ISSN 1738-8716(Print) ISSN 2287-8130(Online) Particle and Aerosol Research Part. Aerosol Res. Vol. 14, No. 3: September 2018 pp. 49-63 http://dx.doi.org/10.11629/jpaar.2018.14.3.049

Electrospray technique for preparation of core-shell materials : A mini-review

Vinh Van Tran⋅Young-Chul Lee1) 1)Department of BioNano Technology, Gachon University, 1342 Seongnamdaero, Sujeong-gu, Seongnam-si 13120, Gyeonggi-do, Korea (Received 26 June 2018; Revised 3 July 2018; Accepted 12 July 2018)

Abstract During the last decade, electrospray (ES) techniques have been used as potential methods for preparing of core-shell materials. Depending on the architecture of nozzle and design of devices, the ES techniques includes monoaxial, coaxial, multiple coaxial nozzle ES and microfluidic ES devices. ES operates based on a basic principle, in which a spray of monodisperse droplets is formed by dispensing an electrically conductive liquid through a capillary charged to a sufficiently high potential. In review of many recent research papers, we take a closer look at ES techniques and their applications for fabrication of core-shell materials. Several advantages of ES technique compared with other methods were emphasized and it may be regarded as a potential tool for fabrication of core-shell materials current and near future. Keywords: Electrospray; Coaxial nozzle; Core-shell materials; Electrospraying mode

* Corresponding author. Tel：+82-31-750-8751, Fax：+82-31-750-4748 E-mail：[email protected] (Y.-C. Lee) 50 Vinh Van Tran⋅Young-Chul Lee

1. Introduction 2. Principle of electrospray technique

The synthesis of core-shell nanoparticles is a 2.1 Basic setup and principle of electrospray complex process. Although “top-down” approaches are technique possible to prepare the core-shell nanoparticles with The basic setup for standard ES consists of several different shapes and sizes, “bottom-up” techniques are major components: a syringe pump, a syringe, a metal mostly preferred (Gawande et al., 2015). Bottom-up needle serving as nozzle, a high voltage power source synthetic methods have been used for the synthesis of and a grounded substrate serving as a collector (Fig. 1) core-shell materials in which there is a wide range of (Smeets et al., 2017). techniques have been developed such as precipitation, co-precipitation, hydrothermal degradation, deposition, sol-gel (Stöber method), reduction, template-assisted synthesis, polymerization, hydrolysis, ion-exchange process, low-temperature solid-state method (Almería et al., 2011; Chaudhuri and Paria, 2012; Gawande et al., 2015). However, most of them suffer from numerous shortcomings, including: modest encapsulation efficiency, batch-nature of the process, difficulty to scale-up, poor control of the particle size distribution, difficulty to generate sufficiently small particles, poor repeatability and limitations with respect to encapsulation of hydrophilic agents (Enlow et al., 2011; Hans and Fig. 1. Schematic representation of basic setup for Lowman, 2002). Recently, electrospray (ES) technique standard electrospray (Reprinted (adapted) with permission from (Luo and Edirisinghe, 2014). Copyright (2018) has been used to produce and process micro-/ American Chemical Society). nanostructured materials (Chen et al., 2018; Xie et al., 2015). Compared with the mentioned traditional Although there are many different types of methods, ES techniques possess several advantages developed ES techniques, they all have operated based such as (1) producing lowest and uniform particle size on a basic principle, in which a spray of monodisperse as possible; (2) easy to control the operation droplets is formed by dispensing an electrically parameters; (3) fast preparation and one step technique; conductive liquid through a capillary charged to a (4) simple set up; (5) extend for bulk production (Chen sufficiently high potential (Cloupeau and Prunet-Foch, et al., 2005; Sridharab and Ramakrishna, 2013; Yeo et 1994; Hartman et al., 1999; Zarrabi and Vossoughi, al., 2005). All these outstanding properties make ES as 2009). Briefly, an electrical source is installed between a fascinating method for fabricating a wide range of a capillary which liquid supply comes from a reservoir micro- and nanostructured core-shell materials applied and a counter electrode placed some distance apart. In in many fields like pharmaceutics, food, and healthcare case of no voltage, a hemispherical droplet emerges to name a few. In this present review, we will provide from the capillary, while a voltage is applied, the an up-to-date appraisal of ES technique and their air/liquid interface becomes polarized causing the potential applications in preparation of core-shell meniscus to deform into a conical shape. The materials. equilibrium then evolves toward the creation of a real cone called Taylor cone (Taylor, 1964, 1969). If the voltage is increased, it finally reaches a level where

Particle and Aerosol Research 제 14 권 제 3 호 Electrospray technique for preparation of core-shell materials: A mini-review 51 the surface tension cannot maintain the liquid inside of the force balance of surface tension, gravity, electric the droplet anymore resulting in the liquid ejection stresses in the liquid surface, inertia and viscous through a thin jet at the cone tip, where the electric stresses; (2) The second process is the breakup of the field is the most important. This jet is directed toward jet into droplets; (3) The third process is the the counter electrode. The jet breaks up further development of the spray after droplet production downstream into a spray of fine charged droplets (Gañán-Calvo et al., 1994; Hartman et al., 1999). In (Bock et al., 2012; Lhernould and Lambert, 2011). the cone-jet mode, a size segregation effect could be produced by different inertia which is formed by 2.2 Electrospray modes electrical interaction between highly charged with According to Wu et al. (2012a)’s review, the ES various sizes. Hence, small sizes will present at the modes and resulting droplet sizes strongly depends on edge of the spray, while the larger droplets will the process parameters such as the applied voltage, present in the spray centre. In addition, the droplet size liquid flow rate, and liquid properties including in cone-jet mode is directly proportional with the electrical conductivity, surface tension, and liquid liquid flow rate, but in inverse proportion to the liquid density. Liquid jet breaks up into droplet due to flow conductivity. Generally, the droplet size is difficult to instability such as varicose instability. Electrical forces be determined. However, many studies supported that make very thin liquid jet, and, because of the surface it can be calculated by the following scaling law tension, thin liquid jet undergoes flow instability. The (Jaworek, 2007) with the confirmation of many obtainment of spraying modes will depend on the experiment results (equation 1) (Ganan-Calvo, 1999). strength of the electric stresses relative to the surface   Q   tension stress on the liquid surface and on the kinetic dD    (with α = 2.9) (1)    energy of liquid leaving the nozzle (Smeets et al.,

2017; Yurteri et al., 2010), it was demonstrated that where droplet sizes dD (m), Q is the liquid flow rate 3 -1 various electrospray modes including dripping, (m · s ), γ is the liquid conductivity (S/m), ε0 is -1 -1 micro-dripping, spindle, Taylor cone-jet and multi-jet permittivity of a vacuum (C V m ), ρ is the liquid -1 mode are formed when increasing the applied voltage density (g/mL), σ is the surface tension (N · m ). (Wu et al., 2012a; Zarrabi and Vossoughi, 2009). The When decreasing flow rate and increasing electrical balance between the surface tension and the electric conductivity of the liquid, droplet size will decrease. stress will identify the eventually obtained mode. To Wu et al. (2012a) indicated that the droplets with determine the operating mode for ES system, it is the suitable size may be produced through changing necessary to consider and evaluate several important the flow rate and the liquid properties in a factors like the electric field strength, flow rate, the well-controlled manner. Therefore, the final particle physical properties of the solution (electric size (dp) is related to the initial droplet size (dp) by the conductivity, viscosity and surface tension) and their equation 2: interplay.  C   dp  dD  (2) Despite the existence of the diverse modes, Taylor  p  cone-jet mode is the most common used ES mode due Where: C is the concentration of solute and  is to producing highly monodisperse particles in a stable p the density of the particle. manner and a reproducible way (Smeets et al., 2017). ES in the cone-jet mode may describe by three different processes: (1) The first process is the acceleration of the liquid in the liquid cone as a result

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2.3 Formation mechanisms of core-shell particle 3. Development of types of electrospray in electrospray technique technique in preparation of core- The formation of core-shell materials by ES shell materials techniques may be explained through three different mechanisms depending on the surface charge density Generally, there are three types of ES commonly and the droplet surface tension (Zarrabi and Vossoughi, used to synthesize core-shell materials including 2009). First mechanism, in case of the low surface monoaxial ES, coaxial ES, multiple nozzle ES. Recent charge density, no coulomb fission appears because the applications in the synthesis of core-shell particle Rayleigh limit will be not attained even when the relating to these types of ES will be discussed in the diameter of the droplets keeps shrinking due to solvent following section and summarized in table 1. evaporation. Second mechanism, the high surface charge density will cause the particles to disintegrate 3.1 Monoaxial electrospray rapidly and form nanoparticles. Especially, in the third Monoaxial ES is a traditional ES technique mechanism, it was suggested that although the surface developed to synthesize micro/nanomaterials due to charge density is not very high, the Rayleigh limit will cheap cost and simple operation. For principle of still reach after solvent evaporation due to shrinking of monoaxial ES, a polymer solution is slowly injected the droplets and coulomb fission occurs. When into a capillary nozzle through a needle by a syringe coulomb fission occurs, the particle size distribution pump and it is charged by a strong external electric will change and it causes the disintegration of particles field. An electric stress condition generated from the to form nanoparticles. free charge will cause the acceleration of the liquid The formation of a core-shell structure relating the away from the needle. In case of increasing the ratio of charge relaxation lengths and inertial breakup electrical potential to several kilovolts, the liquid lengths was explained in some studies of Mei and meniscus at the needle opening develops into a conical Chen (2007, 2008). They demonstrated that to form the shape or the Taylor cone. Soon, a fine polymer jet will core-shell structured droplets, several specific be formed as a result of the electrical conduction of requirements must be satisfied by the ratio of the liquid. The jet eventually breaks up into charged length scales. In order to evaluate the formation of the droplets that fly towards the grounded collector. To droplets, Xu et al. (2013) simplified the surface tension allow the formation of particles with smooth surface model and simulated the tip of the nozzle. The studies morphology, a closed chamber with continuous air or about effects of nozzle electric potentials on the nitrogen flow often used to reduce the evaporation rate structure of core-shell droplets and droplet size of solvent (Cloupeau and Prunet-Foch, 1994; Davoodi prepared by ES process indicated that the cone-jet et al., 2015; Jaworek, 2007; Loscertales et al., 2002; formation near the nozzle tip could lead to the Salata, 2005). core-shell droplet formation due to force balance According to Bock et al. (2012)’s review, core-shell among gravity, surface tension, interfacial tension, particulate may be fabricated by monoaxial ES where the electrical stresses, inertial and viscous stresses (Yan et active agent (drug) is mixed with the polymer solution al., 2016). It was demonstrated that the crucial before ES commences. Core-shell particulate systems will parameters (electrical conductivity, viscosity, dielectric be formed through aqueous nanoprecipitation, constant, flow rate, and voltage) and additional emulsification and solid dispersion (Nikolaou and parameters (interfacial tension, flow rates of liquids, Krasia-Christoforou, 2018). In other study, Yu et al. and the nozzle configuration) will affected the outcome (2014) was successfully prepared CeO2 microspheres by of the core-shell particle formation in the ES process. using the monoaxial ES technique with morphology in

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Table 1. The recent application of electrospray technique in fabrication of core-shell materials

Nozzle/ needle Nozzle Particle Core materials Shell Application Refs geometry size size materials (μm) (μm)

Monoaxial 150 1.34 Doxorubicin PLGA Drug delivery (Almería et al., hydrochloride 2011)

19 coaxial nozzles 70 1.32 Doxorubicin PLGA Drug delivery (Almería et al., hydrochloride 2011)

Single coaxial - 30 PLGA poly-DL- Drug (Xu et al., 2013) nozzle lactic acid encapsulation

Monoaxial 880 5.0 Fe3O4 Eudragit Enhancing gastric (Hao et al., 2014) RS PO antimicrobial delivery

Monoaxial 5000 2.8 Peptides, proteins poly-DL- Drug (Yeo et al., 2005). lactic acid encapsulation

Double-nozzle 500 - Poly-(lactic acid) PLGA Drug delivery (Yan et al., 2016) coaxial (PLA)

Single coaxial - 300 Living cells Alginate Medicine (Zhao et al., 2014) nozzle

Single coaxial 75 ~100 Living cells Alginate Medicine (Zhang and He, nozzle 2009)

Single coaxial 508 1.2 Budesonide PLGA Drug (Lee et al., 2010) nozzle encapsulation

Single coaxial 720 400 Poly-L-lactide PLGA Drug delivery (Nie et al., 2010) nozzle

Monoaxial - 6-9 Congo red/ PLGA Drug delivery (Yao et al., 2016) albumin

Tetraaxial nozzle 2800 2900 Insulin B. longum Medicine (Paz-Samaniego et al., 2018)

Tri-needle coaxial 28500 13.5 Acridine yellow Nile blue Pharmaceutic (Zhang et al., 2017)

25 coaxial emitters 7000 17-39 Ethylene glycol Sesame oil Drug delivery (Olvera-Trejoab and Velásquez-García, 2016)

Single coaxial 1000 - Sodium Na-Alg Biocatalysis and (Wang et al., nozzle carboxymethylcellu Biomimetic 2018) lose

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solid particles. The particle sizes of these structured CeO2 with conventional methods in the nanoparticle fabrication microspheres with different morphologies are 1–2 µm, for drug encapsulation. which suggested that monoaxial ES may be a tool that It was demonstrated that monoaxial ES exhibits a has much significance in the production of many other monotonic dependence of droplet size on liquid flow photocatalysts. In addition, monoaxial ES also showed rates (Davoodi et al., 2016; Xu et al., 2013). The size a high efficiency in the fabrication of core-shell materials of obtained core-shell particles increases when for active agent encapsulation in drug delivery. For increasing flow rate, therefore the optimal condition for example, a novel stomach-specific sinking magnetic operating monoaxial ES is the extremely low flow rate. microparticles enhancing gastric antimicrobial delivery In other words, the productivity will be limited by the were formed via the monoaxial electrospray method low flow rate. In addition, for large scale production, practice (Hao et al., 2014). The size of this material was monoaxial ES also exists restriction due to the low approximately 5 μm and it showed a high density when throughput (Yan et al., 2016). increasing the Fe3O4 concentration in the electrospray For the emulsion ES method, electric field is added inlet flow. This study stated that monoaxial ES is an to the drug emulsion solution to spray particles (Bock effective technique to prepare the high density et al., 2012; Malik et al., 2016). Based on this technique, gastroretentive dosage forms. Especially, a new a novel microsphere of PLGA polymer was successfully monoaxial ES using high frequency AC electric fields prepared to encapsulate two kind of aqueous model drugs, above 10 kHz was developed for encapsulation of DNA, Congo red and albumin from bovine serum (BSA) (Yao peptides, proteins and other therapeutic molecules (Yeo et al., 2016). In the preparation process (Fig. 2A), the et al., 2005). It was demonstrated the AC monoaxial ES emulsion solution formed by adding the aqueous phase may be regarded as a potential technique with a greater of two drugs into the organic phase of PLGA polymer flexibility to encapsulate organic phase soluble was passed an ES system to fabricate drug entrapped therapeutic molecules and drug compounds, compared PLGA microspheres. It was shown that the morphology

Fig. 2. (A) Schematic representation of the emulsion ES process (S1 to S5, the Vw/Vo were 5, 10, 20, 50

and 100 µL/mL, respectively) (B) The BSA-FITC distribution in the PLGA microspheres with different Vw/Vo of 5 (a, S1), 10 (d1–d3, S2), 20 (b, S3), 50 (c, S4) and 100 µL/mL (e1–e3, S5). (a–c), (d1) and (e1) are the 3D reconstruction of z-stack confocal images. (d2) and (e2) are the cross-section of PLGA microspheres; (d3) and (e3) are the drug phase (BSAFITC was green) distribution in the PLGA microspheres (red was rhodamine). (Reprinted (adapted) with permission from (Yao et al., 2016). Copyright (2018) Oxford University Press).

Particle and Aerosol Research 제 14 권 제 3 호 Electrospray technique for preparation of core-shell materials: A mini-review 55 of these PLGA microspheres was affected by the volume al., 2013). The authors used a computational fluid ratio of aqueous drug phase and organic PLGA phase dynamics (CFD) model to simulate coaxial ES process

(Vw/Vo) and the molecule weight of model drugs. With with conditions including nozzle voltage and polymer increasing the volume ratio of aqueous drug phase Vw/Vo solution flow rates. It was suggested that CFD model may from 5 to100 µL/mL (S1-S5), the distribution of aqueous be used to predict the production of consistent compound nanodroplets in the PLGA microspheres was different and droplets and the expected core–shell structured the number of nanodroplets also increased gradually. Yao microspheres. The simulation results indicated that the et al. (2016) showed the drug distributions within the operating conditions (nozzle voltage and flow rates) of different formulation of PLGA microspheres prepared by ES system influenced on the particle size of microspheres. the emulsion monoaixal ES method (Fig. 2B). The 3D When increasing nozzle voltages, the particle size reconstructions of laser scanning confocal microscope decreased and above 6kV, the polymer jet became (LSCM) images for fluorescein conjugated BSA unstable. For various flow rates, the particle size (BSA-FITC) (Fig. 2B(a–c), (d1–d3) and (e1–e3)) increased almost linearly with increasing shell flow rate. confirmed that more drugs were encapsulated with more Also, Nie et al. (2010) demonstrated that coaxial ES can aqueous solution added. And the formation of be used for the fabrication of microspheres with distinct nanodroplets of aqueous phase solution (the green dots) core-shell structure. These core-shell particles have ability dispersed over the PLGA emulsion homogenously. Also, to encapsulate both hydrophobic and hydrophilic drugs it is notable that the formed nanodroplets in the in one single step. Especially, hydrophobic drug is located emulsification process was likely to be maintained in the in the shell, while hydrophilic drug can be encapsulated subsequent electrospray and the density of the drug in the core. In addition, different drug distributions are nanodroplets increased with the Vw/Vo ratio. In summary, reached in the microspheres by altering drug solutions the authors stated that emulsion monoaxial ES will provide between the inner and outer needles, which allow an efficient and simple system to prepare the PLGA different temporal release profiles of each drug (Nie et microspheres with the great drug release control at a al., 2010). desired rate satisfying the need of the practices. Also, coaxial ES has been extensively used for cell microencapsulation using alginate probably given that 3.2 Coaxial electrospray simple operation, reusability, and high production rate The coaxial ES technique has gained considerable (Chakraborty et al., 2009). However, current ES techniques attention in the synthesis of biodegradable polymeric have still existed two main limitations including producing particles for encapsulating therapeutic agents in controlled homogeneous, solid-like microbeads that lack an aqueous and sustained drug release applications (Xie et al., 2006). liquid core or use highly evaporative organic solvents in It can produce core-shell particles with exceptional the fabricating process of a core–shell structure (Kim et properties such as uniform drug distribution within the al., 2013; Lee et al., 2010; Zhang and He, 2009). The particles and high loading capacity (Bock et al., 2012; latter indicated that the applicability of ES techniques in Chakraborty et al., 2009). Recently, ES technique has the encapsulation of living cells is impossible because often been employed to synthesize polymeric composite of the high cytotoxicity of organic solvents. To overcome microspheres, well-known core-shell particles, widely this problem, a novel coaxial ES technology was developed used for drug delivery applications due to its mentioned to synthesize a core-shell microcapsule based on a hydrogel advantages. Xu’s group applied this technique to shell of alginate and an aqueous liquid core of living cells, successfully fabricate a polymeric composite microspheres embryonic stem cells (Fig. 3a) (Zhao et al., 2014). This consisting of a poly (D,L-lactic-co-glycolic acid) (PLGA) coaxial ES technique produced a great core-shell material core and a poly (D,L-lactic acid) (PDLLA) shell (Xu et for ES encapsulation. This was demonstrated by generation

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Fig. 3. (a) schematic illustration of the coaxial electrospray system for generating microcapsules with a liquid core and alginate hydrogel shell; (b) Expression of pluripotency protein markers of ES cells obtained under three different culture conditions: quantitative analysis of mean intensity showed that cells obtained from the miniaturized 3D liquid core have significantly higher expression of Nanog and Sox-2 on average than 3D hydrogel and 2D culture (Reprinted (adapted) with permission from (Zhao et al., 2014). Copyright (2018) Royal Society of Chemistry) of microcapsules with high viability (>90%), but using important factors for designing multi-nozzle ES array for two aqueous fluids without any cytotoxic organic solvent large scale production (Regele et al., 2002). This study usually needed in ES technology to fabricate core–shell results revealed that the formed particle quality microcapsules. Moreover, it was suggested that compared (morphology and core-shell structure) is strongly with the 3D solid-like hydrogel and conventional 2D culture influenced by the interference between neighboring methods, coaxial ES could provide a better biomimetic, nozzles and suggested that optimal spacing should be miniaturized 3D liquid culture microenvironment for ~3000 nozzle/m2 packing density which may be achieved culturing stem cells (Fig. 3b). by adjusting the nozzle-to-nozzle distance greater than 0.018 m. In addition, the authors conducted a 3.3. Complex multiple coaxial nozzle systems comparison between single-nozzle system and double Similar to mono-axial ES, the single coaxial ES nozzle system and calculated the electrical field process exhibits a limitation of the productivity due to distribution and simulated ES process for both single and the low flow rate. (Davoodi et al., 2016; Xu et al., 2013; double-nozzle system to explain the interactions between Yan et al., 2016). For mass production of core-shell adjacent nozzles. It has been found that using cone particles, to overcome the restriction of the low shaped nozzle tip can enhance the productivity (Yan et throughput with single nozzle while maintaining the al., 2016). The distributions of electric filed line released particle size, multi coaxial nozzle ES system has been from the nozzle tips displayed (Fig. 4a, b). While the regarded as an indispensable solution (Deng et al., 2009; electric lines display an axisymmetric distribution along Oh et al., 2008). According to this approach, multi the axis of nozzle single-nozzle system, the electric field coaxial nozzle ES has gained considerable attention in interference between two neighboring nozzles causes a the synthesis of core-shell particle. bend of electric lines in double-nozzle system. The Based on the basic coaxial ES technique, Yan et al. simulation of droplets distribution for single-nozzle (2017) designed a double-nozzle coaxial ES system to system and double-nozzle system is shown in (Fig. 4c, fabricate core-shell microspheres toward large-scale d). For single-nozzle system, the ES displays an production. The nozzle spacing is one of the most axisymmetric distribution, while it shifts from nozzle

Particle and Aerosol Research 제 14 권 제 3 호 Electrospray technique for preparation of core-shell materials: A mini-review 57

Fig. 4. Distributions of electric filed line released from the nozzle tips: (a) single-nozzle system; (b) double-nozzle system; Spatial distributions of charged droplets for (c) single-nozzle system and (d) double-nozzle system (Reprinted (adapted) with permission from (Yan et al., 2017). Copyright (2018) Wiley Materials). axis along X direction in double-nozzle system. In dispersibility, active release, and therapeutic impact (Nii conclusion, to design a double-nozzle coaxial ES system, and Ishii, 2005). Therefore, the development of unique it is very necessary to avoid and minimize the techniques applied for the synthesis of core-shell interference of electric field from neighboring nozzle particles encapsulating two or more active drug will be (Yan et al., 2017). a potential approach. Hence, new ES systems with a These day, a single-dosage form platform encapsulating tri-needle coaxial, tetra-axial or even multiple coaxial and delivering multiple drugs has been considered as one nozzles has been considered for fabrication of core-shell of the most advanced techniques for the development of particle. advanced therapies. In addition, co-encapsulation of Zhang et al. (2017) developed novel core-shell multiple active agents can deliver synergistic therapeutic particles, namely magnetic polymer yolk-shell particles effects and reduce side effects (Parhi et al., 2012). (YSPs), using a tri-needle coaxial ES technique to Moreover, the coencapsulation of both hydrophilic and encapsulate multidrug in the compartments (Figure 5a). hydrophobic drugs in a single-dosage form like The architecture of YSPs showed that magnetic Fe3O4 core-shell particle is an ideal method to enhance the drug nanoparticles (MNPs) and Nile blue (NB) entrapped in

Fig. 5. (a) Tri-needle coaxial electrospray (Reprinted (adapted) with permission from (Zhang et al., 2017). Copyright (2018) American Chemical Society); (b) Tetraaxial nozzle electrospray (Reprinted (adapted) with permission from (Paz-Samaniego et al., 2018). Copyright (2018) Wiley Materials)

Part. Aerosol Res. Vol. 14, No. 3(2018) 58 Vinh Van Tran⋅Young-Chul Lee the outer shell, Sudan red G (SRG) incorporated in the size variation has gained a great interest (Denga et al., central layer and acridine yellow (AY) contained in the 2006; Velásquez-García et al., 2006; Wang et al., inner core. Also, the study stated that three solutions 2004). With an attempt to find an upgraded version of were dispensed into the tri-needle coaxial nozzle and coaxial ES for large-scale production of core-shell the jetting stabilities observed is similar to single and particles, Olvera-Trejo and Velasquez-Garcia (2016) conventional two needle coaxial ESs. Tetraaxial nozzle reported the first MEMS multiplexed coaxial ES ES is next version of multiple coaxial nozzles ES sources in the literature. The device design of the developed for preparing the core-shell materials. MEMS multiplexed coaxial ES sources is shown (Fig. Paz-Samaniego et al. (2018) employed tetraaxial nozzle 6). The device consists two separate liquid reservoirs: ES to fabricate core-shell particles composed of maize the inner liquid reservoir and the outer liquid reservoir bran arabinoxylans MBAX) with insulin in the core, provide the feedstock for the core layer and the shell and maize wastewater arabinoxylans (MWAX) with layer of the particles, respectively (Fig. 6a). The Bifidobacterium in the shell (Figure 5b). For encapsulation structure of the liquid reservoirs includes inlet channels efficiency, the study stated that tetraaxial nozzle ES opening to the bottom of the device. An array of produced a core-shell particle with higher encapsulation rounded square columns will support the ceilings of efficiency of Bifidobacterium compared with other the liquid reservoirs to avoid the collapse of the liquid methods (Zou et al., 2011). reservoirs. Each reservoir feeds a microchannel As mentioned, standard coaxial ES technologies embedded within each conical emitter that ends in a usually have a great limitation of productivity because coaxial nozzle (Fig. 6b). In this study, the miniaturized of only possessing one emitter and operating in the coaxial ES emitters (up to 25 emitters) were designed cone-jet emission mode. Also, a coaxial ES emitter is as monolithic planar arrays to work uniformly in limited by low flow rates. Moreover, the adverse parallel, which significantly increased the throughput of effects in a given application can be caused by the compound micro-droplet source and made this increasing the particle size as a result of increasing the technology compatible with low-cost commercial flow rates of the emitter. An approach to improve the applications. Contrary to the predicted theory, the study throughput of a coaxial ES source without affecting the results demonstrated that the per-emitter current is

Fig. 6. (a) Intersected cross-section of a 3D schematic of a planar array of 25 coaxial electrospray emitters. The hydraulics for the inner and outer liquids are coloured in red and yellow, respectively. (b) Lateral cross-section of the central emitter row (Reprinted (adapted) with permission from (Olvera-Trejoab and Velásquez-García, 2016). Copyright (2018) Royal Society of Chemistry)

Particle and Aerosol Research 제 14 권 제 3 호 Electrospray technique for preparation of core-shell materials: A mini-review 59 proportional to the flow rate of the liquid and it did micromixer was utilized to bring together the imaging not depend on the flow rate of the driven liquid. In reagent stream and the therapeutic reagent stream in the addition, the diameters and the size distribution of the range of microscale and further reduce the stream width formed core-shell particles were likely to be modulated to the nanoscale through the repeated stretching folding by controlling the flow rates (Olvera-Trejoab and function of the static mixing units. The flows of the Velásquez-García, 2016). With similar approach, multilayered mixture of imaging reagent and therapeutic Almeria et al. (2011) prepared a biodegradable polymer reagent were formed the inner needle of the coaxial ES particle using a multiplexed ES system. The system system. The lipids were dissolved in ethanol and flow comprises an array of 19 microfabricated nozzles in through the outer needle of the coaxial electrospray silicon. The study indicated that multiplexed ES system. After the quick evaporation of ethanol, technique have many advantages: (i) allow coating theranostic lipoplexes were formed. As a result, compared agents for drug delivery in a single-step process; (ii) with traditional methods, lipoplexes produced by MES control the particle size and monodispersity of formed were distributed uniformly with a diameter of ~194 nm particles, (ii) avoid particle aggregation, (iv) increases and a polydispersity of ~0.024 and also inhibited good the throughput by orders of magnitude, (v) suitable for therapeutic and imaging ability with little toxicity. a semi-batch process.

4. Electrospray incorporation with others technique for fabrication of core- shell material

4.1 Microfluidic electrospray devices To construct the capillary microfluidic device, two ground capillaries was coaxially assembled on a glass slide. It is notable that the combination of microsphere Fig. 7. Schematic diagram of the static micromixercoaxial particles prepared by microfluidic ES and the enzymatic electrospray device used for theranostic lipoplexes synthesis (Reprinted (adapted) with permission from (Wu inverse opal particles a unique biocatalyst system with et al., 2012b). Copyright (2018) American Chemical specific functions of the enzyme cascade reaction (Wang Society) et al., 2018). To conduct the encapsulation, a coaxial capillary microfluidic chip was integrated with three-bore 4.2 Combination of electrospinning and capillary injection channels using the ES collection electrospray techniques device. This study demonstrated that ES can be Electrospinning is usually used to synthesize continuous incorporated with microfluidic to fabricate the core-shell nano/microfibers deriving from natural and synthetic system with great properties for encapsulation polymers, ceramics and composites (Chronakis, 2005). application. Similarly, Wu and coworkers introduced a Because of the same in the experimental setup, both novel static micromixer coaxial ES (MES) system, which electrospinning and ES also have the same influencing has been designed from the combination of the factors. Besides their independent use for the fabrication advantages between static micromixer and coaxial ES to of various materials, the combination of electrospinning produce uniform theranostic lipolexes in a single step and ES have been also considered to create hybrid particle with high reproducibility (Fig 7) (Wu et al., 2012b). The composite materials (Ramasundarama et al., 2015). Some synthetic process was described as follows: The static reviews indicated that the combination of the two

Part. Aerosol Res. Vol. 14, No. 3(2018) 60 Vinh Van Tran⋅Young-Chul Lee techniques can be conducted by following 3 different Acknowledgement routes: (1) the simultaneous occurrence of electrospinning and ES; (2) the ES and electrospinning process is This work was supported by the Basic Science Research performed onto the same collector, but electrospinning Program through the National Research Foundation of complete first; (3) the ES process takes place onto a Korea funded by the Ministry of Education (NRF-2017 preformed electrospun mat (Jaworek et al., 2009; Nikolaou R1D1A1A09000642). and Krasia-Christoforou, 2018). In Luo and Edirisinghe (2014)’s study about combination of these two techniques, it was demonstrated for the first time that the sheath References polymer solution (low viscosity) to electrospin instead of electrospray in a coaxial electrified jet may be caused Almería, B., Fahmy, T.M., and Gomez, A. (2011). A multi- by simply infusing a liquid in the core nozzle without plexed electrospray process for single-step syn- increasing the polymer concentration. It is the presence thesis of stabilized polymer particles for drug of core liquids that contributes to the suppression of delivery, Journal of Controlled Release, 154, Rayleigh instability, which lead to the transition from ES 203-210. to electrospinning of beads-on-strings. This process has Bock, N., Dargaville, T.R., and Woodruff, M.A. (2012). some crucial parameters such as high surface tension of Electrospraying of polymers with therapeutic the core solvent, high interfacial tension at the core-sheath molecules: State of the art, Progress in Polymer interface and electrohydrodynamic operating parameters. Science, 37, 1510-1551. Moreover, the solvents in this process facilitate the Chakraborty, S., Liao, I.-C., Adler, A., and Leong, K.W. effective fabrication of core-shell polymeric structures by (2009). Electrohydrodynamics: A facile techni- coaxial electrohydrodynamic processes. que to fabricate drug delivery systems, Advanced Drug Delivery Reviews, 61, 1043-1054. Chaudhuri, R.G., and Paria, S. (2012). Core/shell nano- 5. Conclusion particles: Classes, properties, synthesis mecha- nisms, characterization, and applications, In this review, we have summarized the recent Chemical Reviews, 112, 2373-2433. research into the development of electrospray Chen, G.-C., Kuo, C.-Y., and Lu, S.-Y. (2005). A general techniques for fabrication of core-shell materials, and process for preparation of core-shell particles we have also emphasized several important types of of complete and smooth shells, Journal of the commonly used ES techniques. Recent applications in American Ceramic Society, 88, 277-283. the synthesis of core-shell particle relating to Chen, J., Cui, Y., Xu, X., and Wang, L.-Q. (2018). Direct monoaxial, coaxial, multiple coaxial, microfluidic ES and effective preparation of core-shell PCL/PEG was discussed. Several advantages of ES technique nanoparticles based on shell insertion strategy compared with other methods was pointed. ES by using coaxial electrospray, Colloids and technique has been attracting a great interest and it Surfaces A, 547, 1-7. could be regarded as a potential tool for fabrication of Chronakis, I. (2005). Novel nanocomposites and nano- core-shell materials current and near future. ceramics based on polymer nanofibers using elec- trospinning process-A review, Journal of Materials Processing Technology, 167, 283-293. Cloupeau, M., and Prunet-Foch, B. (1994). Electrohydrodynamic spraying functioning

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