbors. New generations are created iteratively, Food Saf. 2014, 13, 945.
according to fixed rules with starting parameters and hypothe- [6] M. Laguerre, C. Bayrasy, A. Panya, J. Weiss, D. J. McClements, J.
ses. By playing with the variables such as the wind, the tree den- Lecomte, E. A. Decker, P. Villeneuve, Crit. Rev. Food Sci. Nutr. 2015,
sity, grass-pine fire interaction, hurricane probability, and so on, 55, 183.
certain patterns tend to emerge ((Figure 6a–c). In other words, [7] E. S. Budilarto, A. Kamal-Eldin, Eur. J. Lipid Sci. Technol. 2015, 117,
1095.
simple and short-range rules can iteratively shape complex and
[8] K. Miyashita, E. Nara, T. Ota, Biosci., Biotechnol., Biochem. 1993, 57,
long-range patterns, something which, in the context of lipid oxi- 1638.
dation, is reminiscent of the physical driving forces. Indeed, apart [9] K. Miyashita, S. Hirano, Y. Itabashi, T. Ota, M. Nishikawa, S.
from the hydrophobic force, which is somewhat long-range, most Nakayama, J. Japan Oil Chemists’ Soc. 1997, 46, 205.
of electrostatic interactions such as hydrogen bonding, dipole– [10] M. Araseki, K. Yamamoto, K. Miyashita, Biosci., Biotechnol., Biochem.
dipole interactions, pi-stacking, etc. are short-range. Practically 2002, 66, 2573.
speaking, the basic idea corresponds to finding the variable setup [11] W. L. Porter, E. D. Black, A. M. Drolet, J. Agric. Food Chem. 1989, 37,
that will best fit with the real data gathered by experimental mea- 615.
surements. This analogy between forest fire and lipid oxidation [12] Y. P. Tsentalovich, L. V. Kulik, N. P. Gritsan, A. V. Yurkovskaya, J. Phys.
may not be so fortuitous, especially when we examine the simi- Chem. A 1998, 102, 7975.
[13] B. Halliwell, Toxicol. Ind. Health 1993, 9, 1.
larity of the spatial distribution of tree trunks in a forest[67] and of
[14] Y. Yoshida, E. Niki, Arch. Biochem. Biophys. 1992, 295, 107.
droplets in an oil-in-water emulsion (Figure 6d,e). The greatest [15] S. P. Aust, B. A. Svingen, in Free Radicals in Biology, Vol. V, (Ed: W. A.
challenge remains, however, in the fact that trees do not move, Pryor), Academic Press, New York 1982, pp 1–8.
while lipid colloids do, in three dimensions! [16] Z. Cheng, Y. Li, Chem. Rev. 2007, 107, 748.
Another source of inspiration for modeling oxidation pro- [17] L. Mei, E. A. Decker, D. J. McClements, J. Agric. Food Chem. 1998, 46,
cesses in dispersed lipids can be found from pharmaceutical 5072.

Eur. J. Lipid Sci. Technol. 2020, 122, 1900209 1900209 (9 of 10) © 2019 The Authors. European Journal of Lipid Science and Technology
Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

www.advancedsciencenews.com
[18] A. Panya, M. Laguerre, J. Lecomte, P. Villeneuve, J. Weiss, J. D. Mc-
Clements, E. A. Decker, J. Agric. Food Chem. 2010, 58, 5679.
[19] M. Kunimoto, K. Inoue, S. Nojima, Biochim. Biophys. Acta, Biomembr.
1981, 646, 169.
[20] L. Mei, D. J. McClements, J. Wu, E. A. Decker, Food Chem. 1998, 61,
307.
[21] K. Fukuzawa, T. Fujii, Lipids 1992, 27, 227.
[22] K. Fukuzawa, T. Tadokoro, K. Kishikawa, K. Mukai, J. M. Gebicki, Arch.
Biochem. Biophys. 1988, 260, 146.
[23] B. Kalyanaraman, W. E. Antholine, S. Parthasarathy, Biochim. Biophys.
Acta, Gen. Subj. 1990, 1035, 286.
[24] J. P. Reyftmann, R. Santus, J. C. Maziere, P. Morliere, S. Salmon, C.
Candide, C. Maziere, J. Haigle, Biochim. et Biophys. Acta (BBA) - Lipids
Lipid Metabol. 1990, 1042, 159.
[25] H. Esterbauer, J. Gebicki, H. Puhl, G. Jürgens, Free Radical Biol. Med.
1992, 13, 341.
[26] L. Reynolds, R. S. Mulik, X. Wen, A. Dilip, I. R. Corbin, Nanomedicine
2014, 9, 2123.
[27] H. Jin, J. F. Lovell, J. Chen, Q. Lin, L. Ding, K. K. Ng, R. K. Pandey, M.
Manoharan, Z. Zhang, G. Zheng, Bioconjugate Chem. 2012, 23, 33.
[28] C. D. Nuchi, P. Hernandez, D. J. McClements, E. A. Decker, J. Agric.
Food Chem. 2002, 50, 5445.
[29] C. C. Berton-Carabin, A. Schröder, A. Rovalino-Cordova, K. Schroën,
L. Sagis, Eur. J. Lipid Sci. Technol. 2016, 118, 1630.
[30] K. U. Ingold, V. W. Bowry, R. Stocker, C. Walling, Proc. Natl. Acad. Sci.
USA 1993, 90, 45.
[31] C. Chaiyasit, R. J. Elias, D. J. McClements, E. A. Decker, Crit. Rev. Food
Sci. Nutr. 2007, 47, 299.
[32] B. Chen, A. Han, M. Laguerre, D. J. McClements, E. A. Decker, Food
Funct. 2011, 2, 302.
[33] E. A. Decker, D. J. McClements, C. Bourlieu-Lacanal, E. Durand, M. C.
Figueroa-Espinoza, J. Lecomte, P. Villeneuve, Trends Food Sci. Technol.
2017, 67, 183.
[34] M. Laguerre, L. J. López Giraldo, J. Lecomte, M. C. Figueroa-
Espinoza, B. Baréa, J. Weiss, E. A. Decker, P. Villeneuve, J. Agric. Food
Chem. 2009, 57, 11335.
[35] M. Laguerre, L. J. López Giraldo, J. Lecomte, M. C. Figueroa-
Espinoza, B. Baréa, J. Weiss, E. A. Decker, P. Villeneuve, J. Agric. Food
Chem. 2010, 58, 2869.
[36] O. Mitrus, M. Żuraw, S. Losada-Barreiro, C. Bravo-Díaz, F. Paiva-
Martins, J. Agric. Food Chem. 2019, 67, 3266.
[37] J. Almeida, S. Losada-Barreiro, M. Costa, F. Paiva-Martins, C. Bravo-
Diaz, L. S. Romsted, J. Agric. Food Chem. 2016, 64, 5274.
[38] K. M. Schaich, Lipid Technol. 2012, 24, 55.
[39] H. W. Gardner, Free Radical Biol. Med. 1989, 7, 65.
[40] C. Walling, P. J. Wagner, J. Am. Chem. Soc. 1964, 86, 3368.
[41] E. N. Frankel, Prog. Lipid Res. 1984, 23, 197.
[42] W. Grosch, in Autoxidation of Unsaturated Lipids, (Ed: H. W. S. Chan),
Academic Press, London 1987, pp. 95–139.
Eur. J. Lipid Sci. Technol. 2020, 122, 1900209 1900209 (10 of 10)
14389312, 2020, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejlt.201900209 by CIRAD - DGDRS - DIST, Wiley Online Library on [06/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
www.ejlst.com
[43] K. M. Schaich, in Lipid Oxidation: Challenge in Food Systems, (Eds: A.
Logan, U. Nienaber, X. Pan), AOCS Press, Urbana, IL 2013, pp. 1–52.
[44] T. P. Labuza, Crit Rev Food Technol 1971, 355.
[45] M. Laguerre, A. Bily, M. Roller, S. Birtic, Annu. Rev. Food Sci. Technol.
2017, 8, 391.
[46] J. W. Nichols, Biochemistry 1988, 27, 3925.
[47] D. J. McClements, S. R. Dungan, J. Phys. Chem. 1993, 97, 7304.
[48] D. J. McClements, S. R. Dungan, J. B. German, J. E. Kinsella, Food
Hydrocolloids 1992, 6, 415.
[49] F. M. Menger, S. D. Richardson, M. G. Wood Jr, M. J. Sherrod, Lang-
muir 1989, 5, 833.
[50] T. S. Awad, D. Asker, L. S. Romsted, J. Colloid Interface Sci. 2018, 514,
83.
[51] P. Villeneuve, E. Durand, E. A. Decker, J. Agric. Food Chem. 2018, 66,
8433.
[52] M. Laguerre, A. Bily, S. Birtic, in Lipids and Edible Oils: Properties, Pro-
cessing and Applications, (Ed: C. Galanakis), Academic Press, New
York, NJ 2019, pp. 243–288.
[53] H. M. Colhoun, J. D. Otvos, M. B. Rubens, M. R. Taskinen, R. Under-
wood, J. H. Fuller, Diabetes 2002, 51, 1949.
[54] J. K. Zehmer, Y. Huang, G. Peng, J. Pu, R. G. W. Anderson, P. Liu,
Proteomics 2009, 9, 914.
[55] A. Herms, M. Bosch, N. Ariotti, B. J. Reddy, A. Fajardo, A. Fernández-
Vidal, A. Alvarez-Guaita, M. A. Fernández-Rojo, C. Rentero, F. Tebar,
C. Enrich, M. I. Geli, R. G. Parton, S. P. Gross, A. Pol, Curr. Biol. 2013,
23, 1489.
[56] J. A. Olzmann, P. Carvalho, Nat. Rev. Mol. Cell Biol. 2019, 20,
137.
[57] H. Chen, Q. Fang, X. F. Yin, Z. L. Fang, Lab Chip 2005, 5, 719.
[58] K. A. Runas, N. Malmstadt, Soft Matter 2015, 11, 499.
[59] Y. Qiao, M. Li, R. Booth, S. Mann, Nat. Chem. 2017, 9, 110.
[60] H. Xu, H. Zhang, G. Liu, L. Kong, X. Zhu, X. Tian, Z. Zhang, R. Zhang,
Z. Wu, Y. Tian, H. Zhou, Anal. Chem. 2019, 91, 977.
[61] C. Banerjee, M. Westberg, T. Breitenbach, M. Bregnhoj, P. R. Ogilby,
Anal. Chem. 2017, 89, 6239.
[62] C. Banerjee, T. Breitenbach, P. R. Ogilby, ChemPhotoChem 2018, 2,
586.
[63] Y. Katsumoto, H. Ushiki, B. Mendiboure, A. Graciaa, J. Lachaise, Col-
loid Polym. Sci. 2000, 278, 905.
[64] M. Laguerre, V. Hugouvieux, N. Cavusoglu, F. Aubert, A. Lafuma, H.
Fulcrand, C. Poncet-Legrand, Food Chem. 2014, 149, 114.
[65] V. M. Paradiso, A. Pasqualone, C. Summo, F. Caponio, Eur. J. Lipid
Sci. Technol. 2018, 120, 1800103.
[66] L. Sagalowicz, M. Michel, I. Blank, O. Schafer, M. E. Leser, Curr. Opin.
Colloid Interface Sci. 2017, 28, 87.
[67] T. Anfodillo, M. Carrer, F. Simini, I. Popa, J. R. Banavar, A. Maritan,
Proc. Royal Soc. B: Biol. Sci. 2013, 280, 20122375.
[68] K. A. Yoon, D. J. Burgess, J. Pharm. Pharmacol. 1998, 50, 601.
[69] N. Chidambaram, D. J. Burgess, AAPS PharmSci 2000, 2, 1.
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