1 s2.0 S0001868621000257 Main

Advances in Colloid and Interface Science 290 (2021) 102384
Contents lists available at ScienceDirect
Advances in Colloid and Interface Science
journal homepage: www.elsevier.com/locate/cis
Historical Perspective
Electrospraying as a novel process for the synthesis of particles/

nanoparticles loaded with poorly water-soluble bioactive molecules
Hadis Rostamabadi a,⁎, Seid Reza Falsafi a, Mohammad Mahdi Rostamabadi b,
Elham Assadpour a, Seid Mahdi Jafari a,⁎
a
Faculty of Food Science and Technology, Gorgan University of Agricultural Sciences and Natural Resources, Gorgan, Iran
b
Department of Food Science and Technology, College of Agriculture, Isfahan University of Technology, Isfahan 84156-83111, Iran
a r t i c l e i n f o a b s t r a c t
Article history: Hydrophobicity and low aqueous-solubility of different drugs/nutraceuticals remain a persistent challenge for
17 February 2021 their development and clinical/food applications. A range of nanotechnology strategies have been implemented
Available online 23 February 2021 to address this issue, and amongst which a particular emphasis has been made on those that afford an improved
biological performance and tunable release kinetic of bioactives through a one-step process. More recently, the
Keywords:
technique of electrospraying (or electrohydrodynamic atomization) has attained notable impulse in virtue of
Electrospraying
Encapsulation
its potential to tune attributes of nano/micro-structured particles (e.g., porosity, particle size, etc.), rendering a
Poorly water-soluble bioactives near zero-order release kinetics, diminished burst release manner, as well as its simplicity, reproducibility, and
Hydrophobic biomolecules applicability to a broad spectrum of hydrophobic and poorly water-soluble bioactives. Controlled morphology
Controlled delivery or monodispersity of designed particles could be properly obtained via electrospraying, with a high encapsula-
tion efficiency and without unfavorable denaturation of thermosensitive bioactives upon encapsulation. This
paper overviews the recent technological advances in electrospraying for the encapsulation of low queues-
soluble bioactive agents. State-of-the-art, advantages, applications, and challenges for its implementation in
pharmaceutical/food researches are also discussed.
© 2021 Elsevier B.V. All rights reserved.
Contents
1. Introduction: Hydrophobic biomolecules are a trend or threat? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

2. Technical advantages of electrospraying vs. conventional techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3. A general overview of electrospraying . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.1. Principles and basic set-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.2. Critical parameters for tuning the attributes of electrosprayed nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.3. Matrices for electrospraying . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.4. Physical/chemical attributes of electrosprayed nanoparticles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.5. Application of bioactive-comprising electrosprayed carriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4. Strategies for delivery of poorly water-soluble bioactives via electrospraying. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4.1. Electro-encapsulation techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
4.2. Adsorptive approach. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
5. Electrospraying for encapsulation of hydrophobic or poorly-water soluble bioactives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
5.1. Phenolic compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
5.2. Carotenoids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
6. Fatty acids and essential oils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
6.1. Liposoluble vitamins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
6.2. Flavors and aroma components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
6.3. Other bioactive components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
7. Conclusion and future challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
⁎ Corresponding authors.
E-mail addresses: hadis.rostamabadi@gmail.com (H. Rostamabadi), smjafari@gau.ac.ir (S.M. Jafari).
https://doi.org/10.1016/j.cis.2021.102384
0001-8686/© 2021 Elsevier B.V. All rights reserved.
H. Rostamabadi, S.R. Falsafi, M.M. Rostamabadi et al. Advances in Colloid and Interface Science 290 (2021) 102384
Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
1. Introduction: Hydrophobic biomolecules are a trend or threat? mechanisms, requiring high temperature or diverse solvents/
surfactants, and low efficiency are the main drawbacks of these tech-
The dissolution extent of a bioactive/drug in the gastrointestinal (re- niques for the synthesis of different bioactive-loaded carriers [22].
ferred to as GI) milieu is one of the main crucial factors in attaining its For example, the popular strategy of emulsification is the most consid-
desirable biological level [1,2]. Unfortunately, the clinical and food utili- erable technique to deliver hydrophobic biomolecules, notwithstand-
zation of diverse influential, low water-soluble bioactives is typically ing, difficulties in manufacturing particle sizes <100 nm, variability in
hindered because of their hydrophobic nature [3–6]. Systematically, encapsulation efficiency (EE), production of non-homogeneous parti-
high hydrophobicity and dissolution rate pose problems of unpredict- cles, and also the risk of bioactive depression in the presence of organic
able absorption, lowered biodistribution, and also poor therapeutic ef- solvents reckon as the main cons of this technique [23]. Moreover, one
fect of low aqueous soluble bioactives after oral administration. of the main downsides of spray drying could be the notable portion of
Furthermore, the poor water solubility induces the aggregation of bioac- aggregated structures retrieved following the spraying process, which
tives/drugs over exposure to bodily milieu, which is relevant to their necessitates the application of other additives like stabilizers. Besides,
local toxicity and also poor oral bioavailability [7]. the fabrication of ultra-fine particles is restricted mainly by the labori-
Enhancing the bioabsorption of active molecules that possess low ousness in the collection of nano-scaled particles via the spray drier
systemic bioavailability to a biologically beneficial concentration has cyclone [24]. These limitations could be kept down by utilizing the
long been an elusive goal for food/pharmaceutical scientists [8,9]. This well-positioned ES technique, by virtue of its advantageous aspects,
has prompted the persistent and urgent development of intestinal including:
“transformers” like delivery carriers to enhance the potency of poorly
soluble bioactives by improving their biodistribution and pharmacoki- • Rapid drying speeds and nanoparticulation mechanism in a one-step
netics [10,11]. A therapeutic vehicle comprises a micro-molecular or continuous manner,
nanoscopic system (polymeric and/or lipid-based vector) and a bioac- • Effectual solvent evaporation process and rendering dry powders of
tive/drug, acting as an efficient reservoir to enhance the biological attri- greater physicochemical resistance compared to nanosuspension sys-
butes of those conventional free bioactive molecules [12–14]. tems,
A broad range of scaffolds e.g., polymeric nanoparticles (NPs), lipo- • Production of the electrosprayed solid powders, which could be po-
somal vehicles, nanoemulsions, nanocomplexes, and nanotubes have tently tailored to comply with different formulations (e.g., tableting
been developed, covalently/non-covalently for conjugating poorly or application in dry food systems),
water-soluble ingredients through an efficient encapsulation mecha- • Generation of encapsulated hydrophobic biomolecules with a very
nism [1,15,16]. In this context, one appealing advancement is the uti- low level of residual solvents, narrow particle size distribution, high
lization of electrospraying, ES (an off-shoot of the electrospinning loading capacity, and minimal bioactive destruction,
process) to generate nano/micro-scaled solid systems of hydrophobic • The lack of constant high-energy shearing forces, which is favorable in
bioactive-loaded carriers, providing their applicability in aqueous shielding susceptible bioactives like proteins,
food systems, allowing their proper distribution in the intestinal • Engineering nano/micro-particles with a better uniformity and stron-
lumen, and thus promoting their bioavailability [17–19]. The benefi- ger mechanical resistance compared to those particles fabricated
cial properties of the electrosprayed form of delivery systems may using other methods,
offer innovative opportunities for the delivery of poorly water- • Comfortable and convenient experimental set-up to fabricate
soluble bioactives and endow novel application areas for food/phar- bioengineered scaffolds with precisely controllable composition, con-
maceutical researches [20,21]. figuration, charge, and size,
The present review has revisited recent advances of a bottom-up • Simplicity, reproducibility, applicability, compatibility, plus cost-
technology relying on the atomization of a bioactive-comprising poly- effectiveness,
mers into ultra-thin particles, which undergo comparatively fast- • Capability of offering a high-throughput of nanofabrication via appli-
drying, viz. ES (or electrohydrodynamic atomization), for the fabrication cation of multiple spinnerets, in parallel,
of innovative nanocarriers encapsulating hydrophobic or poorly water- • Ability in generation of core-shell structures and porous architectures
soluble bioactives/drugs and their potential utilization in the generation of high surface area,
of therapeutically novel formulations with promoted biofunctional at- • Potential of offering improved dissolution manner and programmable
tributes. Hence, the first section briefly highlights ES and its technically bioactive release mechanism,
benefits vs. traditional approaches; the second part introduces the cur- • Capability of producing an encapsulated bioactive in the amorphous
rent state-of-the-art strategies for encapsulation of low aqueous- physical-state for prolonged periods of time owing to their uniform
soluble bioactives via this technique; the third part portrays a general distribution through the carrier network and potential of inhibiting
overview of ES; the fourth addresses the application of ES for the deliv- the molecular motion,
ery of poorly water-soluble bioactives; lastly, the current challenges and • Possibility of the quality investigation of the products with temporar-
perspective are discussed and commented. ily halting the process, which is an appreciated advantage,
• Promoting the (bio)functional features of different poorly soluble in-
gredients e.g., improved in vitro/in vivo dissolution rate, enhanced
2. Technicaladvantages ofelectrosprayingvs.conventionaltechniques bioavailability/biostability, and promoted physicochemical/ thermal
properties.
Engineering of bioactive-loaded micro/nano-particles comprises
a number of conventional methodologies e.g., solvent evaporation,
nanoprecipitation, spray drying, single/double-emulsification, All these properties make this approach an interesting tool for the
sol–gel, and coacervation techniques. Apart from their beneficial ad- production of micro/nano-dimensioned particles for the delivery of
vantages, some properties like being multi-step nanofabrication poorly aqueous-soluble bioactives [25–28].
2
3. A general overview of electrospraying the similar charges within the droplet overcome its surface tension,
leading to its explosion, namely Coulomb fission, into several droplets
3.1. Principles and basic set-up of a lower charge and smaller size. The presence of the electrostatic Cou-
lomb repulsion forces amongst the developed droplets induces their
ES stems from the atomization of charged polymeric droplets via well-dispersion and hinders the coalescence phenomenon upon their
proper electrical forces [29,30]. This approach utilizes a high electrical flight toward the collecting plate. The new particles experience consec-
field to elicit charged droplets of the polymeric solution at a pre-set utive dissolvation and Coulomb fission phenomena which will result in
speed. The micro/nano-particles could be engineered followed by the sol- the fabrication of solidified nanometric off-spring droplets carrying on
vent evaporation process. Solid particles [31], porous configurations [32], average one positive charge [25].
doughnut-shaped structures [31], honey comb-like pore particles There are a number of ES modes, which could be influenced by the
[33], core-shell bodies [34], cake-like matrices [35], shrunken particles liquid characteristics (e.g., viscosity, conductivity, or surface tension),
[36], hollow particles with a single surface hole [37], and other morphol- and the process parameters (like applied electric voltage, tip-to-collec-
ogies can be designed by ES approach, as represented in Fig. 1. The process tor distance, and flow rate). Amongst which, the single cone-jet is the
could be applied either upon room pressure/temperature or upon the most desired mode for effectual nanofabrication of highly mono-
inert circumstances to properly adjust the drying mechanism and avert disperse particulate structures, owing to its reproducibility and high sta-
the likely influences of exterior contaminations [14,25]. bility [40].
Generally, the principles of this technique are similar to that of
electrospinning except that the jet breaks down into the spherical par- 3.2. Critical parameters for tuning the attributes of electrosprayed
ticles in ES. This phenomenon is typically a result of applying a lower nanoparticles
concentration of the polymer solution compared to what is applied in
the electrospinning technique [38]. The nanofabrication of electrosprayed particles is typically affected
The conventional configuration of an ES apparatus comprises four by multiple critical factors, i.e., characteristics of the polymeric solution,
essential components; i) a power supply offering a high voltage; ii) a bioactive agent, and the solvent (e.g., molecular weight, concentration/
capillary metal nozzle; iii) a pumping system; and iv) a grounded viscosity, elasticity, electrical conductivity, polarity, plus surface ten-
metal collector. The ES set-up is cost-effective and convenient: a poly- sion), circumstances of ES (applied electric voltage, the spraying dis-
meric solution is transferred into a syringe equipped with a conductive tance, as well as the feeding rate for the bioactive-polymer system),
capillary nozzle and sprayed at a favorable speed typically applied by a plus the surrounding temperature/humidity (Table 1 and Fig. 3). In par-
pumping system. The metal nozzle is connected to the high electric field allel with polymer concentration, the weighted average molar mass
(positive charge), and the collecting plate, usually grounded or nega- (generally recognized as the molecular weight) is another critical pa-
tively charged, is located at a proper distance (ranging from a few to rameter for tailoring electrosprayed products and their release manner,
several cm) from the capillary nozzle [39]. as both factors directly affect the system viscosity [26]. Aside from these,
The high voltage produces electrostatic forces throughout the drop- the electrical conductivity and the physicochemical features of the
let, which compete with the droplet surface tension, generating a electrosprayed particles could be further improved and tuned through
conical-shaped morphology (the so-called Taylor cone), characteristic altering the formulation ingredients and post-synthesis modifications
of a charged droplet, as shown in Fig. 2. Subsequently, the positively [29]. The diverse engineering factors will cause discrepancies in the at-
charged droplets detached from the nozzle tip and travel toward the tributes and the application of the bioactive-loaded electrosprayed par-
grounded collector. The solvent vaporizes from the charged particles ticles [41]. It is also worth mentioning that as in many bottom-up
and shrink them into smaller structures of a higher charge till they nanosization strategies, developed electrosprayed NPs are mostly pro-
reach their Rayleigh limit; where the electrostatic repulsion forces of duced in an amorphous state [27].
Besides the process parameters, dehydrating procedures might in-
fluence the configuration (size or surface morphology) of electrically
processed carriers, leading to diverse swelling manners and eventually
changing the release behavior of the loaded ingredients [57]. In this re-
gard, Zhao et al. [58] prepared and characterized the polycaprolactone
microspheres by ES and investigated the influence of bead dehydration
techniques on the surface morphology of Ganoderma lucidum spores-
loaded alginate microspheres (GLS/A). In comparison with dried GLS/
A microspheres exposed to vacuum or air (Fig. 4a, b), the surface mor-
phology of the freeze drying-dehydrated revealed more porosity
(Fig. 4c), which could offer a larger surface area to release the encapsu-
lated bioactive [59]. This porous configuration could be associated with
the freeze-drying method, including the freezing and solidifying of the
GLS/A suspension, which then sublimated from ice to gas upon reduced
pressure. The porosity extent and pore size are adjustable via changing
the creation of ice crystals [60].
Tuning the solvent volatility, as a process modification technique for
enhancing the surface area of active material, is another key parameter
affecting the morphology of resultant electrosprayed materials. It has
been reported that an enhancement in the solvent volatility can lead
to the production of electrohydrodynamically produced structures
with a surface micro-texture property (presence of pores or rugosity
on the surface). In this line, Nair & Mathew [61] demonstrated a tech-
nique of engineering porous electrospun/electrosprayed structures
based on cellulose acetate and cellulose nanocrystals. The authors re-
vealed that the application of high vapor pressure solvent systems (di-
Fig. 1. Different morphologies of electrosprayed nano/micro-particles. chloromethane: acetone and acetic acid: acetone) led to the formation
3
Fig. 2. Schematic illustration of the Coulomb fission phenomenon upon electrospraying and forces in the liquid cone.
of porous electrosprayed particles (Fig. 4d, e, f, e), induced by the com- be applied to ES and final particles (spheres or capsules). When
bined influence of phase separation and solvent evaporation from the selecting a proper polymer matrix, there are several beneficial physio-
solvent-rich zones. This structural configuration could be potently effi- chemical attributes e.g., solubility, surface tension, viscosity, plus electri-
cient to improve the exposure of loaded bioactive agents. cal conductivity [63,64], which are adjustable to attain the proper Taylor
Partovinia and Vatankhah [21] introduced a precise empirical model cone stability and desired particle morphology/size. Moreover, the
to correlate variables involved in ES with the size and sphericity of algi- targeted application and bioactive delivery circumstances count as
nate micro-beads by CCD1 and RSM.2 Based on the proposed model, the other critical factors that should be considered. For instance, for a
microbead size was considerably affected by the needle size, electric long-term release mechanism, polymers with a low degradation rate,
voltage, tip-to-collector distance, as well as CaCl2 concentration, while e.g., PCL or PLA, are effectual [65–67]. Besides, when multi-axial ES is
the polymer concentration, needle size, and electric voltage were the utilized, the miscibility of the polymer matrices and solvent system
main factors influencing the sphericity of the designed particles, as (s) will dictate whether mixed-phase or core-shell structures are
shown in Fig. 5. Moreover, the interactions between the polymer con- engineered. Nonetheless, these principles are not limited since the func-
centration and needle size, electric voltage and tip-to-collector distance, tional attributes of polymer matrices are adjustable as nanotechnology
flow rate and distance to collecting plate were highly effective in dictat- advances. As an example, Johns et al. [68] and Li et al. [69] proposed
ing the particle diameter. The quite spherical alginate beads of a mini- the ferric iron chelation and ultraviolet-ozone treatment for enhancing
mum particle diameter (130 μm) were produced at ~1.5% polymer the functional features (e. g., hydrophilicity mechanical properties) of
concentration, 11 kV electric voltage, plus 26 G needle size. The authors polymer matrices.
pointed out the powerful capability of the statistical modeling of the ES In comparison with other polymeric matrices, proteins are more
approach as an effectual and adjustable platform for engineering prone to denaturation that is generally a serious obstacle in the develop-
applications. ment of protein-based delivery systems where high temperatures and
organic solvents are applied. The ES approach, however, can confer a di-
minished contact of these labiles with solvents upon room pressure/
3.3. Matrices for electrospraying
temperature and prove to be superior to traditional methods for the fab-
rication of protein-based carriers, sensitive to denaturation.
The spectrum of electrosprayable materials is appreciably broad. A
Besides, the combined polymeric systems are recently considered as
vast variety of polymers i.e., polyesters, natural/synthetic polymers,
one of the effectual strategies for the encapsulation of bioactives
plus stimuli-responsive matrices have been implemented for ES sys-
through ES. For instance, in a study applied by Fukui et al. [88], a
tems (Table 2), illustrating the broad gamut of circumstances that can
mono-dispersed polyelectrolyte polymeric complex based on anionic
1
alginate and cationic chitosan with high EE (> 99%) was designed
Central composite design
2
Response surface methodology
using ES and utilized for the encapsulation of albumin (Fig. 6a), dextran
4
Table 1 (Fig. 6b), and living cells (Fig. 6c-f). When the polyanionic/polycationic
Critical parameters for tuning the properties of electrosprayed nanoparticles. polymer solution was electrosprayed into an oppositely charged poly-
Parameter Effectiveness Reference mer solution, a spherical interface containing a polyelectrolyte system
Process variables
was shaped through electrostatic interactions and generated microcap-
Distance to collecting • Application of shorter distances leads [25,29,42,43] sules (~100 μm) with a narrow size distribution. The capsule diameter
plate to the creation of stronger electric was controlled in the range of 80 to 230 μm by changing the process
fields and also smaller particles will conditions, e.g., flow rate, working voltage, the needle-to-collector dis-
be produced.
tance, needle diameter, and specially polyelectrolyte concentration.
• Utilization of too small distances
typically results in the formation of
aggregated products, owing to the 3.4. Physical/chemical attributes of electrosprayed nanoparticles
inadequate time for solvent evapora-
tion and also particle consolidation.
The electrosprayed NPs typically utilized in food/medical field pos-
• Employment of too-long distances is
associated with applying higher sess a relatively high functional surface area which facilitates carrying,
operating voltages to compensate for binding, or absorbing a vast variety of bioactive molecules. Therefore,
the decreased electrical field the ever-growing development of these structures in the food/medical
intensity, leading to decreased parti-
realm, stems undoubtedly from such flexibility [89,90].
cle deposition and product yield.
Solution infusion rate • At lower flow rates, smaller, denser, [25,44–46]
The physical/chemical attributes of the electrosprayed NPs count as
as well as more mono-disperse par- one of the main critical factors that can determine the release behavior, bi-
ticles can be obtained. ological impacts, toxicity, as well as the biodistribution of the payload
• Higher flow rates led to the forma- in vitro/in vivo [15]. These features hinge upon different factors e.g., size,
tion of wet products with a broader
homogeneity, morphology, reactivity, porosity, construction, and compo-
size distribution, larger particle size,
and less consistent morphology, sition of developed particles [91]. For example, particle size is an effective
resulted from particle fusion and factor in the reactivity of electrosprayed products, as the biological perfor-
inadequate time for solvent evapora- mance of the nano-dimensional particles differs from that of microscopic
tion. electrosprayed structures [43]. A decrease in size of the NPs is normally ac-
• At too low flow rates, dry products
with a larger particle size were
companied by an increase in their penetration into the cellular barriers
obtained. [92]. When the size of the particles diminishes, the higher surface-area-
Electrical conductivity • It could be easily increased by adding [47] to-volume ratio of engineered structures can increase both aggregation
small amounts of dopants and interaction with bioactives (e. g., vitamins, proteins, lipids, etc.). It is
(e.g., organic salts) to the solvent.
noteworthy that the aggregation phenomenon could be resulted from var-
• The greater the conductivity, the
smaller the size of produced ious interactions, e.g., van der Waals, Born repulsion, structural solvation,
particles. electrostatic, hydrophobic, as well as hydrodynamic [93].
Electric voltage • It offers the driving force for the [48,49] The chemical attributes of the electrosprayed architectures can in-
EHDA and affects the particle size fluence their (bio)stability, bioactive release, and cellular uptake [94].
and morphology.
• Applying the high operating voltages
In light of porosity of the electrosprayed structures, it has been demon-
is associated with the formation of strated that the porous NPs possess a higher capability for bioactive de-
smaller particles with a narrower livery owing to their superior bioactive-loading capacity, targeted/
size distribution, resulted from the sustained delivery, and controlled release manner [95,96]. Besides the
increased jet current, more repulsion
particle size/morphology and surface modification, the particle distribu-
between adjacent droplets, as well as
less coalescence. tion/accumulation on intended locus are also under consideration in
The gauge of the needle • It affects the size and size distribu- [50–52] food/biomedical usages [39].
tion of the dry products by deter- From the mechanical perspective, the features of the electrosprayed
mining the diameter of the base of nanosystems depend on the origin, material composition, plus struc-
the Taylor cone.
• Larger inner needle diameter causes
tural configuration of the matrix [76]. For food packaging applications,
to the formation of either larger the developed products should have a proper mechanical strength to
and/or more polydisperse particles shield the constituents for a long period of time. In the case of bone tis-
or even sputtering of the polymer sue restoration, an appropriate electrosprayed material is a matrix with
solution without creating any
suitable mechanical properties similar to that of the native bone matrix,
particles, because of the enhanced
the effective flow rate of the solution which can strongly support adhesion, growth, differentiation, as well as
at smaller needle gauges. mineralization of the osteogenic precursor cells [97,98].
Solution properties
Viscosity • Increasing the viscosity gives rise to [53]
3.5. Application of bioactive-comprising electrosprayed carriers
the generation of particles with a
higher particle size and polydisper-
sity index. Electrosprayed nano-particulated systems are considered as newly
• In order to diminish the particle size, developed carriers, hence insufficient in vivo investigations having
lower viscosities could be utilized.
been applied and the EE of most of these vehicles has been confirmed
Surface tension, solution • They can only be changed within [54] [55,56]
density, and dielectric narrow limits, and therefore they are
only via model bioactives. In this context, some of the bioactive delivery
constant not highly effective in tailor applications of electrosprayed carriers together with relevant instances
morphology, particle size, as well as from the literature are highlighted in Table 3.
size distribution.
• An enhancement of the magnitude of
surface tension is associated with a 4. Strategies for delivery of poorly water-soluble bioactives via
reduction in particle diameter. electrospraying
• The higher density of the feed
solution, the larger the Different loading techniques i,e., (i) electro-encapsulation and (ii)
electrosprayed particles.
adsorption approaches have either been utilized or could be properly
5
Fig. 3. A schematic representation explaining the effect of diverse electrospraying parameters on the diameter of engineered nano/micro-particles.
Fig. 4. SEM images of air (a), vacuum (b), and freeze dried (c) GLS/A beads produced by electrospraying [58]; electrosprayed structures based on cellulose acetate + cellulose nanocrystal
(dichloromethane: acetone) (d), cellulose acetate + cellulose nanocrystal (acetic acid: acetone) (e), cellulose acetate (acetic acid: acetone) (f), cellulose acetate (dichloromethane:
acetone) (g) [61].
6
Fig. 5. Optical microscopic images, SEM micrographs, and size distributions of electrosprayed alginate micro-beads (G refers to the needle size) [62].
Table 2
A summary of polymers utilized in electrospraying for bioactive delivery.
Material Polymer category Degradation manner Injection Application Reference

set-up
Eudragit L100–55 Stimuli responsive Non-biodegradable Single and Drug delivery [70]
coaxial
Silk fibroin Natural Long-term degradable (proteolytically) Single Drug delivery [71,72]
Octenyl succinic anhydride Esterified natural Hydrolysis of esterified linkages and enzymatic Single Antimicrobial delivery [73]
(OSA)-starch polymer decomposition
Polyvinyl alcohol (PVA) Synthetic Non-degradable Single Drug delivery [74]
PMMA, Eudragit/RS Stimuli responsive Non-biodegradable Coaxial Antibiotic delivery [75]
Chitosan Natural Enzymatic decomposition Coaxial/ single Nanoencapsulation of bioactive [76,77]
molecules
Bovine serum albumin (BSA) Natural Proteolysis and hydrolysis Single Drug delivery [78]
Alginate Natural Non-degradable Single Cosmetic additives [79]
Poly(lactic-co-glycolic acid) Polyester Degradation of esterified linkages by hydrolysis Single Encapsulation of amino acids [80]
(PLGA)
Starch Natural Enzymatic decomposition Single – [81]
Acetalated dextran (Ac-DEX; Stimuli responsive Hydrolysis of acetal groups Coaxial Adjuvant or antigen delivery [82]
Ace-DEX)
Gelatin Natural Proteolysis and hydrolysis Single Soft tissue engineering [83]
Polycaprolactone (PCL) Polyester Degradation of esterified linkages Coaxial Production of core-shell [84]
microspheres
Poly(lactic acid) (PLA) Polyester Degradation of esterified linkages Coaxial Drug delivery [85]
Cellulose Natural Hydrolysis by cellulose enzymes Single Dye adsorption [62]
PEG Polyether Non-degradable Coaxial Drug delivery [86]
Inulin Natural Acids or enzyme hydrolysis Coaxial Drug delivery [87]
Zein Natural Proteolysis and hydrolysis Coaxial Drug delivery [41]
7
Fig. 6. CLSM images of electrosprayed alginate-chitosan particles comprising albumin–FITC (a) and TRITC–dextran (MW = 155,000) (b); phase-contrast images of yeast-loaded alginate-
chitosan particles in YPD media at diverse intervals following the productions: 0 h (c), 8 h (d), 16 h (e), and 24 h (f). The scale bar is 100 μm [88].
considered for the encapsulation of low-aqueous soluble bioactives arrangement demonstrates the benefits of combining the attri-
through electrically particulated systems, as discussed in the following butes of diverse kinds of components, and can develop multiple
sections. particles simultaneously via distinct micro-channel arrays. Fur-
thermore, it facilitates controlling the structure/composition of
4.1. Electro-encapsulation techniques the NPs and adjusting the release mechanism of the loaded bioac-
tives [86,123].
Nanoencapsulation of hydrophobic bioactive agents within the elec- • Side-by-side design: It can be utilized to facilitate the flow of di-
trically particulated systems could be applied by means of a number of verse materials through distinct capillaries [124] (Fig. 7c).
techniques, including:
4.2. Adsorptive approach
• Single nozzle: It includes ES of a bioactive-suspended/dissolved
polymer solution by solidification through evaporation. The bioactive-
In the adsorption method, the bioactive molecule is adsorbed onto
polymer system is electrosprayed followed by the solvent evaporation.
the electrosprayed vehicle by exposing the vehicle to solution contain-
Therefore, the low water-soluble bioactive/drug gets loaded in the
ing active agents. It is worth mentioning that a loose attach of the bioac-
dried carrier matrix.
tive and consequently a notable burst release mechanism is the most
• Blend ES: It considers as the most common and the easiest approach important shortfall of this technique [125].
of ES (Fig. 7a).
• Emulsion ES: Upon this technique, the bioactive molecule, aque- 5. Electrospraying for encapsulation of hydrophobic or poorly-water
ous medium, and oil phase are emulsified into a homogeneous soluble bioactives
emulsion before passing through the single capillary nozzle, to
be electrosprayed into core−shell designed NPs (Fig. 7b) [122]. Electrosprayed micro/nano-particles as food/pharmaceutical reposi-
tories demonstrate multiple benefits for the delivery of different poorly
• Coaxial arrangement: ES via a two-capillary nozzle or two-fluid co- water-soluble bioactives for healthcare and food applications [89–91].
axial ES has exhibited great capabilities, as the coaxially core-shell First, by virtue of the large surface-area-to-volume ratio and micro/
structures will diminish the possible occurrence of the burst re- nano-scaled configuration, electrosprayed particles are susceptible to
lease mechanism and may attain near zero-order release proper- the surrounding environment and typically result in effective bioactive
ties [41]. Besides, it needs less time to generate NPs and carrying to the intended locus [27,126]. Second, the release behavior is
possesses great embedment/loading potential (Fig. 7d). Coaxial adjustable via tuning the porosity and diameter of particles [127]. In
8
Table 3
Food/biomedical applications of various electrosprayed materials.
Electrosprayed matrix Loaded molecule Particle EE (%) Reference

diameter
Drug delivery
Hydroxypropyl methylcellulose Paracetamol 0.76–1.67 μm ~100 [20]
Egg white-alginate Paclitaxel 150–200 nm 10–12 [99]
PVA hydrogel-PCL microspheres Doxorubicin hydrochloride 1.1–5.7 μm ~73–78 [74]
Encapsulation of live probiotics

Acacia gum Lactobacillus plantarum ~2–5 μm N/A [100]
Whey protein Lactobacillus casei ~2–4 μm N/A [101]
Whey protein-pullulan Bifidobacterium strains ~1–8 μm N/A [102]
WPC Lactobacillus plantarum N/A N/A [103]
WPI, Persian gum, and inulin Lactobacillus rhamnosus 359–596 nm N/A [104]
Zein–alginate Lactobacillus acidophilus 259–543 nm N/A [105]
Alginate-pectin Lactobacillus plantarum 105–116 μm [106]
Food additives
Gelatin Epigallocatechin gallate (EGCG) 230–470 nm 96 [107]
Alginate Caffeine ~765 μm ~37–64 [108]
Chitosan EGCG N/A ~80 [109]
Chitosan-gelatin Anthocyanin extracts N/A ~76–77 [110]
Gliadin – ~80–1250 nm – [111]
Gelatin and zein Green tea extract 0.26–0.78 μm 90 [112]
Stearic acid Ethylvanillin ~60–70 nm 70 [113]
Sodium alginate beads Gallic acid 200 μm-1.3 mm ~15–25 [114]
Zein Green tea catechins ~174–187 nm ~90–95 [115]
Ethylcellulose Ethylvanillin 45–85 nm 71–84 [116]
Zein Curcumin N/A 85–90 [36]
Food coating
Maize starch film (40 mm diameter) – – – [117]
W/O emulsions (polyglycerol polyricinoleate and WPI) – – – [118]
Chocolate coating – – – [119]
Sunflower oil – – – [120]
Antimicrobial surface coatings

Chitosan Vitamin E N/A N/A [168]
Tissue engineering/regenerative medicine
Chitosan Ampicillin 520 nm ~80 [50]
Chitosan Boron ~160–174 nm 15 [121]
PLGA Rhodamine B and doxorubicin 60 nm–2 μm N/A [54]
this context, it is principally considered that particles of smaller size ex- 5.1. Phenolic compounds
hibit a higher dissolution rate and a larger surface area, providing faster
release performance [128]. The electrosprayed particles of high porosity Phenolics (e. g., flavonoids, anthocyanidins, hydroxycinnamic acids,
are inclined to make faster bioactive release and clearance of the pay- etc.) are nature-inspired ingredients with one/more aromatic ring
load upon the degradation of the carrier matrix than the particles with (s) and O\\H unit(s), which are found in many fruits, vegetables, tea,
a poorly porous structure [129]. Third, by choosing diverse polymer ma- and even coffee with several health-promotional activities (e.g., anti-
trices (namely natural and synthetic polymers or their copolymers), the inflammatory, anti-microbial, anti-cancer, and antioxidant capabilities).
degradation/mechanical features of electrosprayed particles could be Some of phenolic compounds are poorly water-soluble, whereas others
customized for the intended application [65,130]. Moreover, the de- possess poor solubility in lipids. Nevertheless, various factors such as
gradability is controllable by modifying the ratios of amorphous-to- environmental or digestive circumstances could result in a partial or
crystalline domains or regulating the polymer blend composition. For even complete loss of their bioactivity. In order to prevent degradation
instance, PLGA-based polymers possess a fast degradation period re- and maintain biological activity, numerous attempts have been made
sulted from the hydrolysis of their glycolide constituents. In another to encapsulate and shield these bioactives within micro/nano-capsules
hand, PDLLA3 matrices degrade slower (~12 months) due to the by ES.
presence of the methyl units in their structure [131]. In a PDLLA-PLGA For example, curcumin is a polyphenol with a myriad of bio-
system, the degradability/mechanical attributes are tuneable by con- functional activities, e. g., anti-inflammation, anti-oxidation, and antimi-
trolling different ratios of polymers in the produced structures [130]. crobial effects; but, its food/pharmaceutical functionality and oral
Forth, electrosprayed particles are potent to deliver bioactives to the bioavailability is restricted due to its high insolubility in aqueous
specific sites through restricting systemic side influences. Last but media. Gómez-Estaca et al. [133] developed electrosprayed gelatin
not least, to be specific, uniquely engineered surface area, highly NPs loaded with curcumin to overcome this limitation. The compact
porous configuration, as well as other geometric structures render spherical particles of gelatin-curcumin were around few nm to >1 μm
electrosprayed micro/nano-particles more efficacious in food/medical in diameter (Fig. 8a) and greatly effective in curcumin delivery with
usages [129,132]. EE being close to 100%. The bioactive polyphenol was uniformly dis-
As far as poorly water-soluble bioactives are concerned, various bio- persed through the electrosprayed particles, according to fluorescence
logically active ingredients have been successfully encapsulated within microscopy, while MDSC4 investigation displayed a complete loss of
electrosprayed matrices, as described below. the bioactive crystallinity in prepared solid dispersions. The antioxidant
3 4
Poly(D,L-lactic acid) Modulated differential scanning calorimetry
9
Fig. 7. Schematic illustration of different set-ups for electrospraying.
activity and aqueous-solubility (Fig. 8b) of curcumin enhanced follow- destabilization of the ES jet and production of smaller capsules. It
ing nanoencapsulation. Notwithstanding the negligible antimicrobial was demonstrated that emulsions prepared using ultrasound ho-
capacity of free curcumin at concentrations <100 mg mL−1, the devel- mogenization technique could provide EE up to 97%. Furthermore,
oped protein capsules at a concentration of 4 mg mL−1 could diminish the bioactive-loaded particles had a good stability at neutral/alka-
the microbial population by 1.67, 2.08, 2.18, and 2.70, log counts line pH values (6–9) and low RH (26–53%).
(CFU mL−1) for S. enterica, L. monocytogenes, E. coli, and S. aureus, re- Quercetin as a flavonoid is found in various foods/plants and evinces
spectively. Gómez-Mascaraque et al. [135] also designed a hybrid en- several biological properties, e. g., anti-carcinogenic, anti-diabetic, anti-
capsulation system relying on curcumin-loaded liposomes within a inflammatory, anti-viral, and anti-oxidative effects. In traditional medi-
WPC network via ES. The engineered structures could considerably im- cine, it is mostly employed to hamper phlegm, avert asthma, as well as
prove the solubility, stability, and bioaccessibility (~1.7-fold) of alleviate a cough. Currently, it has been also documented that quercetin
curcumin compared to the free form. Moreover, the loading capacity can be effective in inhibiting cellular senescence and promoting osteo-
of the hybrid vehicles enhanced by the incorporation of polyphenol mi- genic differentiation of stem cells for bone generation. However, this
crocrystals upon nanofabrication. bioactive possesses low solubility in water, a high melting point, and
Tea or tea-based products are recognized to hold a broad range poor oral bioavailability of ~2% in body, causing its application challeng-
of bioactive flavonoids, especially catechins. EGCG is a principal ing. Moreover, quercetin is quickly cleared in vivo as a consequence of
constituent of tea catechin, which reckons as a potent antioxidant, its metabolism in the liver. In this background, a fast-dissolving querce-
radical scavenger, reducing agent, as well as metal chelator. The tin system of prompt performance following oral administration would
main drawbacks of EGCG are its poor lipophilicity and low chemical be considerably beneficial to raise patient convenience. Li and co-
stability, which may complicate incorporating this bioactive into workers [136] designed a quercetin-loaded core-shell system using co-
lipid-based food products, e.g., fats/oils. In a study performed by axial ES, as the core material contained bioactive quercetin and 10% (w/
Paximada et al. [134], emulsion ES technique was introduced as a v) polyvinyl pyrrolidone (PVP) in dimethylacetamide: ethanol (4∶6, v∶v)
promising technology for nanoencapsulation of hydrophilic and li- and the shell matrix comprised of PVP (10% w/v), sucralose (0.3% w/v),
pophilic catechins into WPI/bacterial cellulose based NPs. Different and sodium dodecyl sulfate (0.2% w/v) in water: ethanol (0.5∶9.5, v∶v)
morphologies were attained through the ES of EGCG emulsions re- medium. Electrosprayed products were fabricated with 3 diverse
lying on the applied homogenizing approach (ultrasonication or bioactive loadings of ~8, 11, and 17% (w/w) and yielded the particles
high pressure homogenization) and the bioactive type (hydrophilic with average diameters of ~1.69, 1.74, and 1.85 μm, respectively. The
or lipophilized EGCG). The spherical sub/−micron particles were produced structures were in an amorphous physical state and could
yielded for the emulsions engineered by both techniques (Fig. 8c, successfully improve both in vitro dissolution and permeation rates
d). When the application of ultrasonication led to the generation (~10 folds faster across the sublingual mucosa) of loaded poorly
of homogeneous nano-sized capsules, the high shear homogenizer water-soluble bioactive, quercetin. Such system thus possesses a potent
yielded mixed heterogeneous structures of broader size distribu- potential to increase the (bio)functional properties of bioactives/drugs,
tion and bigger average size (Fig. 8c, d). The reason could be the and to be further utilized as an efficient oral/sublingual bioactive/thera-
higher conductivity of ultrasonicated emulsions, leading to the peutic carrier.
10
Fig. 8. Visible spectra of curcumin-loaded gelatin in water (dotted line) and raw curcumin (solid line) (a); SEM image of electrosprayed gelatin particles fabricated from 5% (w/v) protein
solution (b) [133]; SEM of hydrophilic and lipophilized EGCG (HEGCG and LEGCG, respectively) loaded with emulsion electrosprayed BC-WPI particles: blank sample produced by high
shear homogenizer (HSH) (c1), HSH+ HEGCG + aqueous phase (c2), HSH + LEGCG + aqueous phase (c3), HSH + HEGCG + oily phase (c4), and HSH + LEGCG + oily phase (c5), blank
sample produced by ultrasonication (US) (d1), US+ HEGCG + aqueous phase (d2), US+ LEGCG + aqueous phase (d3), US + HEGCG + oily phase (d4), and US + LEGCG + oily phase
(d5) [134].
Table 4 lists more examples of electrospraying encapsulation of phe- release manner. The authors elucidated that the higher concentra-
nolic compounds. tions of ethanol resulted in the formation of hydrated capsules of
larger size (Fig. 9). Furthermore, the rise of solvent concentration
5.2. Carotenoids possessed a destabilizing impact on the WPI configuration, accord-
ing to fluorescence spectroscopy and data attained from the reactiv-
Carotenoids, as one of the most popular groups of the nature- ity of free sulfhydryl domains.
spired colorants, demonstrate plenty of health-benefits when con- In the ES process, the bioactive/carrier ratio can dramatically in-
sumed at an appropriate level [12]. Particularly, β-carotene is a fluence the EE, loading capacity, and even in vitro release in diverse
highly reputed bioactive carotenoid that can be exploited to hinder fashions as revealed in a study harboring poorly water-soluble β-
a number of ailments, i.e., cancer, cardiovascular diseases, as well as carotene in an emulsion electrosprayed glucuronoxylan-based ma-
macular degeneration [144]. Despite this, the low solubility of this trix [14]. It was demonstrated that increasing the carotenoid/car-
functional ingredient in the aqueous environments hampers its rier matrix proportion intensely decreased the bioactive loading
food/pharmaceutical applicability and weakens its bioavailability/ and EE. This showed how complex the control of different ES fac-
bioaccessibility [145]. In this framework, Rodrigues et al. [146] tors can be, particularly concerning emulsions. The authors also
employed an ES technique to generate β-carotene-embedded NPs pointed out that increasing the β-carotene level (2.5–20%) in
using WPI and investigated the molecular organization of devel- formulated emulsions was accompanied by a nanoparticle-to-
oped capsules in dried or hydrated state. The protein solutions nanofiber transition of engineered structures. In the case of lower
were dissolved in aqueous media of ethanol (5–15%), which were concentrations of the bioactive (2.5 and 5%), ES was the dominant
further applied for carotenoid solubilization. The particle diameter phenomenon and induced the production of uniform NPs, although
of the dried products was around 227–283 nm; however, there nanofibers or the beaded-fiber morphologies were observed for 20
was a notable enhancement in the size of the NPs after hydration. and 10% β-carotene, respectively. Interestingly, the carotenoid-
Solvents are important means to adjust the particle size/morphol- carrying NPs exhibited a higher encapsulated bioactive and greater
ogy, as a result of miscellaneous evaporation rates, which leads to physicochemical/thermal stability compared to those loaded
the generation of more/less porous structures and defines the within electrospun bodies.
11
Table 4
Some examples of electrosprayed carriers for encapsulation of poorly water-soluble phenolic compounds.
Phenolic Carrier Particle size Encapsulation Comments References

compound matrix efficiency (EE)
Olive leaf WPC ~232 to 660 nm 80% < • Nanocapsules were spherical in shape with negative zeta potential. [137]
phenolics • The particle diameter was highly dependent on the core or wall material concentration.
• Application of higher concentrations of the protein solution and bioactive molecule led to a
significant increase in EE.
• Increasing the protein content (15–30%) induced the formation of smaller nanocapsules,
while larger particles were produced after increasing the bioactive concentration
(500–1000 ppm).
• Nanovehicles containing 500 ppm phenolics and 15% WPC had the highest level of
oleuropein, tyrosol, and caffeic acid; but the highest content of hydroxytyrosol was detected
for particles comprised of 15% protein and 1000 ppm bioactive.
Resveratrol Zein 230–330 nm ~68% • Resveratrol-zein system successfully developed for oral administration by addition into food [138]
products or in tablet form.
• Resveratrol-encapsulated protein nanoparticles showed good in vitro stability, sustained
release profiles, increased permeability, and improved bioavailability as compared to the
pure bioactive.
Quercetin PLGA 300–350 nm N/A • The electrosprayed capsules containing the anti-oxidant drug were in a non-crystalline state [139]
with spherical shape, narrow size distribution, and smooth surface.
• The prepared structures displayed a biphasic release profile: a) a rapid release upon a few
hours and b) a sustained slow release during ~2 months.
• Quercetin-loaded nanoparticles exhibited a powerful capability to be utilized in hindrance of
cardiovascular diseases.
Curcumin Gelatin Up to 1.2 μm Close to 100% • Curcumin–gelatin particles were in the amorphous state and showed high anti-oxidant [140]
activity.
• Both bioactive bioaccessibility and water solubility were notably promoted after encapsula-
tion (11.3-times and 38.6 greater than free curcumin, respectively).
Quercetin PLGA 1 to 4 μm ~82% • A long-term release pattern of the bioactive was achieved in vitro (upon 1 month) with [141]
slight sign of a burst release.
• The bioactive flavonoid properly encapsulated within PLGA particles in an amorphous or a
molecularly dispersed form.
• There was no chemical interaction between quercetin-PLGA.
• The electrosprayed particles displayed no toxic effect when treated to INS-1 cells.
Curcumin PLA 3.8–4.4 μm > 95% • A new PLA-curcumin system with various polymer concentrations (1 to 7%), solvent media [142]
(i. e., acetone, dichloromethane, tetrahydrofuran, plus trichloromethane), as well as
curcumin levels (0–15%) was developed.
• The optimized formulation was obtained through bioactive concentration of 10%, speeding
rate of 0.3 mL h−1, and polymer concentration of 3% using trichloromethane as solvent.
• Following an initial burst release (12h), a sustained release of the bioactive from the
electrosprayed structures was attained (〈200h).
• The curcumin-PLA particles represented outstanding anti-bacterial properties (against
Escherichia coli and Staphylococcus aureus), superior anti-oxidant activity, high
biocompatibility, as well as low cytotoxicity.
Curcumin PLGA From hundreds of ~100% • The influence of electric field (0–10 kV, 0–5 kV, or 10–0 kV) and inner/outer speeding rate [143]
Submicron to tens of Coaxial (0.1 to 5 mL h−1) were investigated.
micron arrangement • The best results was obtained through applying 4–6 kV electric field.
• The coaxial electrosprayed products could efficiency shield curcumin and provide optimal
release manner.
Curcumin Zein 175–900 nm ~85–90% • Production of protein nanoparticles from polymer concentrations of 2.5–15% (w/w). [36]
• Generation of compact and collapsed/shrunken nanostructures for 2.5–5% and 10–15% pro-
tein solutions, respectively.
• The lower the applied flow rate, the smaller the nanocapsules.
• Following 3 months of storage upon 43% humidity at 23 °C, neither the size/ morphology of
electrosprayed bodies had experienced remarkable alterations, nor had the bioactive level
changed.
• After nanoencapsulation, the bioactive represented high-aqueous dispersibility in food
matrices e. g., semi-skimmed milk.
Gómez-Mascaraque et al. [147] improved the solubility and in-vitro changing their EE. Some hollow holes were observed for WPC particles
bioaccessibility of β-carotene by encapsulation within protein-based developed by the high-speed homogenizer, suggesting the imperfect em-
electrosprayed bodies. Two diverse emulsification approaches (i.e., high- bedment of β-carotene within the electrosprayed particles, probably
speed homogenization and ultrasonication) and tow protein networks owing to their big dimensions. Besides, ultrasonication led to a remarkable
(including zein and WPC) were employed to apply emulsion ES strategies. decrease in the particle size of WPC particles, resulted from lowering the
It was revealed that emulsion stability was an important parameter emulsion droplet size and the conformational variations of the protein
influencing the EE. All the electrosprayed carriers, apart from those matrix. When emulsions were prepared by high-speed homogenization,
engineered by WPC emulsions through high-speed homogenization, zein capsules with the highest EE of ~34% displayed a rougher surface,
could successfully promote the bioaccessibility of the carotenoid following smaller particles, and greater content of nano-fibrils than those of WPC
in-vitrodigestion,which wasnegligiblein its freeform.Theultrasonication formulations.
technique could be effective in stabilizing the WPC emulsions and in- Ramos-Hernández and co-workers [148] utilized Agave fructan NPs as
creased the EE of the quasi-spherical WPC capsules. However, it possessed a new carrier for nanoencapsulation of β-carotene via emulsion ES, solu-
a slight negative influence on the carotenoid-loaded zein structures as a tion direct ES, and ES coating techniques. The carotenoid-loaded NPs
result of the thermal degradation of bioactive, without considerably were around 440–880 nm (Fig. 10a-e) relying on ES conditions and
12
Fig. 9. TEM images of electrosprayed WPI nanoparticles following dissolution: protein dissolved in 5% (a), 10% (b), and 15% (v/v) ethanol (c) together with carotenoid-loaded WPI
nanocapsules in 5% (d), 10% (e), and 15% (v/v) ethanol (scale bar is 500 nm) [146].
hydrocolloid concentration and had great photo/thermal resistivity. The higher surface-area-to-volume-ratio of smaller particles provides a
optimized formulation, in terms of particle size and shape, were attained faster release mechanism, as these particles can be more efficiently pen-
when about 30 or 40% of carrier matrix was applied. The ES coating offered etrated by fluids, promoting the diffusion of therapeutics and easier de-
benefits when compared to the emulsion or solution direct ES, as it poten- composition of the polymer carrier.
tially facilitated the production of particles with higher payload: carrier López-Rubio & Lagaron [149] revealed that the greatest proportion of
proportions. Besides, the structures yielded through the ES coating ap- larger particles was attained from the protein solution upon pH = 6.4
proach demonstrated superior photo-protection. In another attempt, the (as-received specimen). Either boosting or lowering the pH of the protein
potential of electrosprayed WPC structures (micro-, submicro- and NPs) medium resulted in the formation of smaller WPC vehicles (sub-micron
for the encapsulation of β-carotene was investigated by López-Rubio & or nano-sized particles) that had a narrower size distribution. The addi-
Lagaron [149]. The solvent medium for the generation of protein-based de- tion of glycerol (10–40 wt% with respect to the WPC level), as a potent
livery systems was water, rendering these structures highly appropriate polar co-solvent, into the protein aqueous solution also induced the de-
for the development of functional food products. The round and smooth velopment of round and relatively smooth structures (Fig. 10j), except
electrosprayed WPC particles (at 40 wt% protein concentration) (Fig. 10i) at the highest glycerol level (40 wt%), which caused the accumulation of
were fabricated successfully in a wide pH range and for some glycerol con- an amorphous mass of products on the grounded plate.
centrations, and both factors were effective on vehicle size or conforma- Lycopene, as a commonly used carotenoid, natural red pigment, and
tion. At pH = 4.5, a gel network developed which was inappropriate for antioxidant, is typically found in tomato and other red fruits (such as
ES. However, at pH > 8.5, a protein mass, without a definite morphology watermelon and papaya) and applied to avert chronic diseases
was formed on the collecting plate. From Fig. 10k, l, β-carotene was prop- e.g., atherosclerosis and skin/prostate cancer [152]. Nonetheless, the
erly dispersed through the protein matrix (EE of about 90%), while there presence of many unsaturated bonds in its structure makes lycopene
were some agglomerated structures producing the larger carotenoid- very labile to oxidants, light, as well as heat. Lycopene also possesses a
loaded particles. Agglomeration was revealed to influences the release very poor water solubility, restricting its industrial applicability in
mechanism of the bioactives, as sizes of particle clusters may create orders aqueous-based systems [153,154]. A comparative study on the stability
of magnitude bigger than that of distinct particles. It also complicates the and morphology of lycopene-loaded micro- and nanovehicles was ap-
reproducibility of the release pattern and offers a lower cumulative release plied by Pérez-Masiá et al. [150] using either ES or spray drying tech-
compared to disperse structures [151]. nique. The carotenoid was incorporated within diverse edible matrices
Besides agglomeration, the particle size reckons as one of the most including chitosan, WPC, and dextran, as in the case of the latter two, ei-
critical parameters affecting the release profiles of the electrosprayed ther emulsion or coaxial ES were also compared together. Based on UV–
biologically active molecules. While the larger capsules usually release vis5 measurements, the spray-dried structures possessed a low EE,
the payload more slowly and under a longer period of time, the particle likely due to the necessity of applying high temperatures in this
size diminution can endow various bio-adhesive improvement factors,
i.e., prolonged gastrointestinal transit time through the enhanced adhe-
sive force, offering a superior drug bioavailability. In other words, a 5
Ultraviolet–visible spectroscopy
13
Fig. 10. SEM images of β-carotene-loaded electrosprayed Agave fructan nanoparticles at various polymer concentrations (10% (a), 20% (b), 30% (c), 40% (d), and 50% (e)) (Ramos-
Hernández et al., 2018); electrosprayed WPC capsules prepared from 40 wt% protein aqueous solutions without (i) and with 20 wt% glycerol (j); photographs of β-carotene-
encapsulated WPC capsules obtained through normal illumination (k) and fluorescence source (l) [149]; SEM images of WPC-lycopene capsules fabricated via emulsion
electrospraying (f), coaxial electrospraying (g), and spray drying (h) [150].
approach, which caused a partial decomposition of the bioactive. In an- 6. Fatty acids and essential oils
other hand, the emulsion electrosprayed lycopene-NPs, particularly the
protein-based ones (Fig. 10f,g,h) showed a high EE (about 75%) and α-linolenic acid (ALA), as one of the most relevant ω-3 fatty acids, is
remained thermally/physicochemically stable following the encapsula- efficacious in controlling cellular functionality and protecting the
tion process. In light of dextran solutions, emulsion ES led to the produc- neurovascular, cardiovascular, as well as mental health [156]. Neverthe-
tion of more uniform particle sizes than coaxial arrangement which less, ALA is a thermosensitive hydrophobic bioactive and notably sus-
generated more aggregated structures. Moreover, ES using WPC solu- ceptible to oxidative decomposition in the presence of light and O2
tions led to the fabrication of more heterogeneous particles, no matter [157]. Indeed, ALA counts as the most important precursor of flavor re-
which type (emulsion/coaxial ES) was applied. Interestingly, a higher version [158] and, therefore, this high instability can jeopardize not only
degradation or less encapsulation potential was found for chitosan sam- the nutritional quality of ALA-enriched products, but also their shelf-life
ples than the others, likely because of the acidic environment employed and sensorial attributes [159]. In this context, Gómez-Mascaraque et al.
in the fabrication of electrosprayed vehicles. [160] applied emulsion ES and spray drying strategies to encapsulate
14
ALA in different protein-based matrices (i.e., gelatin, whey protein con- An enhancement in the pectin concentration gradually decreased
centrate (WPC), plus soy protein isolate (SPI)). While the spray-dried the EE of fabricated carriers, as the capsules generated via 100%
system led to the complete degradation of the ALA resulted from its pectin were comprised of around 27.7% bioactive oil. Along with
high thermosensitivity, the electrosprayed ALA-loaded particles the particle diameter and particle size distribution, morphology is
showed EE >70%, and the fatty acid degradation significantly decreased one of the main contributors in adjusting bioactive release charac-
at 80 °C. When the free bioactive contained <8% of alkene groups fol- teristics. It was indeed revealed that wrinkled structures typically
lowing the thermal treatment (27 h), about 67% and 43% still main- resulted in an initial burst release of the payload, which was not de-
tained intact within the WPC and SPI particles, respectively. tected for spherical electrosprayed materials with a mono-disperse
Encapsulation of raw fish oil, as a source of ω-3 fatty acids, has size distribution [166]. The authors stipulated that the surface mor-
intensively investigated via the ES technique, nowadays. In this line, phology of the electrosprayed products found to be rough, and the
García-Moreno et al. [161] utilized an electrosprayed dextran system particles were mostly spherical in shape with some surface wrinkles.
as a polysaccharide vehicle to encapsulate cod liver oil. However, In light of the dried specimens, the wrinkled structures could be as-
owing to the low emulsifying capability of the polysaccharides, the de- sociated with the loss of water upon freeze-drying. The utilization of
veloped structures exhibited poor oxidative stability. Another research higher proportion of alginate in combined system (alginate: pectin
group subsequently pointed out the great potential of the protein- of 100: 0, 80: 20, and 60: 40) led to the production of less agglomer-
polysaccharide system (WPC-carbohydrates combination i.e., pullulan, ated and round-shaped structures, according to Fig. 11a-c1. How-
dextran, plus glucose syrup), as a more appropriate substitute, to encap- ever, the particles engineered by alginate (0%): pectin (100%) were
sulate bioactive oils. Ultimately, the authors revealed the superior capa- less interested in capturing the essential oil and possessed a porous
bility of electrosprayed protein particles in shielding bioactive fatty surface, heterogeneous size distribution, and uneven surfaces
acids than those produced via polysaccharide matrices [162]. (Fig. 11d). The presence of more pores in wrinkled structures facili-
In another study, uniaxially/coaxially-electrosprayed particles tates molecule adsorption rather than bioactive encapsulation. Be-
based on zein and gelatin structures were employed to protect ALA sides, the water penetration is typically more accessible in porous
and EGCG, as a model of hydrophobic and hydrophilic bioactive, respec- bodies, leading to the prompt diffusion of absorbed bioactives/
tively [163]. The material composition induced the size variations and drugs and causing a considerable burst release. In the context of
EE was strongly hinge upon the chemical affinity between the carrier denser structures, the water penetration rate is decreased, which po-
matrix and the payload material; however, in general, superior EE for tentially endows favorable zero-order release [166]. Ultimately, the
both bioactives was belonged to the coaxial systems. Besides, the authors clarified that proper combinations of the alginate-pectin
coaxially-designed particles demonstrated a promoted bioactive pro- system resulted in a synergistic reaction comprising cross-linking
tection capability, according to thermal degradation studies (about between the applied biopolymers, thereby promoting the encapsu-
ALA) and antioxidant activity following in-vitro digestion (about lation mechanism of the bioactive.
EGCG). Moomand and Lim [164] studied the release of a bioactive fish Ghayempour and Mortazavi [52] successfully prepared essential oil-
oil from both electrosprayed and electrospun structures upon simu- loaded alginate micro/nano-capsules via a convenient and effective man-
lated gastrointestinal circumstances. They pointed out that the amount ner, using coaxial ES. An enhancement in the magnitude of operation
of the hydrophobic agent secreted from protein capsules following conditions e.g., ring electrode voltage, feed rate, nozzle diameter, tip-to-
in vitro digestion was considerably greater than those of fibrous bodies, collector distance, as well as polymer concentration/molecular weight
which was associated with the presence of smaller α-helix structures in was accompanied by a considerable increase in particle diameter; how-
electrosprayed products. Notwithstanding the high delivery percentage ever, the applying voltage, CaCl2 content, plus stirring rate were effective
(> 75%) of electrosprayed and electrospun carriers, the main part of the factors in size diminution of developed electrosprayed capsules. This
loaded bioactive was released in the gastric section due to the destabi- approach, thus, was introduced as an efficient route to encapsulate
lization of the protein network as a result of pepsin action. liposoluble bioactives like essential oils, flavors, vitamins, etc. More re-
Docosahexaenoic acid (DHA), as a long chain polyunsaturated fatty cently, Yilmaz et al. [155] utilized ES to fabricate Origanum vulgare essen-
acid of the omega-3 series (ω-3), can exert several positive impacts on tial oil (OEO)-loaded chitosan nanocapsules (290–483 nm) as an
human health e.g., reducing blood pressure, modulating the response effective platform to engineer a thermally stable and anti-microbial car-
to endogenous-exogenous thrombolytic agents, antiarrhythmic effects, rier with high EE (~70–80).
inhibiting platelet activation, modulating inflammation, triglycerides
diminution, as well as lowering the risk of cardiovascular diseases. In a 6.1. Liposoluble vitamins
study, Torres-Giner et al. [167] used ultrathin zein-prolamine based ve-
hicles to stabilize and encapsulate DHA (an oxygen-sensitive bioactive) Besides poorly water-soluble polyphenols, carotenoids, essential
through ES technique. The DHA-entrapped zein system was assessed oils, and fatty acids, other hydrophobic bioactives e. g., vitamins are
with ATR-FTIR spectroscopy which measured the DHA degradation also encapsulated via ES. Vitamins count as vital ingredients to help
rate upon either ambient circumstances or a confined space. At the lat- the proper performance of the body and prevent a vast variety of dis-
ter case (headspace test), that more closely resembles sealed food pack- eases. They have to be supplied through a proper diet and dietary sup-
aging conditions, the zein capsules could remarkably delay deteriorative plements. The addition of vitamins into food formulations as (bio)
reactions of the payload and promote the chemical stability of the oil- functional agents is highly beneficial, yet challenging for their high
loaded particles. The degradation rate was found to be increasing with heat/oxidative susceptibility and lipophilicity (in the case of vitamins
elevating the storage temperature and lowering the relative humidity. K, A, D, and E). Therefore, they need to be shielded via a suitable carrier
In this context, the zein glass lattice demonstrated a clear delaying influ- matrix to preserve their features and effective delivery through the
ence (2.5-fold) on DHA degradation upon high temperatures or humid- human body.
ity environment, compared to the free bioactive oil. In a study by Stoleru et al. [168], a dual-bioactive layer using antiox-
A peppermint oil-loaded pectin-alginate system was designed by idant tocopherol and antibacterial chitosan was immobilized onto the
Koo et al. [165] using a coaxial ES technique. The produced particles polyethylene surface via ES (as coating approach) for biomedical or
were negatively charged (−53.1 to −21.7 mV) and in the range of food packaging applications. The incorporation of tocopherol into the
1.58 to 3.24 μm. The pectin concentration considerably affected the chitosan network led to a remarkable decrease in the polymer viscosity
system polydispersity, as the higher polymer contents could develop and thus altered the gel-like behavior of the polymer solution to a fluid-
particles of superior homogeneity. The highest EE of ~85% was ob- like behavior. This further affected the electrosprayability of the system
tained through the application of alginate: pectin ratio of 80: 20. and deposited coating morphology. The engineered electrosprayed
15
Fig. 11. FE-SEM micrographs of the peppermint oil-loaded electrosprayed capsules at different alginate: pectin concentration of 100: 0 (a), 80: 20 (b), 60: 40 (c), 40: 60 (d), 20: 80 (e), and
0: 100 (f). a1, a2, and a3 refer to samples a, b, and c, respectively at magnification of 40–100× [165].
products exhibited proper antioxidant and pH-responsive properties. (0.25–0.5%) and PVA (1–2%) concentrations, the process led to the gen-
The fabricated composite coating also could powerfully hinder the eration of electrospun fibril bodies. MEO was successfully loaded in
growth of three diverse bacterial strains i,e., Salmonella typhimurium, engineered NPs without any chemical interaction with the host carrier
Listeria monocytogenes, and E. coli. Besides, the prepared electrosprayed matrix; according to FTIR6 and DSC7 experiments. The release mecha-
materials presented superior stability and maintained their anti- nisms and kinetics of the payload constituents fitted well to the
oxidative capability even at harsh conditions of processing due to the Peppas-Sahlin model for a range of simulated foods (i.e., aqueous, acidic,
comparative robust electrostatic and H\\H interactions between for- alcoholic/alkali, as well as oily food models). Ultimately, it was demon-
mulation ingredients. strated that the release profile of the MEO from the Balangu seed gum
From the literature, there is a lack of information concerning the en- nanovehicles was principally controlled by the Fickian diffusion
capsulation of liposoluble vitamins via ES and data stated in the litera- phenomenon.
ture are not sufficient and robust enough to conclude about aspects D-limonene, a colorless aliphatic liquid hydrocarbon present in es-
affecting the delivery of liposoluble vitamins using this technique. sential oil of citrus fruit peels, is categorized as a cyclic mono-terpene
widely utilized as a food preservative, natural flavoring, as well as fra-
grant agent in food/cosmetics applications owing to its antimicrobial ac-
6.2. Flavors and aroma components
tivities and health benefits. The high lipophilicity of D-limonene not only
makes its bioavailability to be dramatically low, but also can limit its
Mentha longifolia L. essential oil (MEO) is an antioxidant and antimi-
industrial usage in the water-based systems. Besides, oxidative vulner-
crobial bioactive derived from diverse parts of Mentha longifolia L. and
ability and high volatility of this bioactive even upon ambient circum-
extensively utilized as a flavoring and aroma agent in food, pharmaceu-
stances may lead to the creation of off-flavors and the loss of its
tical, as well as hygiene industries. However, the low water-solubility,
biofunctional activities. To deal with such shortcomings, Khoshakhlagh
(bio)chemical instability, and vulnerability to enzymes and extreme
et al. [170] investigated the feasibility of engineering Alyssum
temperatures/pHs are the critical factors, limiting its functionality/ap-
homolocarpum seed gum NPs to encapsulate D-limonene using an emul-
plicability. More recently, Rezaeinia et al. [169] fabricated a nano-
sion ES technique. The flavor-containing emulsions were processed
scaled protective shell based on Balangu (Lallemantia royleana) seed
with constant gum concentration of 0.5% (w/w), at 20 kV and
gum and PVA to promote aqueous solubility, bioavailability, EE, and
0.1 mL h−1 flow rate. The results showed that the morphology of devel-
controlled release of the MEO through ES. In this system, raising the
oped nanostructures were highly dependent on emulsion attributes.
PVA concentration enhanced the emulsion viscosity and promote both
EE (~82–88%) and loading capacity (~78–85%) of the MEO within the 6
Fourier transform infrared spectroscopy
electrosprayed nanocapsules. Furthermore, by increasing the gum 7
Differential scanning calorimetry
16
The ES of pure gum led to the formation of aggregated, irregular-shaped extent of bioactive loading, bioactive concentration or evaporation
NPs while following D-limonene incorporation (10 or 20%), spherical rate of the organic solvent. Consequently, the utilization of polymers
and homogenous nanocapsules were produced. The EE for 10 and 20% with high degree of crystallinity e. g., PCL could facilitate the develop-
flavor-loaded NPs was ~87–93%. Nevertheless, the morphology of ment of micro/nanoparticles of homogeneous and reproducible physi-
yielded structures altered to fibril bodies when the bioactive level in- cal features; however, may be insufficient for proper bioactive/drug
creased to 30%. dispersion and thus release attributes [172].
From the literature, only a handful of research studies can be found For example, in a study performed by Ding et al. [173], a plant alka-
where electrosprayed/electrospun structures have been implemented loid, Taxol, with anti-cancer property and poorly water-solubility
for encapsulation of hydrophobic/hydrophilic flavors. It would be valu- was loaded within electrosprayed PCL particles (65 kDa). ES yield was
able for more studies to be developed toward utilizing bioactive flavors ~80% and a sustained release profiles upon 1-month period was
in place of such delivery systems. achieved. The electrosprayed products (1–15 μm) possessed a uniform
shape and smooth surface. When the PCL concentration was enhanced,
6.3. Other bioactive components the particle morphology turned comparatively smoother and fabricated
structures displayed a more compact configuration (Fig. 12e, f, g). The
It is well-established that the degradation of polymeric nano/micro- bioactive release upon 45 days was around 40%, which was attributed
structures initially takes place at amorphous domains, followed by a to the hydrophobic nature of Taxol and the semi-crystalline network
gradual decomposition of the crystalline parts of the matrix. According of the polymer matrix. According to Fig. 12d, there is no indication of
to Freiberg and Zhu [171], particles of lower crystallinity provided supe- significant erosion in particles following 45-day release, indicating the
rior bioactive/therapeutic dispersion and improved bioactive-polymer slow decomposition of the carrier matrix and also high crystallinity of
interaction while the degree of crystallinity is likewise affected by the the polymer lattice. The evaluation of cell uptake attributes of the
Fig. 12. SEM images of electrosprayed PCL particles collected from filter (a); spray-dried PCL particles (b); electrosprayed PCL particles collected from side wall and then went through
ultrasonic stirring and freeze drying treatments (c); electrosprayed PCL particles following 45 days in vitro release (d); a single electrosprayed PCL particle collected from filter (e),
side wall (f); and a single electrosprayed PCL particle filter following 45 days in vitro release (g). CLSM images of Glioma C6 (brain tumor) cells following incubation with Coumarin-6-
loaded microparticles PCL5: particles collected from filter after 30, 60, and 120 min) (h1, h2, and h3, respectively); particles collected from ground needle after 120 min (h4). (Bars:
20 μm) [173].
17
electrosprayed materials demonstrated that the loaded Taxol could be Declaration of Competing Interest
uptaken effectually (Fig. 12h1-h4). This could be due to the surface
charge of the electrosprayed products, efficiently inducing the particle The authors declare that they have no known competing financial
adhesion on the surface of the cells, and thus dramatically increasing interests or personal relationships that could have appeared to influ-
the chance for bioactive uptake. ence the work reported in this paper.
7. Conclusion and future challenges Acknowledgments
As a bottom-up nanofabrication approach, ES, offers a robust ap- The authors gratefully acknowledge the grant support from the
proach for producing particles/ nanoparticles of unique properties for National Elites Foundation of Iran (grant number: 6752766).
the delivery of poorly water-soluble bioactives. In virtue of the high ver-
satility of adjusting the process circumstances for a wide range of sub- References
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Advances in Colloid and Interface Science 290 (2021) 102384

Contents lists available at ScienceDirect

Advances in Colloid and Interface Science

journal homepage: www.elsevier.com/locate/cis

Electrospraying as a novel process for the synthesis of particles/

1. Introduction: Hydrophobic biomolecules are a trend or threat? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Material Polymer category Degradation manner Injection Application Reference

Electrosprayed matrix Loaded molecule Particle EE (%) Reference

Encapsulation of live probiotics

Antimicrobial surface coatings

Fig. 7. Schematic illustration of different set-ups for electrospraying.

Phenolic Carrier Particle size Encapsulation Comments References

7. Conclusion and future challenges Acknowledgments

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