Core-shell microparticles: Generation approaches and applications

Micro-nanoscale coreeshell particles are distinguishable from other particle types because of their unique composition. Core-shell particles combine the features of both the core and shell materials, while exhibiting smart properties resulting from their materials. In the past few years, the research community has paid increasing attention to the generation and application of coreeshell structures. The present review focuses on the coreeshell microparticles, which have found practical applications in various fields. The novel properties of the coreeshell microparticles make them extremely suitable for pharmaceutical and biomedical applications, including cell encapsulation, cell study, targeted drug delivery, controlled drug release, food industry, catalysis, and environmental monitoring. This paper also systematically reviews the different classes of coreeshell microparticles based on their respective materials. Moreover, an overview of conventional and more recent microfluidic methods for the generation of core eshell microparticles is presented. The unique advantages of the microfluidic approaches are


Introduction
Microparticles, which refer to particles with a diameter range between 1 and 1000 mm, have been the topic of many studies over the past decades. Microparticles have served as smart materials with unique properties. Microparticles possess some advantages compared to particles in the macroscale and bulk materials due to their higher surface to volume ratio. Microparticles as biomaterials also play an important role in pharmaceutical and biomedical research due to their controlled interaction with the biological system. In recent years, microparticles have found a range of applications particularly in biomedical fields such as tissue engineering, drug delivery, imaging, and biosensors.
Core-shell structures are a class of particles that are composed of two or more different material layers. One of them forms the inner core and the others make the outer layers or the shell [1,2]. This type of design provides the opportunity to tune the composite material that exhibits characteristics and properties not achievable by the individual materials of the core and the shell. The core could be liquid, solid or gas and the shell is usually solid that could be fabricated using either organic or inorganic materials, depending on the design criteria and the targeted application [2]. Based on the combination of the core and the shell materials, coreeshell beads could be categorised into four groups such as inorganic/organic, organic/inorganic, organic/organic, and inorganic/inorganic coreeshell microparticles. Adjusting the materials of the core and the shell affects the functions and biological, chemical, magnetic, optical properties of the coreeshell microparticles.
According to the unique features mentioned above, coreeshell beads find applications in diverse fields such as food and cosmetic industry, biomedical science, medicine, and material science. Core-shell beads have been employed as thermal energy storage [3], as an encapsulation system to protect active payloads from degradation and chemical reactions, a bioreactor, and as a controlled release system [4]. Furthermore, therapeutics can be loaded in different layers of a coreeshell bead so that they can be released sequentially in the body [5,6]. The controllable structures can encapsulate both hydrophobic and hydrophilic materials [7]. One of the major applications of coreeshell beads is cell encapsulation for the implantation of cells to a wound to replace lost tissues. Cells are protected from the surrounding and sustain longer until adapting to the host tissue [8].
To date, a wide range of techniques has been employed to prepare coreeshell structures including polymerisation, spray drying, solvent evaporation and self-assembly. Among these physical and chemical methods, a sustainable and controllable generation of monodisperse coreeshell microparticles with a narrow size distribution is of great demand. Properties of coreeshell microparticles such as size, morphology, and structure have a great impact on their applications [9]. Fabricating coreeshell microparticles with a desired size and distribution using conventional methods has long been a big challenge. These methods usually result in coreeshell microparticles with high polydispersity, limited control over morphology and low reproducibility. Over the last few years, state-of-the-art techniques such as microfluidics, coaxial electrospray also known as coaxial electro-hydrodynamic atomization (CEHDA) have been developed and are promising solutions for the above problems. These technologies have attracted considerable attention from the research community owing to advantages over conventional techniques including precise flow control in the microscale, highly controlled uniform microcapsules and biological and chemical compatibility. Besides, these techniques are tunable suitable for a broad range of core and shell materials [10].
Micro-and nanoparticles based on coreeshell structure have advantageous and unique properties such as great level of protection, encapsulation and controlled release. A few review papers on coreeshell nanoparticles are available in the literature, explaining the production techniques, materials, their characteristics and applications. In the last decade, reviews have been published on microscale coreeshell structures [9,11,12]. These reviews generally focused on their biomedical applications and some of the preparation techniques. There is still a gap for comprehensively reviewing coreeshell microparticles focusing on the type of core and shell components, their diverse applications and fabrication techniques with updated literature on coreeshell microstructure.
This paper provides an overview of key elements of coreeshell microparticles including their materials, fabrication techniques, and the applications of coreeshell microparticles. The review begins with the discussion about the diverse classes of coreeshell materials that have been used in the past, followed by the various techniques for the generation of these particles. The key contributions of novel methods to produce coreeshell microcapsules to all biomedical research fields will be discussed. Finally, the paper discusses pharmaceutical and biomedical applications of coreeshell microparticles and concludes with a perspective on further development of this area. Fig. 1 provides graphically the overall structure of this paper.

Shell materials
This section first discusses the various materials used for generating the shell. One of the most significant attributes of microcapsules is the diversity of chemical and mechanical, and biological properties that are available, since the microcapsules could be made of organic, inorganic materials as well as organic/inorganic composites. Shell materials could be generally categorized as organic and inorganic groups. An inorganic material lacks carbonhydrogen bonds and are for instance metals, metal salts, and metal oxides. Organic materials are carbon-based compounds [13,14]. The coating material has a significant impact on chemical, physical and biological properties of the shell. This high flexibility in choosing shell materials allows for preparing coreeshell microparticles with diverse functionalities and properties. Indeed, the shell materials can be selected according to the respective application of coreeshell particles. The purposes of the shell are for instance increasing biocompatibility, dispersibility as well as decreasing materials consumption and surface modification of the core [15]. Furthermore, the shell protects chemically active components in the core against oxidative degradation, corrosion, erosion and also provides bioaffinity through surface functionalization with ligands [9,16]. Shell materials for delivery of therapeutics can enhance controlled release, preservation, and stimuli-responsiveness. Shell materials exhibit enhanced thermal stability and can also improve electrical, optical and magnetic properties of the microparticles [13].

Organic materials
The shell can be made of an organic polymer or any other highdensity organic compound. Organic shell coating has been a focus in encapsulation research because of its unique properties. Polymeric materials have excellent properties such as flexibility, optical properties and toughness [16]. In addition, the organic shell make it possible to achieve considerable control over the permeability of its cargoes [17] and biocompatibility. A metal core could be coated with an organic shell to prevent its surface atoms from oxidizing into metal oxide in the presence of oxygen [18]. Organic coating could also increase suspension stability of the core. Organic/inorganic or inorganic/inorganic coreeshell structures have a broad range of applications such as biosensors [19], drug delivery system [20], cell culture studies [21], cosmetics and MRI [22]. Core-shell particles with a magnetic core could also be used for magnetic separation of cells and other biochemical substances.
Among the possible organic materials, much works in the literature have investigated chitosan as shell Material due to its excellent properties such as biodegradability, biocompatibility, safety and non-toxicity [23,24]. Chitosan is a natural polymer which finds use in enzyme Immobilization [25], adsorption of dye molecules dissolved in water, and biosensing. Because chitosan can quickly degrade without causing any toxins and side effects on the human body, it received approval from the European Medicine Agency and the U.S. FDA [26]. Yang et al. developed a novel type of coreeshell chitosan microcapsule to attain programmed consecutive drug release for the treatment of acute gastrosis using the microfluidic technique. The team successfully combined both sustained and burst release modes into a single delivery vehicle composed of an oily core and a cross-linked chitosan hydrogel shell. First by transferring coreeshell microcapsule from an acidic environment of stomach free drug encapsulated suddenly release because the chitosan shell decomposes and then sustained release happens in the gastrointestinal system as shown in Fig. 2 [6]. Sha et al. [27] used core/chitosan shell microparticle for the immobilization of alpha-glucosidase enzyme.
However, organic material as the shell has some disadvantages. For instance, the permeability of polymeric microcapsules could alter due to factors such as the temperature and pH of the medium, light illumination and magnetic field [28]. Conductive polymers such as polyaniline (PANI) has also attracted attention for its use as the shell material. These materials exhibit excellent adhesion characteristics on metal surfaces and could protect the metals against oxidation. But because of inadequate processability of conducting polymers, commercializing the core/shell particles with conducting polymers shell is challenging. For instance, making a large polyaniline film to cover metal surfaces is difficult, as polyaniline is brittle and insoluble in water [29].

Inorganic materials
Recently great attentions have been paid to inorganic shell materials such as metals, metal chalcogenides, metal oxides, or silica. Several works have demonstrated that inorganic shells can be grown on the surface of both organic and inorganic cores [30]. Inorganic coating on an organic core yields many advantages. Inorganic shell on organic core possess the properties of both organic and inorganic substances. An inorganic shell can improve the colloidal and thermal stability of the core and also protect the  [162]; part (B) reproduced with permission from [140]; part (C) reproduced with permission from [148]; part (D) reproduced with permission from [150]; part (E) reproduced with permission from [155]; part (F) reproduced with permission from [158]; part (G) reproduced with permission from [160]; part (H) reproduced with permission from [73]; part (I) reproduced with permission from [78]; part (J) reproduced with permission from [108]; part (K) reproduced with permission from [134].].  core against abrasion [16,31]. Inorganic shells also enhance resistance against oxidation, osmotic pressure and evaporation [16,17]. These materials may also have other unique features such as magnetic, optical [32] and sorption properties [17]. These structures find their usage in paint industry, nano-biotechnology, and textile industry [16]. Apart from these advantages, there are some drawbacks of using the inorganic materials as the shell. One of the main challenges in forming an uniform shell of inorganic materials such as titanium and silica on the surface of colloidal core to control the size and morphology of the particles [33,34]. Micro phase change materials (PCM) with inorganic shells generally exhibits a lower stability in practical applications than microscale PCM containing organic shell. Inorganic components could not resist the thermal stress associated with volume variation during reiterative phase change process because of the inflexibility [35].

Silica-based shell
Among inorganic materials, silica is an excellent candidate for preparing coreeshell particles. Silica has a broad spectrum of practical applications in fields such as medicine, separation, biotechnology, biomedical sensing. The unique features of silica are chemical stability, low cost and formability that allowing for creating spherical particles from nano to micrometer size [36]. The silica shell prevents the core from coalescence and unwanted contamination from the surrounding environment. Furthermore, silica could be modified through a chemical reaction and form an impervious and strong shell [37]. Inorganic materials such as silica are chemically inert; hence they can improve biofunctionality and biocompatibility [2]. Chemical inertia of silica can also be a blocking agent and prevents the degradation of the core [38].
Silica as the shell of metal oxide core decreases the bulk conductivity and increases the suspension stability of the microparticles. Moreover, as silica is optically transparent it can facilitate the spectroscopic investigation of the core [38]. The silica shell also is helpful in increasing the thermal stability of the core materials [39].

Metal based shell
Apart from silica, many other inorganic metal-based materials such as zeolite, titania, gold, and clay have also been studied for their use as shell materials. Over the last few years, metal shell microcapsules have attracted great attention due to the inherent impermeability. The porous nature of polymers prevents retaining active core contents with low molecular weight. Some measures such as increasing the thickness of the shell or cross-linking have been implemented to tackle this problem. However, they can only delay the diffusion of molecules through the polymer shell by a few hours to weeks. A metal shell serves as a more efficient barrier as compared to polymer shells and prevents the undesired release of small molecules in the core [40]. Furthermore, as the thermal conductivity of inorganic materials is higher than polymers, inorganic additives such as metals in the shell can significantly enhance the thermal conductivity of microparticles [41].
Gold is one of the well-known metals being used for making the shell. This inert metal boosts the physicochemical properties of the core and protects it from corrosion [16]. Gold is biocompatible and exhibits good electronic and optical properties, hence it could be the best candidate for biological and medical applications. An example is the gold nanoshells that can be employed as photoabsorbers for remote NIR photothermal ablation therapy [42].
Other metallic shell materials such as cobalt, zeolite, copper, platinum, and nickel also play a great role in applications such as absorption of solar energy, catalysis, and permanent magnetic properties [16].

Core materials
This section is divided into three categories: gas core, liquid core and solid core. The core material can be gas, liquid or solid. The composition of the liquid core can be altered and can comprise of dispersed and/or dissolved. The solid core can be a mixture of active constituents, stabilizers, diluents, excipients and release rate retardants or accelerators [43]. A variety of materials is available for fabricating the core, and these materials specify the chemical and physical features of them. Hence, some important factors should be taken into consideration when choosing core materials such as application, the environmental condition, the compatibility, and the release condition.

Solid core
Solid core could consist of different materials, such as metal, metal oxides, silica, polystyrene, rubber and polymers regarding their applications and the fabrication methods. Core-shell microparticles with a solid core and a solid shell could be produced directly by turning the emulsion droplets into solid coreeshell microparticles. Several techniques such as polymerization, ionic crosslinking, solvent evaporation have been used to solidify the templated droplets to form solid particles. Another method for the fabrication of coreeshell particle with a solid core is to use a hardcore template.
Solid silica core/porous-shell particles could be employed for the separation with fast flow rate and relatively low back pressure in high performance liquid chromatography [1,44]. The small solid core coated with the porous shell results in a bigger particle and higher surface area hence low back pressure for the separation [1].
Using a structure of a solid core coated with a shell layer has a great advantage for synergistic and controlled drug delivery. Core/ shell microparticles consisting of a liquid core and a solid shell could give a burst release after the breakage or degradation of the shell. The solid structure of the core prevents encapsulated actives ingredients from the burst release, as they can only release from the carriers after the polymer layers degrade. Li et al. used capillary microfluidic device for the generation of solid coreeshell microparticle as a synergistic drug delivery system. Li et al. used capillary microfluidic device for the generation of solid coreeshell microparticle consisting of gelatinmethacrylate (GelMa) core and poly(Llactide-co-glycolide) (PLGA) shell as a drug delivery system. Fig. 3(A) illustrates a schematic figure of a microfluidic device used and the solid coreeshell microparticle generation process. The inner GelMa drop was solidified via the polymerization using UV light in the microfluidics device while the double emulsion was formed. Using this approach allows for the highly efficient entrapment of the active ingredients in the core and the prevention of rupture or agglomeration of the core drops during the solidification of shell layers ( Fig. 3(B)) [45].
There are wide varieties of physically strong polymeric materials such as polystyrene [46], poly lactic-co-glycolic acid (PLGA) [47], isotactic polypropylene (iPP) [48] that have been used to make coreeshell particles. Kong et al. [47] used PLGA that is a rigid polymer as the core materials to produce the coreeshell particle. By the reason of high biocompatibility, biodegradability and large range of erosion periods, PLGA has proved useful polymer for biomedical applications as a delivery system for medicines, proteins, DNA, RNA, and peptides and a scaffold for tissue engineering [47,49].
Lukyanova et al. [50] applied two routes to generate solid core/ solid shell structures. In first method the team used poly (methyl methacrylate) (PMMA) particles with average size of 10e500 mm as the solid core and then the cores were encapsulated in the shell using millifluidics device. In second method, ethylene glycol dimethacrylate monomer was used to generate a rigid core through being polymerized under UV light.

Gas core
In recent years, Hollow microparticles ( Fig. (3C)) have been a structure of interest from both technological and research points of view. Due to their unique properties such as higher surface area, lower density, and some superior optical properties compared to the bulk materials [30], hollow microparticles have drawn growing attention. They have extensive applications in biomedical, catalysts, plastics, paint, food and cosmetics industries [51]. Microspheres with hollow interiors are potentially applicable to protect biologically active compounds such as proteins, enzymes, and DNA; as a vehicle for the encapsulation and controlled release [52]of cargos such as cosmetics, drugs, inks, and dyes, and develop artificial cells [53]. They have also found application in fields of storage of energy [54], waste water treatment [55], and in cell culture assays [54]. It has been found that microspheres with hollow interior are more suitable for the cells aggregation in capsule compared to the solid microparticles [56]. So far, various polymers, metal, oxide ceramics [57], glass, ceramics, and inorganic-hetero-composites have been used for the fabrication of hollow microparticles [53].
Various hollow microspheres have been fabricated with polymer, oxide, metal, and glass composite using nozzleÀreactor technique. The main disadvantage of nozzle technique is the limitation of the microspheres size, generally in the order of micrometre [58].
Caruso and co-workers were pioneers in using layer-by-layer approach [59] and demonstrated the applicability of this method for the generation of a range of inorganic hollow spheres [33]. To date, a variety of polymers, a range of inorganic materials such as silica, titanium, zeolite, dioxide, and Laponite nanoparticles as well as magnetic substances have been used as the shell on polystyrene sphere templates. Caruso et al. [60] prepared hollow inorganic silica and inorganic-hybrid particles via the LbL technique. The initial particles were composed of the colloidal cores and silica nanoparticle (SiO2)e polymer multilayers shells and then became hollow by removing the templated core and the polymer. The colloidal core could be eliminated via various techniques, including heating of the particles, thermochemical decomposition of organic material, and leaving behind hollow inorganic particles. The dissolution and decomposition results in hollow particles and hollow polymer shells, respectively [60]. In other work, Caruso et al. used self-assembly methods to prepare hollow shells containing metallo-supramolecular components by the consecutive assembly of Fe(II) metallo-supramolecular polyelectrolyte and poly(styrenesulfonate) on polystyrene particles, subsequent by cross-linked melamineÀformaldehyde particle decomposition and removal [61]. The colloidal templating technique have also been applied by Matijevic et al. for generating Y 2 O 3 hollow particles by coating polystyrene particles with yttrium basic carbonate layers and then calcining at elevated temperatures in air [30,62].

Liquid core
Microcapsule consisting of a liquid core and a solid shell ( Fig. 3(D)) is another important class of core/shell microcapsule that has been extensively studied over the past decade. Indeed, the dense solid membranes inhibit the content of the core to pass  [45]; part (B) reproduced with permission from [45]; part (D) reproduced with permission from [51]; part (D) reproduced with permission from [63].].
through. As a matter of fact, the shell can serve as a barrier between the interior of the capsule and the surrounding environment. The shell of smart microcapsules could be functionalized to release the contents only under a given environmental conditions [61]. Coreshell microcapsules with an aqueous core could be applied for controlling a catalyst, encapsulation and protection of incompatible substances or active ingredients, delivery of the cargos such as medicine and cell, and as a coreeshell catalytic reactor [63]. Such microparticles with an oily core and an aqueous core provide an adequate inner space for encapsulating hydrophobic and hydrophilic components, respectively [64].
A common application of microcapsules with an aqueous core is the encapsulation of cells. Over the last few years, many works have investigated microencapsulation of cells in liquid coreehydrogel shell microcapsules for cell culture. Isolating pluripotent stem cells into an aqueous liquid core allow them to retain stemness. Zhao et al. illustrated that in contrast to the macrocapsules and bulk gel, there exist more single embryonic stem cell aggregates with high viability in microcapsules with a liquid core after 7 days. Because in microcapsules consisting of liquid core nutrients and oxygen could transfer more efficiently into the liquid core. They used two different fluids consisting of living ES cells, mannitol, sodium alginate for preparing an alginate hydrogel core and sodium carboxymethyl cellulose for preparing a liquid core and mixture of purified alginate for forming the shell [65].
Other culture techniques such as micro-patterned wells, hanging drop, and low-attachment plates have been usually used for 3D culture of stem cells. The bottlenecks of these conventional techniques are issues associated with the scaling-up, damage to cells due to shear stress, lack of control on aggregate shape and size [66].
These microcapsules could be prepared through a wide variety of techniques, example includes interfacial polymerization reactions, microemulsions and emulsions, phase separation, spray drying, solvent evaporation or extraction, and multiple emulsions. One of the best strategies for forming an aqueous microcapsule is to imitate nature. One way is to eliminate the usage of lipids and preparing water-in-oil-in-water double emulsion droplets as templates and crosslinking the shell. Another approach is the separation of the inner aqueous compartment from solid layers of the capsule with a lipid bilayer [67].

Techniques of core/shell microparticle fabrication
A variety of the production techniques for coreeshell microparticles have been proposed [11,12], some of them suffer from low encapsulation efficiency and poor monodispersity [12]. With the advent of advanced microdroplet technologies, some reliable and simple assembly methods for producing coreeshell microparticles have been developed and studied. In general, the encapsulation of core materials may be classified into two basic groupings, namely chemical and physical process, being further subclassified into physical-chemical and physicalemechanical processes (Table 1). In this section, the most important methods for fabricating coreeshell microcapsules are discussed and illustrated with examples.

Layer by layer adsorption
The layer by layer adsorption techniques (LbL) being based on the bottom-up principle is one of well-known encapsulation methods. The basis of the LbL method is the electrostatic attraction between oppositely charged species [33]. The composite multilayer constructed using LbL method could include multivalent dyes, polyelectrolytes, polymer, silicate sheets, proteins or inorganic nanoparticles [33,60]. The LbL assembly technique could be applied to encapsulating both liquid and solid materials [68] as well as preparing hollow materials [33]. Using this way provides opportunity to achieve a control on the physical properties of the shell and fabricate coreeshell microparticles with tailored properties and size [68,69]. Despite other methods, the layer-by-layer technique does not depend on the combination of the core and coating materials. But there is the disadvantage of combining a large amount of redundant polymer in the coating layers when the layers are added in distinct steps of about 30 nm [70]. In addition, these distinct steps, which include the repeated adsorption of polyelectrolytes and nanoparticles, centrifugation, water washing, and re-dispersion cycles are time consuming [59].
Caruso and his team [33] fabricated a hollow sphere using the polystyrene particles templated the LbL self-assembly deposition of TiO2, SiO2, or Laponite nanoparticle/polyelectrolytes, followed by the removal of the templated core. The fabrication of coreeshell materials comprising multilayers of nanoparticles and a core could be achieved with a templated core on which the layers of nanoparticle are settled, opening the way to the creation of hollow coreeshell materials. This approach allows for precise control in nano scale over the diameter of the template and the thickness of the layers deposited.

Solegel method
Solegel method is also an important process to prepare coreeshell structures. Solegel process comprises templating of the solegel precursors of solution against crystalline arrays of monodisperse colloidal nano or micro particles. In this method, the template is covered with a thin layer of different chemical composition by the infiltration of its precursor through the colloidal assemblies [59]. Han et al. created ZnO/silica coreeshell particles using the simple and low-cost solegel approach [71]. Wang et al. produced hollow mesoporous silica microspheres via surface solegel process on the template polystyrene-co-poly(4vinylpyridine) coreeshell microspheres in the presence of hexadecyltrimethylammonium bromide surfactant. It is considered that the solegel process of tetraethylorthosilicate on a suitable template is as follows: (i) Quick hydrolysis catalysed by HCl or NH 3 aqueous solution, (ii) condensing Si(OH) 4 to produce silica covered template microspheres, (iii) Condensing Si(OH) 4 to prepare free silica nanoclusters, (iv) Capturing free silica nanocluster onto the template, and aggregating the free silica nanoclusters into irregular aggregates [72].
Zhong et al. [73] fabricated hollow spheres of TiO 2 and SnO 2 using solegel technique. Fig. 4(A) illustrates the schematic procedure of the fabrication of the hollow spheres. The crystalline Table 1 Methods employed for microencapsulation.

Chemical process
Physical process Physical-chemical Physical-mechanical Polymerization; Interfacial, In-situ emulsion, Suspension, and precipitation Layer-by-layer adsorption Spray-drying Solegel encapsulation Electro-spraying array of polystyrene beads was fabricated between two glass substrates. By evaporating water at room temperature, the hydrodynamic size of the polymer beads decreases by almost 20%. The electrostatic interactions between the polymer beads determine the amount of shrinkage of the beads. The interactions strength intensely depends on the charge density on the surface of each polymer bead and the concentration of free electrolytes in the water. Polystyrene beads are separated from each other by infiltrating the packing cell with a solegel precursor solution by capillary action. By exposing the sample to the moisture in the air, the precursor hydrolysed to metal oxide sols. The gel network aggregated and fabricated a dense, homogeneous, thin layer around polystyrene beads. The cell was immersed in toluene before the separation of the top substrate to dissolve the polystyrene template. After disassembling the cell, the ceramic hollow spheres were released from the substrate by sonication in a water bath. The main disadvantage of the solegel method is tailoring the pore morphology of macro-porous materials. Also, there are difficulties in controlling the thickness of the pore wall and in fabricating the structures with closed pores. Because alkoxides reaction for the production of metal oxides leads to the generation of water and alcohol, evaporating water and alcohol generated through drying and heat results in significant shrinkage and cracks in the materials [59,74]. In the solegel technique, the stirring rate and the amount of emulsifier account for the two key parameters in determining the particle size and the size distribution [75].
The solegel technique could be combined with other approach to prepare coreeshell microparticles. For instance, Zhang et al. [76] combined solegel technique and microfluidic emulsification techniques to produce zirconium dioxide ceramic microspheres [7]. Water/oil/water (W/O/W) double emulsions as the inner phase was prepared with a zirconium precursor with a glass capillary microfluidic device. Adding ammonia to the continuous aqueous phase triggers the zirconium precursor solution to gel. Subsequently, drying and sintering lead to the generation of ZrO 2 ceramic microspheres. Using the double emulsion structure result in uniform and spherical solegel microspheres because of the improvement in the uniformity of the solegel reaction rate.

Spray-drying
Spray-drying, which is an elegant single step constructive process offers a scalable means of the coreeshell particle fabrication. Although, most particles generated using this method generally present a solid dispersion [72]. Using spray-drying technique liquid solutions or suspensions turn into dried particles through quick evaporation of the solvent using a hot gas [70]. Fig. 4(B) shows a schematic figure of the formation process of coreeshell microparticles via the spray drying method. Primary dispersed suspension is transferred to a spray-drying apparatus using a pump. In the twofluid nozzle, the mixing suspension is dispersed by a preheated nitrogen carrier gas into fine droplets. Then the suspension is dried in the cylinder and subsequently after the separation in the cyclone is collected in the collector. Due to the evaporation-driven shrinkage of the encapsulated droplets, the particles with a certain degree of the agglomeration, specific shape, and size can be generated via capillary forces. In spray drying, the condition of drying and precursor solution composition have significant impact on the morphology of the particles [77]. Furthermore, such an facile and reliable process emerges to be applicable for the sustained and large scale preparation of coreeshell heat sensitive particles [78]. For example, Li et al. produced silicon/carbon composite microspheres with a hierarchical coreeshell structure via a method based on spray drying and surface coating to use as anode in lithium ion batteries [79]. Bruinsma et al. employed spray drying to make hollow spherical particles [77].  [73]; part (B) reproduced with permission from [78]; part (C) reproduced with permission from [85]; part (D) reproduced with permission from [108].].

Electro-spraying
Electrohydrodynamic atomization (EHDA), or simply electrospraying is another well-known technique that have been employed for the production of polymeric coreeshell microparticles ranging from tens of nanometres to hundreds of micrometres. A high voltage is applied to the conductive polymeric slurry flows at the needle tip to generate a jet and droplets [76]. The electrostatic force overcomes the surface tension and generates monodisperse droplets at a controlled rate [80]. The basic concept of electrospinning and the electrospraying are the same with the only difference in the concentration of the solution utilized in the process and the chain entanglement density of the polymeric slurry [80,81]. Electrospraying results in nanoparticles and microparticles at a lower solution concentration, whereas electrospinning produce fibres using a higher solution concentration [82]. Electro-spraying can generate droplets without consumption of too much solvents and templates in a single step. By adjusting the needle diameter, the size of the droplets generated can be easily tuned from nano to micro scale [83]. The droplet generated with this technique usually have narrow size distribution. Their size and shape could be controlled by changing the experimental parameters [80]. Compared to the conventional mechanical spraying setup, the production condition of electro-spraying system is relatively simple, and of low cost [84]. For instance, Hwang et al. make coreeshell microcapsules consisting of polystyrene (PS) core and poly(ε-caprolactone) (PCL) shell and polymethylmethacrylate core and PCL shell in uniform size using the coaxial electrospraying. Microcapsules were produced by injecting distinct polymer solutions in a single step. The combination of polymer species in the core and shell has a high degree of freedom due to the separate supplement of solutions from an inner or outer capillary nozzle ( Fig. 4(C)) [85].
Some research reported the combination of single nozzle electrospraying and spray drying as a convenient technique for the control of particle size and the removal of corona discharge [86,87]. Combining coaxial electrospraying and spray drying allows for fabricating particle with more uniform size and morphology. Additionally, the applied electrical potential can prevent the aggregation of particles [86,87]. Ho et al. combined the advantages of spray drying and electrohydrodynamic coaxial jetting to generate coreeshell particles for protein drugs. The electrohydrodynamic force causes a further decrease in the aggregation and particle size. Particle and the release study of the model protein, lysozyme illustrated that the encapsulation efficiency was improved because of an applied electric field [86]. In some other works, the combination of heterophase polymerization and a solegel process has been applied to prepare polymeric or ceramic hollow spheres [64].

Interfacial polymerization
Interfacial polymerization or polycondensation has been employed to encapsulate a wide variety of core materials such as cholesteric liquid crystals [88], pigment [89], oils [90], peptides and proteins [91]. Because of the mild encapsulation condition of the interfacial polymerization, biological activity of the protein is maintained [91]. Interfacial polymerization occurs through the growth of shell through rapid polymerization of monomers at the interface of an emulsion. Firstly, by emulsifying an organic phase comprising oil soluble reactive monomer and core materials in an aqueous phase droplet are formed. The usual reactive monomer is isocyanate or acid chloride in an aqueous phase. Adding a water soluble reactive monomer leads to the growth of a polymer due to the reaction between the two monomers at the interface of the dispersed core droplets [92]. Shenoy et al. [93] reported the preparation of coreeshell particles with liquid cores based on interfacial polymerization. The interfacial system initiates with an enzymatic reaction between glucose and glucose oxidase. The reaction results in hydrogen peroxide that generates hydroxyl radicals in the presence of iron (Fe 2þ ). Hydroxyl radicals induces (meth)acrylate monomer chain polymerization. The shell is achieved by restricting the initiation reaction through confining one or more of the initiating species in a hydrogel core and the other components and monomers in a coating solution.

In situ polymerization
Recently, a special interest on in-situ polymerization method has emerged for surface modification of inorganic particles such as silica, copper sulfide with nanolayers such as clay and carbon nanotubes because of the great interfacial interaction, considerable coverage, and strength [94,95]. Although in-situ polymerization approach improves the interfacial interaction and the coating, the weaker van der Waals interactions between explosive crystal and polymer binder could not entirely modify the surface coating flaws [94]. In-situ polymerization is not generally applicable to all polymers, and the polymerization occurs often incompletely [96].
In situ polymerization is also an effective chemical encapsulation technique that is almost similar to interfacial polymerization. The differentiating features of in-situ polymerisation is that there are no reactive monomers in the core material. All the polymerisation carried out in the continuous phase, instead of in the interface between the core droplets and the continuous phase, as in the case of interfacial polymerisation [97].
Over the last few years, several works have been published on the fabrication of coreeshell microparticles via in-situ polymerization. Lin et al. [94] synthesize coreeshell 1,3,5-triamino-2,4,6trinitrobenzene/polydopamine (PDA) microparticles using in-situ polymerization of dopamine on the surface of explosive crystals. The shell thickness of the PDA was efficiently controlled by tuning the time of the polymerization reaction. A year later, Li et al. [98] used the same method to fabricate coreeshell structured 1,3,5,7tetranitro-1,3,5,7-tetrazocane (HMX)@Polydopamine (PDA) energetic microspheres. The team tuned the amount of PDA coating on the surface of HMX by varying the coating. Salaun et al. [112] produced microcapsules with n-hexadecane core and melamine formaldehyde shell using an in-situ polymerization technique. Xuan et al. [99] reported the synthesis of Fe 3 O 4 @polyaniline coreeshell microspheres with well-defined blackberry-like morphology microspheres using this technique.

Suspension polymerization
Suspension polymerization is a chemical technique used in some encapsulation methods to create coreeshell particles. In this technique, polymerization performed with a soluble initiator in the monomers, and both insoluble monomers and initiators in the medium of the polymerization. In the first process step, the monomer phase consisting of monomers, blowing agent, and an initiator is suspended in the medium containing a stabilizing agent in is formed as microdroplets using a stirrer. Then, in the second process step the polymerization is initiated within the monomer droplets and is continued to completion. Finally, the microdroplets of monomer are switched to polymer microbeads of the same size. The polymer precipitates out from the monomer droplets because of insolubility. A three-phase system including monomer, polymer, and water is formed [100,101].
Jonsson et al. [101] employed suspension polymerization approach to prepare a thermally expandable coreeshell structure with polymer. The particles comprised a hollow core encapsulating an inert hydrocarbon with a size of approximately 10e20 mm. The composition of monomer feed and the polymerization temperature have significant impacts on the particle morphology. Ting et al. [102] implemented suspension polymerization using a conventional free radical polymerization technique to synthesize coreeshell microparticles. The coreeshell microparticles comprised a poly (vinyl neodecanoate) crosslinked with poly (ethylene glycol dimethacrylate) core and a poly (ethylene glycol methacrylate) shell.
Besteti et al. [103] and Lenzi et al. [104] combined suspension and emulsion polymerization for producing coreeshell polymer beads. First, a non-porous polymer core was formed via standard suspension polymerization. Next, all components required for a classical emulsion polymerization were added to the reacting system during the suspension reaction. Finally, due to the high viscosity and viscidity of the suspended polymer particles, the emulsified polymer particles agglomerated on the surface of suspending particles and the coreeshell bead was formed.

Precipitation polymerization
Precipitation polymerization can be employed to generate coreeshell microparticles. The primary state of the reaction mixture in both precipitation polymerization and dispersion polymerization process is the same that is a homogeneous solution. Though, in precipitation polymerization, initial particles do not swell in the medium, and is called a "precipitation polymerization" [100]. Polymer microparticles fabricated via precipitation polymerization or co-polymerization have functional groups and clean surfaces, because they are implemented without using any stabilizer or emulsifier [105]. Li and Stover [106] created coreeshell polymer microparticles through two-step precipitation polymerization. The team developed cross-linked coreeshell polymer microparticles with diameters of 2e8 mm through semi batch and two-step precipitation polymerization without any stabilizer. These particles were composed of a divinylbenzenes core and several functional monomers such as monovinyl, chloromethylstyrene or divinyl methacrylic shell. Type of the shell, porous or nonporous, depends on the reaction medium and the monomer. The authors used acetonitrile and toluene/acetonitrile mixtures as the reaction media. Functional comonomers such as maleic anhydride, chloromethylstyrene, and methacrylates resulted in the formation of monodisperse copolymer microparticles, whereas a suitable cosolvent such as toluene resulted in porous microspheres [106].
To date, several research groups reported the fabrication of coreeshell microparticles using precipitation polymerization. Werts et al. [107] fabricated inorganic/organic coreeshell particles through precipitation polymerization and inverse microsuspension polymerization. The microparticles consist a titanium dioxide core and a polymer shell. Titanium dioxide was coated with cross-linked polystyrene shell through precipitation polymerization of styrene and divinylbenzene in the presence of titanium dioxide. This approach prevented titanium dioxide from adsorption to the surface of the electrode and led to the reduction in particle density. Pretreating the titanium dioxide particles with 3-(trimethoxysilyl) propyl methacrylate improved the encapsulation.
Barahona et al. [108] produced molecularly imprinted polymers (MIP) microspheres, with coreeshell structure by precipitation polymerization in a two-step procedure. As shown schematically in Fig. 4(D), first nonporous polymer cores were achieved by precipitation polymerization of divinylbenzene-80 (DVB-80) in acetonitrile. The core microspheres were utilized as seed particles in the synthesis process of functional molecularly imprinted polymeric shells. The copolymerisation of DVB-80 and methacrylic acid (MAA) in the presence of thiabendazole (TBZ) in a mixed solvent porogen (acetonitrile/toluene), resulting in a porous shell.
A few papers reported polymer-based coreeshell microparticle prepared via other class of polymerization methods. Rudin et al. [109] produced monodisperse latex coreeshell microparticles with a diameter of 3 mm via a series of consecutive seeded growth emulsion polymerizations. Laus et al. [110] prepared monodisperse polystyrene particles with diameter ranging from 3 to 10 mm. The authors used polycarboxylic acid or polyepichlorohydrine steric as a stabilizer for the shell. Okubo et al. [111] conducted a two-step polymerization of chloromethylstyrene and styrene on polystyrene seeds. The first step was generating monodisperse polystyrene particles with micron size using dispersion polymerization with 2,2 0 -azobisisobutyronitrile as initiator in ethanolewater medium and poly (acrylic acid) as a stabilizer in different conditions. Subsequently, seeded copolymerization of styrene and chloromethyl styrene occurred in the presence of the 1.9-Мm monodisperse polystyrene particles.

Microfluidic technique
Conventionally, low-ordered multiple emulsions are generated in two sequential emulsification steps through high shear generated by mechanical agitation [112,113]. First, a primary single emulsion is formed through powerful mixing of two immiscible liquids and then mild mixing of the first emulsion in a large volume of another immiscible liquid resulting in the double emulsion [10,114]. Compared to other methods, emulsification is a relatively simple technique for generating multiple emulsions. However, bulk mixing is associated with low batch-to-batch reproducibility, high materials and energy consumption, lack of precise control over processing parameters, the size of the droplet, and the number of core droplets Encapsulated [112].
Microfluidic technique has emerged as a versatile process and alternative to old routes for preparing coreeshell droplets as a template for production of coreeshell microparticles. Microfluidics can overcome the drawbacks of the old methods mentioned above. Devices for the fabrication of droplet-based microfluidics are small and can be fabricated at a relatively low cost [115]. Microfluidic technology could provide highly precise control over small volumes of fluids in microchannels that allows for accurate adjustment of the size of the core droplet and the thickness of the shell. Droplets generated with this method have a narrow size distribution and can be generated at regular Intervals [116]. One of the most remarkable features of microfluidics is that it allows for the generation of microemulsion with two, three or even more cores [113]. In recent years, microfluidic technology has achieved considerable advances in the encapsulation of cell via microemulsion method [117]. The encapsulation of live cells using conventional emulsification methods have shown difficulties. Cells may be damaged by the complex processes such as coating, surface modification, chemical reaction, centrifuging, washing, and dispersing. In contrast, microfluidics enables to maintain the cell viability and uniformity [56].
Generating double emulsions via microfluidic technology has been reported by a large number of papers. In a broad sense, droplet-based microfluidic methods could be classified into two groups: one-step methods and two-step methods [118]. Both 2D and 3D microfluidic devices could be employed to generate double emulsion droplets in one-step either two-step methods [114].

Preparation of double emulsions using 2D device
a) One-step method One-step droplet formation has only a single step. Nie et al. developed a 2D flow-focusing microfluidic device for the generation of coreeshell droplets in one step. In this device, a double flow focusing unit force three immiscible fluids into an orifice and then form the droplets in the downstream chamber as shown in Fig. 5(A). The outer fluid was injected through two side channels and the inner and middle fluids were supplied from the middle channels [119].

b) Two-step method
The two-step method is the most prevalent technique for preparing double emulsions. In two-step methods, oil in water in oil (O/W/O) and water in oil in water (W/O/W) emulsions are formed through two consecutive steps. First, internal droplets form and then outer layers of the shells set around the core. Next, the solidification of the coreeshell droplets using methods such as ionic cross-linking [120], freezing [121], photo or thermally induced freeradical polymerization [122], solvent evaporation [123] can result in coreeshell microcapsule.
The two-step process combines two key factors, opposite wettability connected serially and droplet forming geometries. The first geometry forms the core droplets. The second one forms the outer droplet and encapsulates the core. Examples include two flow-focusing, co-flowing, two T-junction, and two cross-flowing and so on [118,124]. Adjusting the flow rates of the fluids and the geometry of the microfluidic device can precisely modulate the fabrication frequency of the droplets, the size of the core, the thickness of the shell, and even the number of cores encapsulated in the shell [12,118].
Abate et al. [125] prepared double emulsion using PDMS devices in two steps with two flow focusing cross-junctions. The team utilized flow confinement to pattern the wettability of PDMS. The team physically confined a chemical treatment changing wettability in selected areas of the device using an inert fluid. They also employed thermal-initiated and photo-initiated surface treatments with their method. This measure allowed for the preparation of both W/O/W and O/W/O double emulsions in this device as illustrated in Fig. 5(B).

Preparation of double emulsions using 3D device a) One-step method
Utada et al. [126] developed a glass capillary microfluidic device for the preparation of coreeshell droplets in a single step. The main parts of their microfluidic device are a square capillary and two cylindrical glass capillaries with a tapered end shape. These round glass capillaries were inserted coaxially into the glass square tube as shown in Fig. 5(C) [127]. The inner and middle fluids were transferred from the cylindrical capillary and the outside area of this capillary from the same direction, respectively. The outer fluid was injected from the outside region of another cylindrical capillary from the opposite direction. Then coaxial flows forced into the outlet orifice at the outlet of the rounded capillaries are broken up to form double-emulsion droplet. This fluidic design offers precise control over the number of cores encapsulated in coreeshell droplets as well as the size of core and shell droplets.
Adding more injection capillary to this microfluidic design allows for the generation of double emulsions with multiple core droplets [118]. For instance, Zhao et al. [128] fabricated a multiple double emulsion composed of multiple oil cores using a glass capillary microfluidic device with multiple injection tubes ( Fig. 5(D)). The multiple double emulsion was utilized as a template to produce the photonic crystal barcodes. Five different capillaries, four capillaries to deliver the oils and an inner capillary to transfer the aqueous phase were utilized in this device. The aqueous fluid was also pumped through the region between the outer quadrate tube and the injection cylindrical capillary covered five injection capillaries.
The glass capillaries device with a similar structure to the device shown in Fig. 5(C) were employed for producing multiple emulsion drops of high order but with a little difference in shape and surface modification of the glass capillary [118]. Kim et al. [129] developed  [125]; part (D) reproduced with permission from [128]; part (E) reproduced with permission from [129]; part (F) reproduced with permission [67].]. a device with two tapered circular capillaries, one for injection and another for collection. Both capillaries were placed into a square tube, on the two ends of the tube as illustrated in Fig. 5(E). Additionally, a small capillary with tapered end was placed in the region between the collection and the quadrate tube to concurrently pump a second immiscible fluid. The surface of all circular capillaries was modified to be hydrophobic. The surface of the outer square tube was modified to be hydrophilic.
An aqueous fluid flowing along the cylindrical circular injection capillary forms the core droplets and an oil phase delivered through the square tube from the same side forms the intermediate membrane. The other aqueous phase and oil are simultaneously pumped from the area between the circular collection capillary and the outer square tube and from the small circular capillary, respectively. By reason of the hydrophobicity of the circular capillaries and the hydrophilicity of the outer square tube, the aqueous fluid flows along the inside surface of the square tube and oil flows along the outer surface of the collection tube. These four immiscible fluids are forced into the orifice to break up into triple emulsion droplets [129].
Kim et al. [67] introduced a novel and feasible co-axial capillary microfluidic device (Fig. 5(F)) to generate double emulsion drops with an ultra-thin middle layer in one step. They inserted coaxially a circular capillary with the tapered tip into a larger capillary and fix them into another square tube. To restrict the flow at the exit of injection tip a rounded capillary was placed at another side of the square capillary. The oil and the aqueous fluid flow along the capillary wall and from the central capillary, respectively. The biphasic flow form coreeshell structured emulsion with a very thin membrane at the outlet of injection tube. This system simplifies the generation process of double emulsion with an ultra-thin shell and viscous organic solvents.

b) Two-step method
The basis of the formation of coreeshell droplets is the same in both 2D and 3D devices [118] with a difference in the fact that 3D devices eliminate the restrictions on wettability imposed by 2D device [130]. In contrast to 2D devices, the droplets in 3D microfluidic devices have minimum contact with the channel wall. This feature can prevent the fragile shell from rupturing during early interfacial polymerization and the channels from wetting [112].
Davies et al. utilized a step design or 3D channel structures to fabricate PDMS microfluidic devices [131]. Non-planar devices can be fabricated with two complementary PDMS moulds. Fig. 6(A) schematically shows this device assembled face to face, one of them on top of the junction and another one on the bottom. This type of microfluidic device allows for achieving coreeshell droplets with different inner structures, as an example single-cored emulsion droplets, dual-core double emulsions and even coreeshell droplets with three distinct cores [112]. Either W/O/W or O/W/O emulsions can be formed in the same device [130].
Another non-planar microfluidic device for the preparation of double emulsion comprises two cylindrical capillaries, one with a tapered tip and another with a thick wall, as an injection tube and a transition tube, respectively, a collection tube and two square capillary tubes. The capillaries were coaxially assembled on glass slides, so that the end of the injection capillary fits into the transition capillary and both were nested within the square capillaries as illustrated in Fig. 6(B). The other end of the transition tube was placed into the collection capillary [132]. In this case, the monodispersity of emulsion droplets, the size and the number of inner droplets can be well controlled [118].
The 3D geometry of flexible two co-axial capillaries microfluidic device also proposes the production of a tuneable double emulsion in two steps. Fig. 6(C) schematically shows this device in which two capillaries were placed coaxially inside a T-junction along its main axis. These devices consist of capillaries with hydrophilic or hydrophobic inner walls. The inner capillary was employed to make the core droplet and the middle capillary was employed to generate the shell droplets. Then coreeshell droplets were dispersed in an outer continuous aqueous fluid. This capillary-based design with hydrophilic or hydrophobic inner walls can solve the problems of modifying the surface energy of capillary fluidic devices for the generation of double emulsions [133].
Another type of 3D microfluidic device (Fig. 6(D)) for producing higher-order multicomponent emulsions was fabricated using three basic building blocks: a drop maker, a connector and a liquid extractor. The drop maker makes droplets and then droplets generated merge using the connectors. The liquid extractor sends out unwanted fluid in the continuous phase. This kind of fluidic device is scalable and controllable. Assembly of device utilizing different types of the building blocks result in the formation of multicomponent multiple emulsions with different structures. The size and the number and the ratio of the co-encapsulated droplets could be easily tuned [134].
In the microfluidic domain, advances are not only restricted to producing liquid in liquid in liquid (L/L/L) microemulsion; researchers have demonstrated the generation of gas in water in oil (G/W/O) as well as gas in oil in water (G/O/W) emulsions. This technology has shown great advantages in preparing G/W/O and G/ O/W emulsions that could be used as a template for generating hollow microparticles. A few research groups have attempted to prepare G/L/L emulsion using different devices such as flowfocusing, double flow-focusing, co-flowing geometry, co-flowing geometry, T-junction, and dual-coaxial.

Applications
Core-shell microparticles have been extremely desirable for different applications in many fields where, the encapsulation and the protection of active substances [135], targeted delivery and controlled release of various materials [27], and the confined reaction of chemicals [7,11] are needed. The examples consist of food industry [136], agriculture [69], cosmetics [137], pharmaceutics [138], and the constructing self-healing materials [139]. In this section, we discuss the applications of these smart microparticles.
One of the important applications of microencapsulation is in pharmaceutical and biomedical industries. Core-shell structures have tremendous potential in the development of delivery vehicles, cell biology, and biosensors. Although many applications have been explored over the last few decades, there are still more functions and innovations to be explored.

Targeted drug delivery
In recent years, controlled delivery systems have been attracting attention of researchers. Compared to the traditional uncontrolled drug release, the novel delivery systems have a great impact in improving the therapeutic and pharmaceutical properties of medicines administered. By developing smart particles with complex structure, precise drug delivery to a given part of the body is possible. These delivery systems are extremely important for targeting of gene, protein, therapeutic agents, vaccines to these specific sites.
Core/shell microparticles have emerged recently as promising vehicles for targeted drug delivery, because of their unique properties. These composite microparticles as drug delivery vehicles pose several advantages, including the combination of multiple functionalities within a single carrier, the decrease of the initial burst release, adjustable and regular drug release rate, and ability to carry a wide range of biomolecules [125]. Such structure with diverse formulations allows for the encapsulation of agents distinctly and with adjustable distributions and changeable release profiles, either burst or delayed. Core-shell microparticles could encapsulate multiple ingredient and release them during a multistage process, according to requisites that is for instance beneficial in the treatment of cancer [140] or tissue engineering [141]. However, traditional techniques produce coreeshell particles with a wide size distribution and is not suitable for drug delivery. Utada et al. [126] surveyed the use of microfluidics for the generation of coreeshell microparticles and succeeded to prepare W/O/W double-emulsion droplets using a concentric microcapillary device. The advance has opened a new avenue for pharmaceutical and biomedical applications [142]. The coreeshell droplets produced via microfluidics allow for high encapsulation efficiency and loading efficiency. The microparticles have low size distribution, uniform structure, and composition resulting in a consistent and controlled drug release. The microparticle size is a key parameter for the selection of the suitable drug administration route [9]. Microparticles with a size ranging from a few to hundreds of microns are more suitable for oral administration [143].
Lensen et al. [20] prepared monodisperse liquid-core microparticles and hollow biodegradable PLLA microcapsules using a flow-focusing microfluidic device for the purpose of drug delivery. The team prepared double emulsion droplets with a liquid core. The dye Oil-Red-O served as a hydrophobic model drug and was encapsulated by a PLLA shell. Eliminating the liquid core through lyophilization resulted in drug-loaded PLLA hollow capsules. The model drug was encapsulated both in the liquid core and the polymer shell of the microcapsule. The release profile has illustrated that the drug trapped into the core was released during the first hour, whereas a significant amount of the drug in the shell remained unreleased.
Xu et al. [144] fabricated a doxorubicin-loaded coreeshell structured microsphere by coaxial electro-hydrodynamic atomization technique. Microspheres were comprised of a poly (D, L-lactic-co-glycolic acid) (PLGA) core and a poly (D, L-lactic acid) (PDLLA) shell. Doxorubicin, a type of hydrophilic chemotherapy drug, was used as a model drug and encapsulated within the core. As shown in Fig. 7(A), doxorubicin was efficiently encapsulated, and the shell was approximately drug free. The release of doxorubicin was a two-stage process with a constant release rate.
Nei et al. [140] also used the same technique for the production of microparticles with a distinct coreeshell structure. Two different hydrophilic drugs were encapsulated in microparticles with high encapsulation efficiency in a single step. The study showed that varying the ratio of the outer flow and inner flow affected the ratio of core and shell, and consequently different drug release profiles. By comparing two different microparticles with swapped distributions of paclitaxel and suramin (A and B) with free drug and free drug controls (P/O and S/O), the team observed that single-drug controls are highly toxic to U87 cells. Also, free drug control groups induced the apoptosis unsustainably, however the primary impact is advantageous. In the contrast, samples A and B induced the apoptotic activities increasingly during the time and performed better than free drug controls at day 6. The sample B outperformed sample A. Furthermore, samples A and B induced the apoptotic activities much better than the single-drug controls. Moreover, invivo tumour growth inhibition study against subcutaneous U87 glioma in BALB/c nude mice showed that the number of tumour cells decreased significantly in the mice treated with samples A and B after 21 days (Fig. 7(B)). The results showed the benefits and potential application of multi-drug release system in treating brain tumours. Fig. 7(C) illustrates an interesting example of a coreeshell droplets; where a dewetting transition occurred and the release was triggered because of osmotic shock. The team utilized double emulsion droplets as a template to produce PEG-PLA polymersomes by assembling amphiphilic deblock copolymers. The polymersomes were used for the encapsulation of a fluorescent hydrophilic solute. By adding salt, an osmotic pressure difference triggered the breakage of the polymersomes, and the solutes were released. This simple and efficient release mechanism could be used in different biomedical fields for designing the encapsulation and controlled release [127].  [114]; part (B) reproduced with permission from [132]; part (C) and (D) reproduced with permission from [133,134], respectively.].

Cell biology
In a living tissue, cells reside in a 3D extracellular matrix containing proteins and polysaccharides [145]. The cells phenotype and properties are affected by the features of the extracellular matrix. Biocompatible microparticles have been used for cell encapsulation and as a 3D matrix. The microparticles can imitate various characteristics of the extracellular matrix, hence they account for a reliable platform for in vitro cell culture. Microparticles with the high surface area and the porous wall allow for the exchange of nutrient molecules, oxygen and waste materials. The incorporation of the cell into the microcapsule can protect them against harsh in-vitro and in-vivo environmental conditions such as the attack of the enzyme and UV irradiation and increase the cell viability [9]. Microparticles have emerged as a promising device for biomedical purposes including single cell study, tissue engineering, regenerative medicine.
Among different methods for producing cell-laden microparticles, droplet microfluidics is a more acceptable technique because of the continuous generation of monodisperse droplets with a high yield. Using microfluidics, the encapsulation efficiency and the number of cells entrapped into the microparticle could be precisely controlled [9].
Core-shell microparticles with either a hydrogel or a liquid core and microgels are the suitable for cell encapsulation. Microparticles generated from double emulsions could be divided into two classes; matrix-core-shell and liquid-core-shell microcapsules. The crosslinked microparticles should be quickly transferred into liquid to prevent any detrimental impacts on the cells [9].
Core-shell microcapsules composed of a hydrogel core could prevent the cells from escaping, hence allowing for long-term cell culture studies. Covering the cell-laden microparticle within a nondegradable gel shell could prevent cell from the egression and allow for studying the behavior of the cell in various condition even for 2 weeks [146]. For instance, Allazetta et al. [147] encapsulated different cell types including embryonic stem cells (ESC), fibroblasts, and cancer cells into cross-linked poly (ethylene glycol)-based microgels prepared using a T-junction microfluidic device by electrostatic self-assembly of peptide amphiphiles. The team investigated the proliferation of mouse embryonic stem cells encapsulated in microcapsules with different elasticities. Their results showed that the cells in microgel with higher stiffness proliferated lower and remain viable lower compared to the soft microgels after 4 days of culture. The team found the cell escape depends on both the microgel features and cell type and by co-encapsulation of microgels in a nondegradable layer of gel with 200-mm thickness the number of escaping cells decreases.
The microcapsules with liquid core can be used to incorporate cells to generate cell aggregates, as the liquid core improves interactions between the cells. This approach is advantageous for stem cell study. For instance, culturing P19 EC cells encapsulated in a liquid coreeshell microparticles formed a single spherical embryoid body after 2 days. However, several clusters of cells encapsulate in the microbeads only form a bumpy shape [9,56].
Chen et al. [148] created 3D coreeshell scaffold templated w/w/ o double emulsions. For the first time, by assembling heterotypic cells into the 3D coreeshell hydrogel scaffolds, a "organ in a droplet" platform was created. Monodisperse double emulsion were generated using a flow-focusing microfluidic device. The coreeshell structure allowed different cells to arrange and generate into an artificial liver in each droplet. Fig. 7(D) shows hepatocytes incorporated in the core. Fibroblasts were immobilized by cross linking of alginate network in the shell.  [140,144], respectively; part (C) reproduced with permission from [162]; part (D) reproduced with permission from [148]; part (E) reproduced with permission from [150]].
Core-shell structure has also been used for single cell screening playing a great role in cell biology and treatment of various disease. For example, microparticles comprised a polyelectrolyte shell surrounded by an agarose bead was produced using a microfluidic device [9]. Fischlechner et al. [21] evaluated enzyme, encoding DNA, and fluorescent dye enclosed in multilayer gel/ shell beads that could serve as a coding platform with genetic information. This system was used for the performance of the directed evolution of a bioremediation catalyst confined in gel/ shell beads and the isolation 20 times faster in less than an hour. The team succeeded to develop a practical technique for highthroughput screening that results in a composite material with evolvable protein components.

Magnetic resonance imaging
In the recent years, particle-based magnetic resonance imaging (MRI) contrast agents have attracted a great attention, because the multimodal particles concurrently allow for delivery, imaging, and treatment of targeted tissues [149]. The coreeshell structures with a magnetic core and a porous shell have attracted a major interest for the application in magnetic resonance imaging. Dibbern et al. [22] synthesised a novel type of protein coreeshell microstructure using poly (R, L-glutamic acid) as an imaging contrast agent for MRI. The authors found that the microspheres were stable in different pH and temperatures of the body. The hydrophobic core of these spheres could comprise various imaging agents, and the polymer shell could be simply modified according to the targeted location in the body.

Biosensors
The use of coreeshell particles as biosensor in biomedical applications such as medical diagnostics has been the focus of some recent studies. Because an implantable biosensor is highly demanded for consistently monitoring and the detection of analytes in body, different diseases could be diagnosed early monitored in real time [150]. Biosensors containing biological detection agents and signal transduction elements could be used for the detection of biomarker such as glucose, enzymes, ions, DNA, and antibodies [9,150]. Microfluidics has provided an opportunity to generate smart microparticles with complex structures for the fabrication of biosensors with extensive features [150]. Xie et al. [150] created hollow polyethylene glycol microcapsule for the encapsulation of nanosensors in the liquid core. In-vivo application of implantable biosensors used for the detection of biomolecules is limited by the transfer or clearance from the implantation place. One approach to solve this problem is encapsulating nanosensors in hydrogel scaffold. But, nanosensors in contact with the hydrogel wall can disrupt the sensor function. Hence, the team developed a microcapsule with a liquid core through microfluidics to prevent the contact of nanosensors with hydrogel. Nanosensors including glucoseresponsive quantum dots, heparin-responsive gold nanorods, and gold nanorods were encapsulated into the core, Fig. 7(E). Biomolecules such as glucose and heparin were spread via the shell and the interaction of them with the nanosensors resulted in detectable optical signals.
Microparticle-based sensors are not restricted to the recognition of analytes; some sensors can detect environmental conditions such as temperature, the concentration of osmolyte, and pH [9]. For instance, Kanai et al. [19] fabricated microparticle-based microsensors using capillary microfluidic device. The shell was made of gel-immobilized colloidal crystal that was responsive to temperature. By increasing the temperature of the microcapsule, the shell shrinks swiftly at about 32 C, resulting in a change of the diffraction colour or Bragg diffraction wavelength. These microcapsules could be employed as biological and chemical sensors to monitor chemical reactions in the encapsulated materials or changes in environments through colour change. Compared to the bulk substances, the crystal shell can react and stimulate much faster because of their thin shell.

Food industry
Core-shell structure also has a great potential for application in the food industry. Some bioactive food ingredients such as minerals, vitamins, lipids, proteins, probiotic bacteria, and amino acids play an important role in both physiological field and food processing industry. These substances could be used for developing functional foods with properties and function beyond typical nutrition [151]. These sensitive and bioactive substances should be protected during processing, storage, and from surrounding environment to reach the targeted site in the body [151,152]. Microencapsulation has recently emerged as a powerful mean for protecting food components against heat, oxidation, moisture and pH [135]. By encapsulating food components, the texture, the aroma and flavoring agents release could be controlled, and less fat and oily foods can be produced. Using this approach food companies incorporate into their products minerals, vitamins, flavours and polyunsaturated oils. Microencapsulation could cover the components taste [153] such as mineral salts adding for the food fortification [69].
A good example is the encapsulation of flavors in chewing gums that release during chewing, the encapsulation of yeast releasing during baking, and the encapsulation of probiotic bacteria to be protected in gastric environment and be released along the small intestine. Furthermore, microencapsulation can facilitate the food production process through transforming liquids components into solid powder [69].

Environmental
Recently, water pollution has become a crucial environmental challenge, particularly toxic organic pollutants. Many measures have been explored for the removal of toxic pollutants from water. However, the traditional techniques are of high throughput, but have disadvantages such as high cost, imperfect or no degradation, producing intermediate materials as secondary pollutants. Using ion exchange or chelate resins for the elimination of heavy metals causes a huge amount of toxic and detrimental components concentrate on the sorbent substances surface [154]. Sorbents with surface charge can cause several detrimental environmental impacts and also harm human beings [155].
Over the last few years, a great attention has been paid to adsorption technique to eliminate organic pollutants, as it is practical and low-priced [156]. Core-shell particles have also found their usage as a mean for treating wastewater. The solution is the confinement of harmful pollutants into the core made of sorbent components [155].
Menzel et al. [155] investigated the scavenge of a cationic pollutant from aqueous solutions using a cross-linked poly (acrylic acid) (PAAc) coreeshell microparticle with a polyelectrolyte core and a hydrophobic shell. The team studied the absorbance of methylene blue and cationic substances such as Ca2þ, Cu2þ, Sr2þ. Ion exchange and/or chelation bonding on the carboxylate pendant groups of the polymer result in the adsorption of cationic substances onto PAAc. The coreeshell structure efficiently adsorbed and immobilized the pollutant samples, Fig. 8(A).

Catalytic activities
Core-shell microparticles have been studied for the potential applications for catalytic activities. In a sequential reaction, an active catalyst generally consists of two active sites. The first one catalyses the first reaction, and the second one catalyses the subsequent reaction. To achieve an ideal catalytic operation, the dispersal of two active sites and at the same time their proximity to each other should be improved. Facilitating the transfer of the products obtained in initial reaction to the active sites of subsequent reaction considerably impacts the product selectivity. Typically, active sites are located irregularly on the surface of a bifunctional catalysts, causing the random reactions in the products because the first reaction abandons the catalyst unreacted at the second active sites. A coreeshell structure catalyst is seemingly promising for achieving better transformation of the reactants to the active sites with a desired selectivity. In this system, the intermediate products are generated in the core, thus the reactants should cross the shell to reach the core catalyst. Subsequently, by migrating the intermediates from the core to the active sites of shell channels, final products are produced [157].
As an example, Chen et al. [158] developed a coreeshell catalyst consisting of a Pt/C catalyst and a polyaniline shell. Core-shell particle was produced by coating the carbon surface of core via polymerization of PANI (Fig. 8(B)). It was shown that using this system the catalytic activity and stability increased significantly compared with unmodified Pt/C.

Three-dimensional (3D) printing
Different types of materials, such as metal-based powders, thermoplastics, polymers have been used for producing 3D-printed structures. But 3D structures printed from these traditional materials have limited applications. To create smart 3D structures with wider applications and to enhance the utility of 3D printing, more practical materials have to be developed. Core-shell particles as a printable material can enhance the applicability of 3D printed structures in a range of applications. Hong et al. created conductive 3D Printable CueAg coreeshell particles via the solideliquid method. Both Cu and Ag are highly conductive, hence coppersilver coreeshell particles are suitable candidate for printed electronics [159]. Inks or pastes formed based on such a conductive coreeshell structured particle could be employed for various applications such as printed circuit boards, solar cells, transparent conductive electrodes, touch screens [160,161].
Pajor-Swierzy et al. generated a conductive printable ink using a non-oxidative Cu/Ag coreeshell microparticles. Silver nanoparticles conventionally used in ink formulations are highly conductive and stable against oxidation. But silver is costly for application in large scale production. Copper could be the best alternative for silver as it is less expensive and highly conductive. Though the principal problem associated with copper is the quick oxidisation in the presence of air that cause the reduction in electrical conductivity. Hence, the production of inks with ingredients, which are resistance to oxidation and low-cost are highly sought after. The promising approach to tackle this problem is covering the copper particle with an air-stable conductive shell, such as noble metal. The Cu/Ag coreeshell particles produced by the team were resistant against oxidation for 6 months at environmental condition and throughout the sintering process. According to their results, adding carboxylic acids to the CueAg core-shell-based ink considerably enhanced the conductivity of deposited metallic films. Oleic acid enhanced the conductivity to 1.8 times [161].
Hu et al. generated a printable conductive elastic composite comprising polystyrene/silver coreeshell microparticles and the PDMS matrix. Polystyrene/silver coreeshell microspheres were of lower cost than silver nanoparticles and prevented silver nanoparticles to aggregate in the polymeric matrix. The viscous pastes prepared could be used for the fabrication of conductive conductors or be printed on different substrates. The polystyrene/silver/PDMS film prepared was electrically conductive and stable under mechanical deformations. The team also produced high resolution elastic circuits through screen printing of polystyrene/silver/PDMS paste on different substrates such as glass, bended polyimide film, paper, and woven textiles, as shown in Fig. 8 (C) [160].

Conclusion
In this review, various kinds of coreeshell microparticles are first discussed based on the materials applied in the core and the shell structures. This smart combination of a core enclosed with the shell layers not only offers the exclusive properties of both the core and the shell materials, but also poses combined properties not achievable separately by the core and the shell materials. In the recent years, coreeshell structures have been the center of research focus because of their unique properties. Compared to bulk  [155]; part (B) reproduced with permission from [158]; part (C) reproduced with permission from [160].]. materials and simple particles, they exhibit more stability, excellent potential for protection core compounds from adverse environment, time-programmed controlled release of payloads, and the improvement of physical, biological and chemical properties for application in diverse fields. The selection of the core and the shell materials are based on the corresponding application of particles. The most interesting aspect of the coreeshell structures could be the diversity of chemical, mechanical, and biological features. Generally, shell materials could be classified into two basic groups: organic and inorganic and the core material can be in one of the three phases: gas, liquid or solid.
This review also provides a general overview of different techniques for the generation of coreeshell microparticles including microfluidics, chemical, physical-chemical, and physicalmechanical approaches. Conventional techniques have some issues that have considerably restricted their applications. The main disadvantages of these methods are low monodispersity, high material utilization, poor batch-to-batch reproducibility, and poor control on processing parameters, encapsulation efficiency, particle size, the morphology, thickness of the shell, and the number of cores entrapped. Microfluidics technology has been developed for generating coreeshell structure with controlled features and addressing the challenges mentioned above. Hence, this paper places the main emphasis on the fabrication of coreeshell microparticles through microfluidics. Microfluidic devices are geometrically classified as 2D and 3D devices. Both geometries could be designed to generate coreeshell droplets using single or two sequential emulsification steps.
The core-shell microparticles have proved their capabilities for diverse applications. These microparticles are widely used in biomedical and pharmaceutical fields such as targeted drug delivery, cell biology, MRI, and biosensors. Apart from the biomedical applications, coreeshell microparticles are also promising devices for food industry, environmental, catalytic activities, and 3dimensional printing. However, more investigation still requires to be carried out to overcome the outstanding challenges and to expand their applications. One of the major challenges is the bringing such smart coreeshell structure out of academic research into industry on a large scale. Microfluidic technique seems to be a great solution to overcome the drawbacks of conventional methods, but also has its own disadvantages. The need for surfactants, the limitation of usable liquids and ability to control the morphology of coreeshell droplets limit the proliferation of this method. Thus, further study is needed to improve the existing techniques and to develop novel methods and devices for strengthening the capability of coreeshell particles.

Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.