Microfluidics for core–shell drug carrier particles – a review

Core–shell drug-carrier particles are known for their unique features. Due to the combination of superior properties not exhibited by the individual components, core–shell particles have gained a lot of interest. The structures could integrate core and shell characteristics and properties. These particles were designed for controlled drug release in the desired location. Therefore, the side effects would be minimized. So, these particles' advantages have led to the introduction of new methods and ideas for their fabrication. In the past few years, the generation of drug carrier core–shell particles in microfluidic chips has attracted much attention. This method makes it possible to produce particles at nanometer and micrometer levels of the same shape and size; it usually costs less than other methods. The other advantages of using microfluidic techniques compared to conventional bulk methods are integration capability, reproducibility, and higher efficiency. These advantages have created a positive outlook on this approach. This review gives an overview of the various fluidic concepts that are used to generate microparticles or nanoparticles. Also, an overview of traditional and more recent microfluidic devices and their design and structure for the generation of core–shell particles is given. The unique benefits of the microfluidic technique for core–shell drug carrier particle generation are demonstrated.


Introduction
Core-shell particles are a category of particles consisting of two or more distinct layers of material, usually a core and a shell by its name. Different or the same materials with various structures may be used for the core and the shell. This structure offers the features and properties that are not achievable by the core and shell's individual materials, providing a synergistic effect, stabilizing the active particles, and biocompatible properties. 1 The core could be solid, liquid, or gas. The shell is typically solid, which, depending on the design requirements and the intended application, may be produced using either organic or inorganic materials. 2 The core-shell particles can have different core shapes, shell thickness, and surface morphology. 3 Over the past few decades, the core-shell particles have been used more frequently in drug delivery, biomedical science, tumor therapy, food and cosmetic industry, medicine, material science, and so forth according to their different properties compared to the bulk materials. 2,4,5 Nanoparticles (NPs) synthesis is a challenging process, and due to their usage in the advanced materials, new techniques have been made for these nanoparticles' synthesis. 6 The development of characterization techniques has led to the production of structures for these different core-shell nanocomposites. 7 Because of these nanoparticles' different chemical and physical properties, classical physics laws would fail to explain these properties. So, some new theoretical models in nanoscales were introduced to better understand these nanomaterials. Also, the use of these nanoscales' materials leads to new advanced technologies and strategies in different elds. 8,9 A wide variety of methods, including polymerization, spray drying, solvent evaporation, and self-assembly, have been used to prepare core-shell structures. Among these physical and chemical methods, the controllable generation of monodisperse core-shell microparticles with a narrow size distribution is of great demand. Core-shell microparticle properties such as size, morphology, and structure signicantly inuence their applications. It has long been a signicant challenge to produce core-shell microparticles with the desired size distribution using traditional methods. These methods typically lead to high polydispersity core-shell particles. Also, they have limited control over morphology and poor reproducibility. 2 Recently, there are many improvements in making coreshell drug carrier particles due to their specic characteristics. Microuidics has been developed and is a promising solution for the above problems. 2,10 microuidic systems made up of these components usually are not more than a few centimeters in size. 13,23,30,31 All these processes can be monitored by various monitoring methods, such as optical and ultraviolet microscopes. 32,33 In addition, the physical and chemical properties of uids in small volumes and within capillary tubes differ from their macro-scale properties. 34,35 In many cases, this makes it easier to work with uids in this volume. These properties are also widely used to design chips and perform specic functions such as moving uid inside a channel or mixing uids. 9,36 There is a lot of research and diagnostic tests in biology, chemistry, and medicine in which samples and soluble substances can be evaluated, so microuidic devices have a wide range of applications in these areas. In microuidic devices, each part of the chip can act as a part of the laboratory, and so these lab chips are called lab-on-chip. 37,38 A lab-on-chip is a device used instead of a laboratory process, usually on a scale of square centimeters or even millimeters in size (Fig. 2). It will do everything have to be done in a laboratory on a small device called a chip, which has become more useful in recent years. 39,40 Another factor that has led to the use of lab-on-chips devices in recent years is the use of small amounts of uid in these chips, which reduces costs and time of process. 42,43 Also, the accuracy of these chips is very high. Because it is a continuous process and the operator is not involved in them, it causes less pollution to enter them and drastically reduces human errors due to high accuracy. Also, short execution time has gained a lot of attention. 10,44,45 3. Drug delivery Pharmaceutical systems use targeted transfer technology or control the release of therapeutic agents. 46 The development of appropriate drug carriers in biomedical applications to reduce the side effects is desirable and has benecial therapeutic effects. [47][48][49] Nanoparticles are essential as drug carriers because of their ability to transport various types of drugs to different parts of the body and release them at the right time. 50,51 Drug delivery is the mechanism or process of delivering a pharmaceutical substance that involves releasing a bioactive agent at the optimal and required rate. 51,52 Cancer is a leading cause of death, and despite tremendous efforts to ght cancer and the existence of multiple therapy modalities, cancer treatment still is a signicant problem. [53][54][55] Chemotherapy is a widely used treatment for cancers, and this has led to trials for a considerable number of chemotherapeutic anticancer drugs. The biggest drawback to the clinical use of these drugs is their broad bio-distribution and short half-life. The major disadvantage of traditional drug delivery methods is their weak selectivity. Also, healthy cells are exposed to drugs' cytotoxic effects, and an inadequate portion of the applied drug arrives at the tumor position in most cases. 5,[54][55][56] In addition, there is a need for high drug dosage, and it is another unwanted side effect. So, new drug delivery technologies need to be promoted to solve these limitations and improve cancer therapies' potency. 5,54,57 Recent drug delivery approaches deliver the drug to the tumor position and reduce side effects. Different types of drug delivery methods are developed for multiple healing applications. Nanoparticles are one of the most widely used carriers that, due to their ability to achieve therapeutic targets at acceptable times and doses, have a great interest in their potential in drug delivery. 5,56,58 4. Core-shell particles Core-shell particles were initially introduced to make production methods in the eld of biotechnology more effective. Nowadays, with the advent of encapsulation technologies using core-shell particles, medicines can stay active for longer periods of time. 59,60 They protect the drug against harsh conditions and provide the possibility of release under specic temperature or pH conditions; that's why these micro and nano-capsulation methods have gained more attention. [60][61][62] Core-shelling can be dened as a process for trapping one substance, usually the drug, in a shell as a physical barrier to protect the core from adverse factors and conditions. The application of this method in the pharmaceutical industry has been increased recently. Also, microcapsule methods are widely used today. The application of microcapsules and nanocapsules has become very important in the pharmaceutical industry in the past few years. Therefore, a lot of research has been done in this specic eld. 63,64 The core-shelling method's properties include protection against moisture, heat, ultraviolet radiation, oxygen, and adverse conditions. Using these methods usually causes the drug to act under certain physical or chemical conditions, reducing drug usage. Also, taking these kinds of medication may reduce the drug's side effects and increase its effectiveness. 65,66 Some types of core-shells particles are shown in Fig. 3. Different colors are used for the core and the shell. The core may be a single sphere (Fig. 3a) or have a hollow shell with a small sphere inside, a rattle-like or yolk-shell structure (Fig. 3b). It is also possible to have an aggregation of several small spheres (Fig. 3c). The shell structure can be a continuous layer (Fig. 3a-c) or attachment of smaller spheres onto a big core sphere ( Fig. 3d and e) or aggregated core spheres (Fig. 3f). 1 4.1 Goals of using core-shell drug carrier particles 4.1.1 Drug protection against adverse conditions. The protection of drug components can be considered as one of the primary reasons for encapsulation. 67 The core-shell particles can maintain the active compound's stability during the synthesis, storage, and consumption stages. Shells are used as protection; core-shell drug carrier particles are produced to protect the core, most of the time the loaded drug, against destruction or releasing in undesired parts of the body. 68,69 The drawback of interaction between substances, which may affect drugs' acceptable shelf-life, can be solved in core-shell drug carrier particles. 31,63 4.1.2 Controlled release. Core-shell particles are useful for drug delivery in the right place at the right time. 70 This method creates an appropriate delay. 71 There are two different types of release: delayed and stable. 56,61,65 The rst type referred to the release of active compounds with the delay in the desired location. There are many examples of delayed-release core-shell particles like encapsulated probiotics and tablets protected in the stomach against gastric acid by encapsulating them and releasing them in the small or large intestine. 72,73 The other example of the delayed-release is using core-shell nanoparticles prepared using microuidic chips for oral delivery of chemotherapeutics for colon cancer. They would only be released in the colon. 54 The second type is a stable release, a mechanism designed to keep the release rate of compounds constant at the desired location. Gradually and evenly, the drug exits the shell and enters the body. The sweeteners can be encapsulated in chewing gum, which keeps the taste steady for a while. 74 The appropriate selection of shell material for therapeutic delivery can improve controlled release, preservation, and responsiveness to stimuli. 2 4.1.3 Reduce the side effects of the drug. Most medications have several side effects. 75 For example, chemotherapy drugs can cause hair loss, fatigue, and many other problems. When they are used in the core-shell type can signicantly reduce these side effects. Because they have a delay, and the medicine would only release near the tumor, and it will not function in the whole body. The ability to release the drug only with the causative agent and only affect the causative agent and not damage other parts of the body may be considered a factor that leads scientists to work further on these core-shell drug carrier particles. 46,56,58 4.2 Core-shell drug carriers release methods 4.2.1 Temperature-triggered core-shell drug delivery particles. Nowadays, some polymers have specic physical properties that can be used in drug delivery. These polymers can release drugs and nanoparticles under certain conditions in the body, such as higher or lower temperatures, only in the desired areas. For example, poly-N-isopropyl acrylamide (PNIPAAm) polymer has unique physical properties that are used for drug delivery, including the fact that at temperatures above 32 C, it is insoluble in water and blood. Furthermore, it is soluble in water at a temperature below 32 C. So this polymer can be used for drug delivery to tumors near the skin surface because by cooling that area, only the drug would be released in that specic area. 61,65 Drugs can be used as a core, and PNIPAAm can be used as a shell.
4.2.2 pH-triggered core-shell particles for drug delivery. Many polymers which are used for drug delivery have specic chemical properties that make them be released only under particular pH conditions. For example, some cancer cells can be acidic or slightly basic compared to the environment and other cells, and so on. This feature can be used with a pH-sensitive shell to release the drug only where needed. 76,77 According to previous reports, most tumors have a pH between 5.7 and 7.8, and the pH of the uid associated with them is very rarely less than 6.5, so this feature can be used for medication. Moreover, the pH-sensitive methods have more advantages over the temperature-sensitive ones. For example, the pH-triggered core-shell particles can be useful in parts of the body that its temperature cannot be changed. 65,78

4.2.3
Sustained-release of core-shell drug carrier particles. Multiple parameters, including particle size, shell thickness, particle shape, and matrix mesh size, could control the release of drugs in microparticles by diffusion or degradation of the polymer matrix. Drugs can be progressively released from the microparticles for a specied period by tuning these parameters. The increase in particle size and shell thickness usually decreases the rate of release and prolonged duration. The encapsulation of therapeutic agents or biologically active molecules in core-shell nanostructures is a valuable technique for increasing the bioavailability of low water solubility drugs; avoiding burst releases that could cause toxicological effects, achieving sustained and extended releases; and generating temporal and spatially controlled releases. 79,80 As mentioned in Section 4.1.2, core-shell particles could provide a controlled release of the drug. The shell may allow the core of which drug is in it, sustained-release at a steady rate, and avoid sudden release of the drug at specic parts in the human body. 2,81 One of the most frequently employed methods to encapsulate, deliver, and release active ingredients in a sustained manner, is to trap active ingredients in polymer matrices in the shape of microspheres with a tunable degradation rate. Polylactic-co-glycolic acid (PLGA) is a biocompatible polymer with a degradation rate that can be tuned and is commonly used for the controlled release of drugs. However, according to the hydrophobic nature of PLGA, single PLGA microspheres are usually constrained by a low loading efficiency for hydrophilic active agents, and it remains difficult to customize their release kinetics and prevent undesired release patterns. These problems can be solved using composite microspheres with complex structures, such as core-shell composite microspheres. 82 Deshpande et al. 83 made core-shell nanogels with PNIPMAM shell and gold nanoparticles as the core for sustained and triggered release of doxorubicin (DOX).
Microparticles with a polymeric matrix with uniform size can release the encapsulated drugs more predictably. In addition, the formation of the microparticles with the porous matrix can provide more permeable sustained-release structures. In contrast, microparticle engineering with core-shell structures facilitated improved preservation. It decreased burst release, which is useful for the long-term treatment of several diseases such as asthma, angina, and psychiatric disorders. 65 An encapsulated atorvastatin loaded porous silicon (PSi) NPs with a reactive oxygen species (ROS) was applied for diabetic wound healing. 84 As it was mentioned, the polymeric shell formation can solve burst payload release, which is the main barrier for porous materials. The release kinetics can be easily adjusted by the shell material's choice, as the release of atorvastatin can be stimulated only by the coexistence of overproduced ROS. The release rate can be sustained for more than 24 h, making the core materials more appropriate for predicted biomedical applications. 11 Core-shell microparticles can be obtained through evaporation of the oil from the middle layer and consolidation of the shell materials using water-in-oil-in-water (W/O/W) double emulsion with the middle oil phase containing biodegradable shell materials like PLA and PLGA as templates. For example, the PLA shell of the microparticles gradually degrades due to the hydrolysis of ester groups in the PLA chain, allowing the sustained-release of contents in the inner aqueous core. 65 A DLPC shell and PLGA core were developed by Liu et al. 85 for the sustained and controlled release of anticancer drugs with paclitaxel as a model drug. Paclitaxel's typically controlled release prole enables the use of NPs for the delivery of anticancer drugs. Sustained-release includes the ability to consistently ght cancer cells, resulting in a decline in cancer cells' viability.
Thi et al. 81 showed that the sustained-release of DOX-loaded SPION@HP continuously lasted at a steady rate without an initial burst release up to 120 h, thereby retaining the therapeutic level of therapeutics for treatment over a long time.

Core-shell materials
The core part can be gas, liquid, or solid, and the shell is usually solid, but its nature depends on the targeted application. 86 Table 1 shows some examples of core-shell drug carrier materials, their base, the loaded drug, and their drug delivery application.
Hollow microparticles have attracted increasing attention because of their specic properties such as higher surface area, lower density, and certain superior optical properties than bulk materials. 87 Hollow internal microspheres are possibly used as an encapsulation vehicle to secure biologically active compounds such as proteins, enzymes, and DNA in controlled drug release. 2 Core-shell microcapsules with an aqueous core could be applied to encapsulate and protect incompatible substances or active ingredients and drug delivery. 88 Microparticles with an aqueous core and an oily core have appropriate space for hydrophilic and hydrophobic materials to be encapsulated in them, respectively. 65 As can be seen in Table 1, the aqueous core can encapsulate a hydrophilic anticancer drug (doxorubicin hydrochloride). Simultaneously, the solid shell of it can encapsulate a hydrophobic anticancer drug (paclitaxel). 89 Different materials, such as metal, metal oxides, silica, polystyrene, and polymers, could form the solid core based on their applications and production processes. One approach for producing a solid core core-shell particle is to the application of a hardcore template. Another approach is to generate core-shell particles directly by converting the emulsion droplets into solid core-shell particles, with a solid core and a solid shell. Solidi-cation techniques include solvent evaporation, polymerization, and ionic crosslinking. A solid core structure coated with a shell layer has a great advantage for synergistic and regulated drug delivery. Although a burst release of drug is possible in a core-shell particle with a liquid core and a solid shell aer the shell's breakage or degradation, the solid core structure solves this problem because it can release from the carriers only aer the degradation of polymer layers.
Shell materials are commonly classied as organic and inorganic groups. There are many available materials for core and shell fabrication, and these materials specify the physical, chemical, and biological properties of them. This high versatility in the choice of core and shell materials enables core-shell microparticles with different functionalities and properties to be prepared. The shell materials can be chosen according to the application of core-shell particles. The shell also protects the core's chemically active components against corrosion, oxidative degradation, and erosion. Also, shell materials offer increased thermal stability and enhance the microparticles' electrical, optical, and magnetic properties. 2 In the following, the most commonly used core and shell materials will be described.
Polymer. An organic polymer or any other organic compound of high density may be used as the shell material. 2 Polymers play one of the most prominent roles as shells in the pharmaceutical industry, whether organic polymers or natural polymers. They can have unique properties and characteristics that are very important and useful in drug delivery. 20,90 These polymers are oen used due to their unique properties, such as exibility, optical properties, and rigidity, to target the drug and protect them against physical conditions. Examples include chitosan and poly-N-isopropyl acrylamide. 2,65,91,92 Moreover, the organic shell makes it possible to obtain signicant control over its cargo's permeability and biocompatibility. A metal core could be covered with an organic shell to prevent the oxidization of surface atoms into metal oxide in the presence of oxygen. 2 There are various physically rigid polymeric materials such as polystyrene, PLGA, and isotactic polypropylene (iPP) used to produce solid core particles. 2 As mentioned in the Section 4.2.3, PLGA has proved a useful polymer for drug delivery systems because of its high biocompatibility, biodegradability, wide range of erosion periods, and providing sustained-release of drug. 82,93 Lukyanova et al. 94 presented two microuidic routes for producing solid-core/solid-shell particles. Poly(methyl methacrylate) (PMMA) was used as the solid core and encapsulated in the shell using a microuidics device. Also, ethylene glycol dimethacrylate monomer was polymerized under UV light used to generate a rigid core.

Silica.
Silica is one of the materials used in the encapsulation. It can have high efficiency in drug encapsulation due to its large cavities and contact surface area, and it is very biocompatible. Also, by adding organic and inorganic materials to it, it can be given unique properties suitable for drug release. 54,56,59 In elds such as healthcare, separation, biotechnology, and biomedical sensing, silica has a wide variety of practical applications. Chemical stability, low cost, and formability are the unique characteristics of silica that allow spherical particles from nano to micrometer size to be formed. 95 The silica shell protects the core from coalescing and from undesirable contamination of the surrounding. Also, through a chemical reaction, silica could be modied and form a resistant and rigid shell. Silica chemical inertia may be a shielding agent which prevents the core from being degraded. Also, because silica is optically transparent, it can enhance the core's spectroscopic analysis. 2,96 In high-performance liquid chromatography, solid silicacore/porous-shell particles could be used for the separation with a high ow rate and relatively low backpressure. The small solid core protected by the porous shell results in a larger particle and a higher surface area, resulting in lower backpressure for the separation. Compared to polymer shells, a metal shell such as zeolite, titanium, and gold acts as a more powerful barrier and prevents small molecules' undesired release into the core. Furthermore, since inorganic materials' thermal conductivity is greater than that of polymers, microparticles' thermal conductivity can be greatly enhanced by inorganic additives such as metals in the shell. There may also be other special characteristics of these materials, such as magnetic properties. 2 Metal and metal oxides are mostly used as cores and for drug delivery. Because with the help of a magnetic eld, the drug can be easily transported to the desired location. Various metals and their oxides nanomaterials are unsuitable and toxic to the human body. However, MnO, TiO 2 , and ZnO nanoparticles have been considered in drug delivery. 5,98-100 4.4 Materials for improving core-shell drug carriers 4.4.1 Magnetic nanomaterials. In the 1970s, Widder's theory of magnetic drug delivery was introduced. 101 Magnetic core-shell carriers have gained a lot of interest because of their physicochemical and structural properties. Localized treatment and stability under external magnetic elds are the main aspects of magnetic nanoparticles (MNPs). In addition, to obtain a responsive property to a particular stimulus, such as pH, heat, or even enzymes, these MNPs may be coated or functionalized. 102 The core-shell drug carrier particles produced using magnetic nanoparticles could be led to the specic neighborhoods for releasing the drug in the body using an external magnetic eld. For example, aer nanocarriers' injection in magnetically induced systems, an extracorporeal magnetic eld is used to concentrate drug-loaded nanocarriers at tumor sites. Some suitable magnetic stimulation candidates are structured core-shell nanoparticles coated with silica, polymer, or magnetoliposome (maghemite nanocrystals encapsulated in liposomes). 103 Due to magnetic nanoparticles' instability in aqueous solutions, they cannot be used alone as drug carriers. A practical method to eliminate or minimize this problem is to use some coatings. Pharmaceutical magnetic nanoparticles with a magnetic core should be stabilized because these magnetic materials should be kept stable to use for drug delivery purposes. 104 The magnetic core is used to release the drug to a specic location, and the polymer is used to load, transfer, and dispense the drug. In general, magnetic nanoparticles have high chemical activity and are easily oxidized in the presence of air. [104][105][106] As a result, their magnetic properties will be lost. When these magnetic particles are coated with a suitable shell, they are protected from oxidation, which leads to a reduction in toxicity, and aggregation of these materials would be minimized. Also, the coating can enhance the stability of these magnetic drug carrier particles. 107 In addition to protecting and stabilizing magnetic particles, suitable coatings can be used as a surface agent to make them more functional due to the presence of amino, hydroxyl, and carboxylate groups. One of the best coatings for this method is chitosan. Chitosan nanoparticles are one of the most promising protective coatings for magnetic nanoparticles due to their unique properties. As shown in Fig. 4, a multi-core or single-core magnetic structure can be used for chitosan nanoparticles. 108 4.4.2 Polymer-metal nanomaterials. Wang et al. 109 synthesized Au-impregnated polyacrylonitrile (PAN)/polythiophene (PTH) core-shell nanobers, which had improved semiconducting properties such as mobility. Various polymer-metal nanocomposites are made of silver, gold, platinum, palladium, etc. 3 The nanocomposite preparation is achieved by adding a metal precursor to the polymer solution and reducing the metal material's precipitation. 5,110 Silver nanoparticles have antibacterial properties, and this feature is the basis of their application. 110 Mixing silver nanoparticles with polymer and making nanocomposites is one of their most-used application method. 5,111 Silver nanoparticles with anti-fungal and anti-inammatory effects are environmentally friendly, non-thermal, heatresistant, and highly corrosion-resistant. As an example, in 2015, hydrogel granules of chitosan/silver nanocomposite were produced in the presence of NaBH 4 as a reducing agent. 5,111 Gold nanomaterials have attracted a great deal of attention in biomedical applications due to their high biocompatibility, low toxicity, and relatively low reactivity. They tend to accumulate in various forms of rods and prisms during synthesis. They have signicant applications as sensors, solar cells, and in the eld of pharmaceutical and tissue engineering. Gold nanoparticles and chitosan bound to glycolic acid were reported to be synthesized for pharmaceutical and engineering applications. 131,132 While copper and its compounds have antibacterial properties already known in ancient times, they currently receive renewed attention due to copper's possible use in healthcare situations as an antibacterial material. 133 Compared to other metals, copper is less toxic to bio cells and has a higher potency than micronutrients. Although copper nanoparticles are known for their unique characteristics, there is not much research on these nanoparticles. Anticancer activity of various metals such as Cu, Si, Se, Zn, Ag has been reported. In the meantime, copper has become more widespread due to its unique and excellent electronic conguration. Participation as a signicant factor in the oxidation-reduction cycle of enzymes is one of copper's interesting properties. The anticancer role of copper compounds such as CuO, CuS has been reported in some research. 5,131,132 The antibacterial effect of novel core-shell nanostructures based on copper and silver metals against Escherichia coli (E. coli) has been investigated. These nanostructures were prepared separately using the non-toxic, biodegradable, and biocompatible biopolymers chitosan and guar gum-polyvinyl alcohol (GG-PVA). A well-diffusion approach against E. coli analyzed the antibacterial property of the core-shell nanostructures. Due to the high ratio of NZVCu in the nanostructure, Cu/CuO@SiO 2 nanostructures are very effective against E. coli. 134 Also, recently, Fe 3 O 4 @copper(II) metal-organic framework Cu 3 (BTC) 2 (Cu-BTC) as core-shell structured magnetic microspheres were investigated. The slowly released copper ions and improved production of reactive oxygen species (ROS) played a role in Fe 3 O 4 @Cu-BTC antibacterial activity by promoting the successful isolation and transfer of photoexcited electron-hole pairs. 135 4.4.3 Carbon nanomaterials. Research on carbon nanomaterials containing carbon nanotubes, graphite, graphene, etc., is considered because of their unique mechanical properties. Carbon-based core-shell (CBCS) materials can provide rapid interfacial transport at various porous length scales due to their porosity mimicking natural systems, the high surface area for reactions, and strong dispersion of active sites, and decrease the diffusion effect or shorten the diffusion pathways that can be effectively utilized in energy storage. 136 So, the advantages of both materials can be taken by producing composite materials from carbon and natural polymer. For example, graphene oxide is a two-dimensional nanomaterial made from natural graphite. [137][138][139] This material has a low-density capability, a very high electrical conductivity, and excellent strength. Recently, the application of graphene oxide in biomedical elds, especially pharmaceuticals, has become widespread due to attractive properties such as large surface area and excellent stability in water. Changes in the level of graphene oxide are signicant for effective release to achieve appropriate drug loading and biocompatibility. 138,140,141 Meanwhile, chitosan polymer is a naturally occurring cationic polycarbonate with better biocompatibility and degradability properties than other cationic polymers. Compared to graphene oxide (GO), graphene oxide-chitosan (GO-CS) nanocomposites are smaller in size, positively charged, and less toxic. As an example, it was reported that the CpG oligodeoxynucleotides (ODNs) delivery system based on GO-CS nanocomposites signicantly improved the loading capacity and cellular uptake. Therefore to increase the delivery efficiency of CpG ODNs, GO-CS nanocomposites will serve as efficient nanocarriers. 140,141 4.4.4 Amines. Some researchers have suggested that adding some particular amines to the surface of the core-shell nanoparticles can cause the shell to be more inclined to that specic cell's surface than other cells. Alternatively, it may go away, and this can lead to a more controlled drug release. This property allows amines to be used to improve drug release and drug delivery performance. 65,142,143 In another research, the use of amine-containing core-shell nanoparticles has been studied as possible drug carriers for intracellular delivery. Thick poly(ethyleneimine) PEI shells (approximately 30 nm) greatly improved the drug loading potential of the complexed nanoparticle up to 23% (w/w). 117 Also, silanes are available by different amine groups and can improve the functionality of the magnetite nanoparticle surface for protein conjugation. Therefore, silane-coated MNPs result in high-quality materials for magnetic drug delivery systems. 5

Microfluidics devices in drug delivery systems
Microparticles with controllable structures are needed to be capable of quantitative encapsulation of drugs and regulated release of them to the desired location to ensure reduced side effects and optimized therapeutic efficacy. The traditional delivery methods, including oral, intravenous, sublingual, and intramuscular drug deliveries, have drawbacks, such as interactions with foods, low solubility and permeability, and irregular absorption, making steady-state dosing difficult to achieve in patients. Many drugs are also toxic to normal tissues or toxic when overdosed, but they are useless when underdosed. Consequently, control of the amount of encapsulation and drug release rate is needed. The fabrication of uniform microparticles with controllable and exible sizes, compositions, and internal structures is needed to fulll these demands. 65,144 Most traditional bulk drug synthesis methods suffer from many drawbacks, such as the need to use a high quantity of valuable drugs or chemicals, the generation of polydisperse particles that inuence the release prole, the limitation of the generation of multiple therapeutic agent-loaded carriers, and the difficulty associated with locating the delivery of drugs and in vivo investigation of the therapeutic or toxic effects that needs many animals. 50 New technologies, like microuidics, can solve these problems. For the production of effective drug carrier particles, microuidic devices offer specic advantages. Compared to bulk methods, microuidic technology allows the production of highly stable, uniform, monodispersed particles with higher encapsulation efficiency by effectively regulating the fabricated chip's geometries and the ow rates of multiphase uids. 50,144 In traditional bulk synthesis methods, both the inertial and viscous effects govern mass transport in uids, associated with nonlinearities that give rise to numerous instabilities, such as turbulence. In contrast, the inertial effect becomes negligible in microuidics. This feature allows microuidics to synthesize nanoparticles in a highly regulated and reproducible manner that has been difficult to achieve in traditional macroscale methods. 68,123,145 Microuidics-templated emulsions facilitate the controlled drug release by producing highly uniform microparticles with well-controlled sizes, shapes, and compositions. 65 Microuidics can be used for polymer synthesis with precise forms or chemicals for drug delivery application. For example, a technique developed by Nie et al. 146 to use the capillary instability-driven break-up of a liquid jet made up of two immiscible uids for producing polymer particles with various shapes and morphologies. The stated strategy allows the emulsication process to be precisely controlled, leading to monodispersed droplets with controlled morphologies ranging from 20 to 200 mm in size. 144 In addition, some conventional delivery methods, including painful and harmful injections, can benet from microscale technologies by fabrication of microneedles or needle-free injection devices. In order to improve the comfort and quality of life of patients, microuidic systems have recently been developed for transdermal administration of drugs. 51 Also, microuidics' drug delivery systems have improved drug encapsulation efficiency, allowing the use of two or more drug molecules in the same carrier for combination therapy or dual function. 12 Microuidic systems can be used for the direct delivery of active molecules, in addition to the potential of producing complex drug carriers. 147 In order to maximize the local availability of the drug and reduce the side effects induced by the drug's interaction with other organs and tissues, such systems are capable of efficiently transporting drugs to a targeted location. Furthermore, for so-called transdermal delivery, which is direct drug delivery through the skin, microuidic systems have been successfully used. These systems, which utilize a needle or an array of microneedles, transfer the drug across the skin (epidermis) barrier. 51 Recent advances in developing and utilizing such platforms for drug delivery systems have been discussed elsewhere 12,20,[49][50][51]65,144,145 are not reviewed here. In the following section, we will focus on core-shell drug carrier particles production in microuidic devices.
In addition to basic solid microparticles, microuidic devices offer a exible approach to producing more complex functional microparticles with core-shell particles with multicompartmental structures for co-encapsulation and synergistic release of specic drugs. Also, they provide highly efficient encapsulation and regulated release of hydrophilic or hydrophobic drugs and. For biomedical and pharmaceutical applications, diverse controlled release types, such as sustainedrelease, triggered release, and combined release of both release styles can be accomplished based on their advanced shell functions and internal structures. 65 By their name, core-shell particles are a category of particles that contain a core and a shell. Different materials or the same materials with different structures can be used as the core and the shell. Due to the combination of superior properties not exhibited by the individual components, core-shell particles have gained a lot of interest. The structures could integrate core and shell characteristics and properties, where the surface properties of the shell are passed to the core, bringing new features to the core-shell particles. 86 Core-shell particles are typically synthesized by a two-step or multi-step process. First, the core particles are synthesized, and, based on the type of core and shell materials and their morphologies, the shell is then formed on the core particle through various methods. 1 In the following section, we will describe microuidic devices' application for core-shell drug carrier particle production and discuss various microuidic systems that have been utilized for core-shell drug carrier particle preparation, characterization, and application.

Microfluidic devices for core-shell drug carrier particles preparation, characterization, and application
Microuidics' adaptation to the development of micro-sized structures has become more important since the rst theoretical work was carried out more than 10 years ago. The primary reasons for this technology's adoption originate from the emulsion homogeneity and the high degree of control over the operation. Because of the uids' properties in the microuidic channels, control over the entire production chain is possible. Therefore, these systems might be used for the production of single or double emulsions. 11,12,20,148 In recent years, a lot of research has been done about the application of microuidic devices for making core-shell particles used in drug delivery. It is possible to use only a small proportion of samples in these microstructures, and controlled composition is one of the other signicant advantages of this method. In microuidic devices, drug-loaded particles' volume and permeability can be controlled more straightforwardly than other methods, making microuidics more suitable for the fabrication of pharmaceutical drug carrier particles. So far, many microuidic chips have been designed for the formation of core-shell nanoparticles drug carriers. 24,32,63,142 The microuidic method signicantly reduces material costs and improves drug encapsulation efficiency. The most important advantage of using microuidic devices is uniform coreshell droplets size. The polydispersity index (PDI) of these particles is usually less than 1%, which can be adjusted by the uids' physical properties. 20 Core-shell particles for drug delivery application are mainly fabricated by droplet microuidics. 12,20,[49][50][51]65,144,145 6.1 Droplet microuidics for core-shell drug carrier particles preparation Droplet microuidics has been increasingly developed in recent years. It allows precise control of droplet creation, encapsulations, and release kinetics using nonlinear channel geometries, such as T-junctions, co-owing, and ow-focusing constrictions. 149 A single emulsion is a droplet of one liquid dispersed in an immiscible uid that forms the continuous phase. 25 The common single emulsion includes oil-in-water (O/W) and waterin-oil (W/O) emulsions. 20 It is complicated to make core-shell droplets made of more than one immiscible liquid by other possible methods. However, it is possible to make these multi emulsion core-shell droplets more easily in the droplet-based microuidic devices. 5,150,151 The droplets can be generated from a single emulsion of two partially miscible or immiscible uids or multiple emulsions (mostly the double emulsion) of three or more immiscible uids. 11,12,149 The single emulsion does not guarantee that multiple therapeutics are loaded simultaneously, and it is more complicated where the payloads have different solubility. Thus in drug delivery systems, double emulsions are also commonly used. 20 Usually, if multi emulsion core-shell droplets are needed, a sequential process of producing a single emulsion should be continued to place the primary emulsied droplet in the secondary droplet. 49,152 Double and multiple emulsions are frequently produced by a combination of two or more ow geometries. 5 The most common geometries in 2D are T-and Yjunctions, while for the 3D design, ow-focusing, co-ow, and various combinations of the previous designs used for the production of double emulsions. 11 The vital point in droplet-based microuidics is that the two liquids must either be partially miscible or immiscible. If they are miscible in each other, the core-shell droplets that will carry the drug cannot be produced. Fig. 5 shows different common geometries of droplet-based microuidic devices for producing single and double emulsion.
We can classify microuidic methods into single-step and sequential methods for double or multiple emulsion particle fabrications despite the different geometries of droplet micro-uidic devices. First, we will introduce important dimensionless numbers associated with droplet-microuidics. Then we will describe different geometries of droplet-based micro-uidics, and then we will discuss single-step and sequential methods for core-shell particle preparation.
Ca ¼ mu s In these equations, u is the uid's velocity, l is the characteristic length, r is the uid's density, m is the uid's viscosity, s is the surface tension, and D is the mass diffusion coefficient. Reynolds number and Pe reect the uid ow characteristics and molecules' action within the uid. 20 The Reynolds number describes the relationship between inertial forces and viscous forces. A ow pattern of different streamlines that are parallel to the uid direction (Fig. 6a) is reected in the laminar ow (usually Re number < 1800). On the other hand, the uid ow with a high Reynolds number (usually >2300) is categorized as turbulent ow, providing a chaotic pattern without distinct streamlines (Fig. 6b). Steady streamlines characterize the laminar ow, so the uids and molecules within the uids can be accurately manipulated to produce controllable and monodisperse droplets, reecting the desirable characteristics of drug encapsulation in droplet microuidics. 11,20 The Péclet number is a commonly applied dimensionless number for mass transfer processes, reects the diffusion or convection of molecules in the uids. 11,20 Because of the small volumes and the laminar ow pattern, the transfer of molecules is slow in droplet microuidics, primarily by diffusion instead of convection. Thus droplet microuidics minimizes the transition of molecules from the dispersed phase to the continuous phase, allowing the high efficiency of drug encapsulation into the droplets. 20 Two forms of instability in the uid's behavior in a dropletbased microuidic device are described: dripping and jetting regimen (Fig. 6c and d). The transition from one regimen to the other happens by increasing the ow rate and dimensionless parameters (e.g., capillary and Weber numbers). 12 The Weber number, dened by eqn (3), is an essential descriptor of deformation in the droplets. The Weber number determines the relationship between surface tension and inertial forces. With the increase in deformation, this number increases; higher energy is therefore meant to generate smaller emulsions. 11,12 The capillary number described by eqn (4) expresses the ratio between the viscous forces over the uid's surface tension. In droplet-based microuidics, the capillary number is of particular importance since it enables the investigation of various break-up patterns identied by different capillary number ranges. In the case of low values of the capillary number (range <10 À2 ), the droplet formation is not inuenced by the shear stress. In order to form a thread and nally squeeze out the droplet, it is only dependent on the accumulated pressure in the inner channel. According to Rayleigh-Plateau instability, droplet formation will occur when the droplet's maximum extension is greater than 1. 11 Dripping and jetting regimen happens when the inner uid is pumped into the secondary immiscible uid, like in the formation of single emulsion droplets. Parameters related to uids such as their viscosities, surface tensions, densities, ow rate, and the ratio between ow rates and the device characteristics such as geometry and surface chemistry control the formation of the droplet. 153 The two-uid system's behavior can be expressed according to the outer uid's capillary number and the inner one's Weber number, i.e., the outer uid's viscous forces and the inner one's inertial forces. Monodispersed drops result from dripping instability since the device disruptions that lead to drop formation are insensitive to any external intervention, whereas the jetting regimen creates polydispersed drops. The processes leading to the formation of the drops are identical in the case of double emulsions. The uid stream breaks simultaneously when the inner and middle uids' rates are equal, leading to the creation of a double emulsion presenting one internal drop. The outer uid ow rate governs the transitions in the double or multiple emulsion devices between the two regimes; dripping happens while the outer uid is slower, and vice versa for jetting. 12 As mentioned, co-ow, ow-focusing, and T-junction, under a dripping or jetting regimen, are the most common geometries in droplet microuidics. The junction shape denes the interface between the two immiscible ows. The droplet will be generated when the drag force is higher than the viscose force. 20 We can control the droplet formation by understanding these theories, and droplet sizes can be perfectly controlled with passive methods by tuning the microuidic device geometry, interfacial tension and viscosity of liquid phases, ow rates, and pressure, or with active methods by electrical forces, magnetic force, temperature, and acoustic force. 5,12,143,154,155 6.1.2 Flow-focusing geometry. The dispersed phase and continuous phase ow through two sides of the channel in owfocusing droplet microuidic devices and meet before the inner capillary orice. The droplets are formed at the orice (Fig. 5a). The physical mechanisms in the ow-focusing geometry are complicated, and in a device presenting such geometry, both dripping and jetting regimes can be created. 20,156 When uids with different velocities are introduced side by side, hydrodynamic focusing evolves. Hydrodynamic ow-focusing systems are generally easy to manufacture and operate and capable of generating particles with a uniform size distribution. Flowfocusing particles are usually <1 mm, which is too small for long-term payload release applications. 25,145 6.1.3 Co-owing geometry. Two co-axially aligned uids move in the same direction in a co-ow system. So, two capillaries have to be aligned co-axially. 25 The co-ow geometry describes a structure in which the dispersed phase in the inner capillary ows in the same direction through an orice of specied dimension into a continuous ow from the outer capillary (Fig. 5b). The droplets are mainly formed due to Rayleigh-Plateau instability in this conguration; thus, the jetting regime is oen involved. 20,156 In the industry, some ttings allow you to do this, but they are expensive. Using a cylindrical capillary for the inner liquid and a capillary with a square crosssection for the outer uid is a cheaper way. Naturally, alignment is accomplished by matching the outer diameter of the cylindrical capillary's circular cross-section and the inner side of the outer one's square cross-section. 25 6.1.4 T-junction geometry. The simplest and most used microuidic geometry is T-junction (Fig. 5c). The orthogonal channel in standard geometry includes the dispersed phase that intersects the main channel, which is lled with the continuous phase and droplets synthesized by cross-ow at the channel intersection. 20,30,49,152,157 Oil-in-water (O/W) emulsions or waterin-oil-in-water (W/O/W) double emulsion can be generated in hydrophilic channels. In contrast, water-in-oil (W/O) or oil-inwater-in-oil (O/W/O) emulsions can be generated in hydrophobic channels. 158,159 In this geometry, the droplet size can be regulated either actively or passively. Active control can be modulated using external actuation such as magnetically or pneumatically actuated micro-valves and integrated microheaters. In contrast, passive control can be regulated by ow rate controlling. 50,160 The advantage of T-junction is to produce better monodisperse droplets. 20 A Y-junction has the same process, but only the branches' angle makes it different from a T-junction. Also, by adding more branches to these specic designs, they can produce multi emulsion core-shell particles. [161][162][163] 6.1.5 Single-step method. As it was mentioned in the development of microparticles for drug delivery, all three described geometries and a combination of them have been used to generate double and multiple emulsions. Double emulsions are typically generated using a combination of two geometries (Fig. 5d-g). 20 By its name single-step droplet formation method has only one step. 164 A conventional double emulsion microuidic device in a single-step method is made of two round capillaries with the orices facing each other where the round capillaries are inserted into a square capillary (Fig. 5d). The inner phase goes through the inner capillary. In contrast, the middle and outer phases in the same and opposite direction of the inner ow go through the outer square capillary. This can be regarded as a co-ow that incorporates ow-focusing geometry. Once the three uids enter the inner capillary facing the other inner inlet capillary, which operates as a collection tube, the double emulsion is formed. Water-in-oil-in-water (W/O/W) and oil-inwater-in-oil (O/W/O) are included in the double emulsions. In the production of drug delivery microcapsules with a hollow core and a polymer shell, the W/O/W emulsion has been commonly used. The inner and outer droplets' size can be controlled by adjusting the ow rates and ratios of the inner, middle, and continuous phases, thus controlling the size and shell thickness of the generated microcapsules. The double emulsion drops' size is mainly controlled by the continuous phase ow rate in the dripping mode, while the middle layer determines the shell thickness. Thus the greater the ow ratio between the inner and middle phases, the thicker the capsule layer, for a set ow rate of the continuous phase. 165 The multiple-component emulsions can be produced by incorporating two inner uids simultaneously (Fig. 5e). 166 Kim et al. 165 introduced a single-step emulsication method that creates monodisperse double-emulsion drops in a coreshell geometry with an ultra-thin wall as a middle layer using a co-axial capillary microuidic device (Fig. 7a). A circular capillary with the tapered tip was inserted co-axially into a larger capillary and xed into another square tube. A rounded capillary was located on the other side of the square capillary to limit the injection tip's exit ow. The aqueous uid and oil, respectively, ow along the capillary wall and from the central capillary. The core-shell structured emulsion with a very thin shell with a thickness of 100 nanometers or even less was generated at the outlet of the injection tube aer solidication. Despite the small shell thickness, these particles are very stable and have great encapsulation ability. It was demonstrated by developing biodegradable poly(lactic acid) microcapsules with a shell thickness of about 10 nanometers, potentially useful for drug delivery.
For synergistic combinations of drugs in therapeutic applications, simultaneous encapsulation of multiple active substances in a single carrier is important. However, conventional carrier systems frequently lack efficient encapsulation and release of integrated substances, mainly when drug combinations must be released at concentrations of a specied ratio. Windbergs et al. 89 introduced a novel biodegradable coreshell carrier system produced in a solvent-free single-step microuidic device. The aqueous core is encapsulated with a hydrophilic drug (doxorubicin hydrochloride), while the solid shell is encapsulated with a hydrophobic drug (paclitaxel). In this process, it is possible to control the particle size and composition precisely. Also, core-shell drug-carrier particles can be dried and stored as a powder. Two tapered cylindrical capillary tubes nested inside a square capillary whose inner dimensions correspond to the cylindrical capillaries' outer diameters were used in the microuidic device (Fig. 7b).
A multiple-core double emulsion composed of multiple oil cores was developed by Zhao et al. 167 using a glass capillary microuidic system with multiple injection tubes (Fig. 7c). There are ve separate internal channels in the injection tube, allowing four different oil phase uids (indicated in red, green, blue, and gray colors) and one aqueous phase uid (indicated in the center of the four oil uids as cyan color) to enter the devices separately. The multiple core double emulsion was used as a template to create the photonic crystal barcodes. Barcodes are made of polyethylene glycol (PEG) hydrogel shells and multiple photonic crystals or magnetic-tagged ethoxylated trimethylolpropane triacrylate (ETPTA) cores. Under magnetic elds, the presence of magnetism in the barcodes provides their controllable motion. So they have a unique characteristic that makes them a perfect choice as encoded microcarriers for biomedical applications.
In addition to 3D and capillary microuidic devices used in the single-step method for producing core-shell particles, 2D devices can also be used. Nie et al. 146 presented a 2D owfocusing microuidic device to produce core-shell droplets in a single-step method. A double ow-focusing unit in this system forces three immiscible uids into an orice and then forms droplets in the downstream chamber (Fig. 7d).
6.1.6 Sequential method. The general procedure for preparing double emulsions is the sequential process. Two consecutive steps in sequential methods generate emulsions of oil-in-water-in-oil (O/W/O) and water-in-oil-in-water (W/O/W). First, the inner droplets form, and then the shells' outer layers are set around the core. Then, using methods such as solvent evaporation, 168 photo or thermally induced free-radical polymerization, 169 ionic crosslinking, 170 and freezing, 89 solidication of the core-shell droplets can result in core-shell microcapsules. The sequential method usually combines two geometry. The core droplets are generated in the rst geometry and the outer droplet, which encapsulates the core generated by the second geometry. 20 Two ow-focusing, co-owing, two Tjunction, and two cross-owing, and so on can be used in sequential method. 171,172 The production frequency of the droplets, the size of the core, the thickness of the shell, and even the number of cores encapsulated in the shell can be precisely modulated by changing the ow rates of the uids and the geometry of the microuidic device. 171,173 Through a sequential process in two steps (Fig. 5f), a double emulsion may be formed by T-junction geometry. The inner uid is encapsulated in the rst step by the middle uid, creating a single emulsion. The droplets then ow into the second drop maker and are encapsulated, and the double emulsions are produced by the outer uid. 20 The basis for the generation of core-shell droplets is the same in both 2D and 3D devices, 171 except that 3D devices remove the wettability constraints imposed by 2D devices. The droplets in 3D microuidic systems have minimum interaction with the channel wall in comparison to 2D devices. This ability will prevent the fragile shell from rupturing and the channels from wetting during early interfacial polymerization. 2,164 A microuidic double emulsion geometry (Fig. 5g) has been developed to obtain very thin shells: the inner capillary is placed into a middle capillary. The middle capillary is then placed into the square outer capillary facing the collection capillary orice within the outer capillary. In this case, the inner, middle, and outer phases ow through multiple capillaries but in the same direction, combining co-ow and co-ow geometry. 165 Wang et al. 174 developed a hierarchical and exible micro-uidic device fabricated from a combination of three building blocks, including a drop maker, a connector, and a liquid extractor that allows multiple emulsions to be strongly controlled by multicomponent generation (Fig. 8a). Droplets are made in the drop maker and then merged using the connectors. The liquid extractor removes excess continuous phase. The size, number, and ratio of the co-encapsulated droplets could be precisely tuned. This combination also enables the scale-up of Chang et al. 175 presented a 3D microuidic device with two co-axial capillaries for the polymer core-polymer shell particles' tuneable generation in two sequential steps (Fig. 8b). As can be seen, the device consists of two capillaries with hydrophilic or hydrophobic inner walls co-axially placed inside a T-junction along its main axis. The core and shell droplets were generated in the inner and middle capillaries, respectively, and coreshell droplets then were dispersed in an outer continuous aqueous phase.
Development in the microuidic eld is not limited to the creation of liquid-in-liquid-in-liquid (L/L/L) microemulsion; researchers have demonstrated the generation of emulsions of gas-in-water-in-oil (G/W/O) and gas-in-oil-in-water (G/O/W). In preparing G/W/O and G/O/W emulsions that could be used as a template for producing hollow microparticles, this technology has shown great advantages. A few academic researchers have attempted to use various devices such as ow-focusing, double ow-focusing, co-owing, T-junction, and dual-coaxial geometry to prepare G/L/L emulsion. 2 6.2 Recent advances of microuidic devices for core-shell particles preparation In addition to common microuidic devices for the fabrication of core-shell particles, some complicated microstructures have been introduced recently. In order to produce microcapsules with a core-shell structure, Jin et al. 176 showed the application of focused surface acoustic wave (FSAW) microuidics with one or two focused interdigital transducers (FIDTs) and a bonded polydimethylsiloxane (PDMS) microuidic channel on a lithium niobate (LiNbO 3 ) substrate (Fig. 9a). The FIDTs are placed on both sides of the ow channel to generate opposing FSAWs. It drives the particles back and forth across the oil/water interface, ideal for generating solid core-shell microcapsules and coating an aqueous microdroplet core with the oil shells. In comparison with previous methods, including T-junction, ow-focusing, co-owing microuidic devices, and pillar-based microuidic devices, solid particles or liquid microdroplets in multiphase laminar ow are generated by the acoustic radiation force resulting from the FSAW without any special modication using one or two FIDTs on a microuidic device with a simple conguration. This work provides a new active technique for producing a structure of the core-shell on the solid particles. More FIDTs can be added to the device to create more microcapsule layers if necessary. Thus it is possible to synthesize single-layer, two-layer, or even multi-layer microcapsules as desired. 176 Kim et al. 177 proposed a microuidic method for the fabrication of organic-inorganic hybrid core-shell microparticles in which the core is from poly(1,10-decanediol dimethacrylate-cotrimethoxysilyl propyl methacrylate) (P(DDMA-co-TPM)) shell is from silica nanoparticles. In this method, in combination with in situ photopolymerization, the droplet-based microuidic method generates highly monodisperse organic microparticles from P(DDMA-co-TPM) in a simple way (Fig. 9b). The silica nanoparticles gradually develop on the surface of the microparticles prepared by hydrolysis and tetraethoxysilane (TEOS) condensation in a simple ammonium hydroxide medium without excessive surface treatment. This approach leads to a decrease in the number of processes and, compared to traditional approaches, facilitates signicantly improved size uniformity. 177 Ahrberg et al. 178 demonstrated an automated microuidic capillary droplet reactor for the multi-step iron oxide/gold coreshell nanoparticles synthesis. Synthesis outcomes can be monitored in real-time by incorporating a transmission measurement at the outlet of the reactor.
Recently a novel fabrication technique for core-shell structure nanoparticles was created by combining microuidic chip and electrohydrodynamic atomization to resolve the drawbacks of drug-loaded nanoparticles, such as high initial burst release and wide size distribution. The mixture solution of the surfactant (1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol) and the polymeric coating material (polylactic-glycolic-acid) was injected into the microuidic chip's outer microchannel as the shell of the particle in this experiment. The encapsulated drug (paclitaxel) was injected into the inner microchannel as the core. Then by applying an electric eld on the laminar ow that was developed in the microuidic chip, the particles with a nanoscale-sized core-shell structure were created. The drug release of these nanoparticles may be extended for more than ten days over a considerable period of time. It can be anticipated that this innovative technology will provide a useful platform for the production of drug-loaded core-shell nanoparticles. 179

Microuidic devices for core-shell drug carrier particles application in drug delivery
Core-shell drug-carrier particles are known for their unique features. Due to the combination of superior properties not exhibited by the individual components, core-shell particles have gained a lot of interest. As drug delivery carriers, core-shell particles have many benets, including the reduction in initial burst release, sustained and controlled drug release rate, and the ability to carry a wide variety of biomolecules. 2 Core-shell particles could be used in cancer treatment because they could encapsulate multiple ingredients and release them during a multistage process. In contrast, core-shell particles with a broad size distribution produced by conventional techniques are not appropriate for drug delivery. 180 The core-shell droplets generated using the microuidics technique allow for high encapsulation and loading efficiency. The microparticles have a narrow size distribution prole, uniform morphology, and composition resulting in a steady and controlled drug release. The microparticle size is an essential factor in selecting a suitable drug delivery method. 80 For example, microparticles with a size distribution from a few to hundreds of microns are more appropriate for oral drug delivery. 181 Li et al. 10 produced a new form of core-shell particles for synergistic and sustained drug delivery. They were made from gelatin methacrylate (GelMa) aqueous solution as core and PLGA oil solution as shell in which different hydrophilic and hydrophobic drugs, such as doxorubicin hydrochloride (DOX) and camptothecin (CPT) could be loaded, respectively. Since the inner cores were polymerized in the microuidics when the double emulsions were generated, the hydrophilic actives could be trapped with high efficiency in the cores. During the solidi-cation of the microparticle shells with other actives, the cores' rupture or fusion could be avoided. During microuidic emul-sication, the microparticles' size and components can be easily and precisely controlled by adjusting the ow solutions. The encapsulated actives were only released from the delivery systems with the degradation of the biopolymer layers due to the solid nature of the resulting microparticles. Thus the burst release of the actives was prevented. These characteristics of the microparticles make them suitable for drug delivery applications. 2 Xu et al. 182 developed a doxorubicin-loaded core-shell structured microsphere through a coaxial electro-hydrodynamic atomization process. A PLGA core and a poly(D,L-lactic acid) (PDLLA) shell were included in the microspheres. As a model drug, doxorubicin, a hydrophilic chemotherapy drug, was used and encapsulated within the core. Doxorubicin was effectively encapsulated and lead to an approximately drug-free shell. Doxorubicin release was a two-stage operation, with a steady rate of release.
Nie et al. 180 also used the same approach for the development of a distinct core-shell structure of microparticles. In a single step, two different hydrophilic drugs were encapsulated in microparticles with enhanced encapsulation efficiency. They showed that different drug release proles were affected by varying the outer and inner ow ratio. In addition, the performance of different microspheres in cytotoxicity, cellular apoptosis were analyzed in vitro. Also, tumor inhibition against subcutaneous U87 glioma xenogra was performed in vivo. The benets and potential applications of this kind of multi-drug release system in the treatment of brain tumors were demonstrated.
Ho et al. 183 dened a exible technique for developing monodisperse polymersomes with biocompatible and biodegradable diblock copolymers for the efficient encapsulation of active substances, which is a good demonstration of core-shell droplets where a dewetting transition occurred. Due to osmotic shock, the release was triggered. The double emulsion droplets were used as a template to generate PEG-PLA polymersomes by using amphiphilic diblock copolymers. The polymersomes were used for the encapsulation of a hydrophilic uorescent solution. An osmotic pressure difference caused the polymersomes' breakage by adding salt, and the solutes were released. This easy and efficient release mechanism could be used to design encapsulation and controlled release in various biomedical applications.

Microuidic devices for core-shell drug carrier particles characterization
Size, shape, drug loading, and stability are the most important properties of nanoparticles to be characterized before probing their interaction with biological systems. Also, the development of novel particle characterization tools for drug delivery greatly affects the probability of an effective therapeutic translation. An inability to verify the drug delivery system's safety in vivo is one real obstacle to the clinical-scale application of nanoparticles. 145 This section presents microuidic techniques capable of characterizing drug delivery nanoparticles.
6.4.1 Size and morphology characterization. The most fundamental feature of drug delivery nanoparticles is particle size, a major determinant of bio-distribution and retention in target tissues. 184 For particle size determination, dynamic light scattering (DLS) measurements are widely used. DLS can calculate the size of particles in suspension, according to the Stokes-Einstein equation. 145 Microuidic devices can create a platform for real-time in situ monitoring of nanoparticle formation, allowing the fundamental reaction processes of nanoparticle synthesis to be investigated. To optimize nanoscale particle production, the investigation of mechanisms behind nucleation and growth is important. The synthesis of cysteine-capped quantum dot nanocrystals between two interdiffusing reagent streams was investigated in a continuous ow microuidic device in one platform using spatially resolved photoluminescence spectroscopy and imaging. 185 In addition, to demonstrate the kinetics and mechanisms of nanoparticle nucleation and growth during synthesis in a microuidic channel, small angle X-ray scattering (SAXS) was used. Although recent developments in label-free particle characterization, particle detection remains a challenge for integrating highthroughput microuidic technologies. So size and morphology characterization of particles can be assessed using advanced microscopic techniques such as atomic force microscopy (AFM), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and DLS. 145 6.4.2 Drug loading and release characterization. The behavior of drug release is a key parameter for the application of nanoparticles and is directly related to drug stability and therapeutic effects. The rate of drug release usually depends on (1) the solubility of the drug, (2) the desorption of the surfacebound or adsorbed drug, (3) the diffusion of the drug out of the nanomaterial matrix, (4) the erosion or degradation of the nanomaterial matrix, and (5) the combination of the mechanism of erosion and diffusion. Therefore, it is important to evaluate the degree of the release of the drug and obtain such knowledge that most release methods involve the separation of the drug and its delivery vehicle. The particles' drug loading ability is generally dened as the amount of drug bound per carrier mass. This parameter is calculated by various traditional techniques, such as UV spectroscopy or high-performance liquid chromatography (HPLC) and gel ltration. 145 Microuidic-based liquid chromatography (LC) has attracted a lot of attention because of its improved sensitivity, reduced sample utilization, and ability to multiplex measurements. Gao et al. 186 developed an integrated microuidic device with mass spectrometry (MS) detection for high-throughput drug screening. A concentration gradient generator, cell culture chamber, and solid-phase extraction columns were incorporated into this microuidic device into a PDMS chip. The method of drug absorption and cytotoxicity assessment may be achieved simultaneously with the use of combination systems.
With a low amount of reagent usage, integrated devices may provide a means of high-throughput drug analysis. In addition, many microuidic-based nanospray emitters 187,188 and microuidic-based LC-MS analysis 189,190 have been introduced.

Conclusions
In this review, various kinds of core-shell microparticles are rst discussed based on the core and shell structures' materials. The motivation of using core-shell particles is to combine the desired properties of different materials and structures to offer a synergistic effect, stabilize the active particles, or provide biocompatible properties. In addition, using core-shell drug carrier particles aims to reduce the drug's side effects with protection against environmental conditions, deliver it to the desired location, reduce its production cost, and increase its efficacy and controlled release. The choice of shell material and sometimes core for pharmaceutical systems is very complicated and should be chosen depending on the conditions. For example, suppose the desired area for releasing the drug is close to the skin's surface. In that case, it is possible to use a shell destroyed by the temperature. It is possible to direct it to the target position using a magnetic eld if metal or metal oxide is used.
This review also provides an overview of microuidic techniques for the generation of core-shell drug carrier particles. Conventional methods have some drawbacks which have considerably limited their applications. The main disadvantages of these methods are low monodispersity and high material usage. Microuidic devices have been developed to generate core-shell particles with controlled features and providing many advantages such as cheapness, uniformity of particle size and shape, and simplicity of application compared to the other alternatives. Different microuidic chip designs can be used based on the desired type of core-shell drug carrier particle, so there are more alternatives than the other available methods. Microuidic devices are classied based on their geometry, and they could be designed to generate core-shell particles using single-step or sequential emulsication methods.
On the other hand, nanoparticles can be easily made in nanoscale by applying microuidic devices, which is very difficult or impossible to achieve in the other methods. In some cases, particles made with microuidic devices reach a few hundred nanometers in diameter, making this method popular. The microuidic method has some more advantages, such as automation, integration, miniaturization, and the possibility of reducing human error. Their coherence makes these chips the best choice for the pharmaceutical industry. All of the above is evidence that microuidic chips are the perfect choice for making core-shell drug carriers particle.

Conflicts of interest
There are no conicts to declare.