Vancomycin is frequently prescribed in pediatrics, especially in intensive care unit settings, to treat Gram-positive bacterial infections. This work aims to collect the top-cited articles of pediatric and infectious diseases areas to gather the current evidence and gaps of knowledge on the use of vancomycin in these populations. The most relevant journals reported in the “pediatrics” and “infectious diseases” categories of the 2019 edition of Journal Citation Reports were browsed. Articles with more than 30 citations and published over the last three decades were collected. A bibliometric analysis was performed and 115 articles were retrieved. They were published in 21 journals, with a median impact factor of 4.6 (IQR 2.9–5.4). Sixty-eight of them (59.1%) belonged to “infectious diseases” journals. The most relevant topic was “bloodstream/complicated/invasive infections”, followed by “antibiotic resistance/MRSA treatment”. As for population distribution, 27 articles were on children only and 27 on neonates, most of which were from intensive care unit (ICU) settings. The current literature mainly deals with vancomycin as a treatment for severe infections and antibiotic resistance, especially in neonatal ICU settings. Lately, attention to new dosing strategies in the neonatal and pediatric population has become a sensible topic. Staphylococcus aureus (MRSA), and C. difficile. It inhibits cell wall synthesis by binding to the D-Ala-D-Ala terminal of the peptide chain and has a volume of distribution of 0.4–1 L/kg [Vancomycin is one of the most frequently prescribed glycopeptides, especially in children and newborns in intensive care unit (ICU) settings for the treatment of Gram-positive bacterial infections by coagulase-negative Staphylococci (CoNS), Enterococci spp, methicillin-resistant 4–1 L/kg . Its bacS. aureus (MRSA) infections after the exposure to prolonged vancomycin therapy, due to the selection of resistant subpopulations under the pressure of antimicrobial exposure [Another concern is the emergent antibiotic resistance issues, with the appearance of vancomycin-intermediate strains in methicillin-resistant exposure . More reexposure ,5.The pediatric infectious diseases consultant is often involved in choosing the most appropriate antibiotic therapy in complex cases and implementing antibiotic stewardship programs. Pediatric infectious diseases as a clinical sub-specialty is accessible by pediatricians and infectious diseases specialists who share the management of severe infections and choice of therapy in pediatric patients and, therefore, require extensive knowledge and experience. Most scientific papers address mainly or exclusively the adult population, and evidence on children or neonates is often scattered in journals of both pediatric and infectious diseases areas. This might increase the difficulty in finding the most relevant sources. Their collection might help trainees and consultants improve their knowledge and monitor what is new in this field.This bibliometric analysis aims to collect the top-cited articles in the last three decades related to vancomycin and its use in the pediatric and neonatal population. Secondary aims are to identify the most relevant scientific journals dealing with pediatric infectious diseases and summarize the most important topics regarding new dosing regimens, especially for neonates, in order to underline relevant gaps of knowledge to date. Journal Citation Reports (JCR): Science Edition was browsed by category to identify highly indexed journals. All the journals of the first quartile belonging to the “pediatrics” and “infectious diseases” categories were considered in order to include those with the highest impact factor (IF). Overall, 55 journals were searched for the study. Thirty-two belonged to the “pediatrics” category, and the remaining 23 to “infectious diseases”. A complete list of the journals, ranked by their IF is provided in the The 2019 edition of Web of Science–Science Citation Index Expanded database was searched on September 10th, 2021. The inclusion criteria were the English language, a minimum of 30 citations, publication dates ranging from January 1990 to September 2021, the pertinence with vancomycin in general, and its use in children and neonates, assessed by the authors, excluding all studies only addressing the adult population. The articles meeting the inclusion criteria were ranked by citation number. If two or more articles were equally cited, the IF of the journal was considered the discriminating factor. A top-cited list was produced.The C. difficile treatment, dosing strategies/intermittent vs. continuous infusion, state of the art, antibiotic resistance/MRSA treatment, bloodstream/complicated/invasive infection treatment. The articles were further classified according to article type, topic, population, ICU vs. non-ICU setting, and country of origin. The topics were classified by the Authors, starting from the keywords of the articles, and were included in the following categories: adverse reactions, MIC interpretative criteria, ototoxicity, pharmacokinetics and pharmacodynamics, antibiotic stewardship, healthcare epidemiology, nephrotoxicity, PubMed/MEDLINE database was searched for further information on these topics. Continuous data were reported as median and inter-quartile range (IQR), while non-continuous data were reported as numbers.Among the evaluated parameters in our bibliometric analysis, we made a gender description of the first and last authors. The Lancet Infectious Diseases (IF 24.446), and the one with the lowest was Pediatric Nephrology (IF 2.676). One hundred and fifteen top-cited articles were retrieved in total, published in 21/55 journals, with a median IF of 4.6 (IQR 2.9–5.4). The excluded articles only addressing adults were 227. The journal with the highest IF was Sixty-eight articles (59.1%) were published in “infectious diseases” category journals. The median number of top-cited articles per journal was 2 (IQR 1.5–3), and the journal with the highest number of top-cited articles was “clinical infectious diseases” with 46 manuscripts. As for gender description of first and last authors, male authors were predominant . Only in the pediatrics area subgroup, was there an almost equal number of male and female first authors .The median number of citations was 94 (IQR 51–178), ranging from 30 to 2796. The complete list of the top-cited articles in the “infectious diseases” and “pediatrics” categories is displayed in As for article type, 57 top-cited articles were original articles, 38 were guidelines and/or Reviews of the literature, and only nine papers were clinical trials. As shown in C. difficile treatment  for the initial episode, severe or non-severe, with a slow décalage in case of recurrence [Concerning the treatment of currence ,112,113.Other topics were “nephrotoxicity”, with six articles, “healthcare epidemiology” and “antibiotic stewardship” (four papers each). Papers dealing with nephrotoxicity mostly identified high vancomycin trough levels (>15 mg/L) and concomitant furosemide use as risk factors for the development of kidney injury ,70.Studies on epidemiology mainly focused on hospital-acquired and MRSA infections in Neonatal Intensive Care Units (NICUs), antibiotic exposure, and inflammatory bowel disease development ,10,11,12The least reported topics were respectively “pharmacokinetics and pharmacodynamics” (PK/PD) and “adverse reactions” (three papers each), “ototoxicity”, in relation to hearing screening in newborns, and “MIC interpretative criteria”, with two articles each .S. aureus (MRSA) with MIC of 1.0 µg/mL or greater, proposing an increase of the dose to 60 mg/kg/day [In particular, only one of the retrieved articles on PK/PD was specific for the pediatric population, while the other two dealt with PK/PD features in general and about drug penetration in biofilm ,14. The g/kg/day ,121.Twenty-seven papers dealt with neonates, 18 of which in NICU contexts, dealing with vancomycin for the treatment of neonatal infections, especially late-onset sepsis due to Gram-positive bacteria, mainly CoNS and MRSA . Major tKey points on vancomycin use in pediatric patients emerging from our analysis, including what is already known and gaps of knowledge for the development of future studies, are summarized in To our knowledge, this is the first bibliometric analysis with a special interest in vancomycin in the pediatric and neonatal populations. We chose evaluative bibliometrics and the method of citation analysis to evaluate research performance in this particular field and to highlight gaps of knowledge for the development of future studies. We decided to consider the last three decades as a definite search period, because especially in those years vancomycin was extensively used, with a consequent selection pressure, determining the emergence of resistance ,26 Figu. Not surprisingly, the journal with the highest number of top-cited articles was in the infectious diseases and not the pediatric area, being ranked third among the journals of the same area. Among the top-ranked journals of the pediatric area, there were no pediatric infectious diseases sub-specialty journals. This may suggest that the search for the most relevant articles in pediatric infectious diseases should be performed not only among pediatric journals but mainly on the most impacted journals treating topics of infectious diseases. C. difficile infections, correctly reflecting the main fields and emerging issues involving vancomycin and its use in pediatric patients. As for the article types, the second most cited, after original articles, were guidelines and/or reviews of the literature. According to the hierarchy provided by the Center for Evidence-Based Medicine, the latter presents the highest level of evidence . They moEnterococci (VRE). As regards S. aureus, vancomycin-intermediate (VISA), and vancomycin-resistant S. aureus (VRSA) strains are described, together with the resistance of S. epidermidis, mainly linked to biofilm [The two most treated topics in the top-cited articles were complicated infections and antibiotic resistance. Again, this is not surprising, thinking of the extensive use of vancomycin to treat invasive infections in critical patients, leading to antibiotic selection pressure after prolonged exposure, with an increased risk of treatment failure ,32,33,34 biofilm . TherefoC. difficile infections. Two papers had the implementation of antibiotic stewardship programs as a primary focus, one of which in the context of a pediatric critical care unit [Among the 115 retrieved articles, 27 were about children as a selected population, dealing above all with the management of invasive infections and are unit ,115. ThiDespite the widespread use of vancomycin since its introduction on the market, only three top-cited papers dealt with PK/PD and one only specifically on the pediatric population. PK/PD studies and RCTs are lacking for the neonatal population, especially for preterm and extremely preterm infants, as reported by the many reviews retrieved in this study. Dosing and safety in the pediatric and neonatal population are challenging, especially concerning continuous infusion, because of pharmacokinetics changes throughout the different ages. In general, ototoxicity and nephrotoxicity pathophysiological mechanisms are still unclear. The relation to dose exposure and treatment duration has not been proved, and focused studies are still lacking. One central question is still open regarding the administration of vancomycin by continuous versus intermittent infusion in children and neonates. Adult evidence suggests that continuous infusion of vancomycin decreases nephrotoxicity and the incidence of infusion-related adverse events, while also diminishing time to therapeutic concentrations and drug costs ,124. StuRegarding gender description, the highest number of female first authors belonged to the Pediatrics area and were almost as represented as their male counterparts. Nevertheless, we identified a gender gap in medical research. Male authors were predominant as both first and last authors in the Infectious Diseases area and generally more represented in senior authorship in both areas. We decided to include this description as we believe it could be an interesting bibliometric parameter to be evaluated, as an added value for the readers. Any assumption related to a minor involvement of women in research teams or a less frequent presence as senior faculty members cannot be made based on our data and goes beyond the focus of our research. Last, limitations to our study are intrinsic to the analysis type. Above all, the most recent articles may not have reached 30 citations due to a mere matter of time, and all relevant studies published in languages other than English may have been missed. Clinical Infectious Diseases. The most treated topics were bloodstream or complicated infections and antibiotic resistance/MRSA treatment. The pediatric area is indeed a critical one in the field of antibiotic therapy. In the last three decades, though less reported, also the role of antibiotic stewardship and attention to new dosing strategies in the neonatal and pediatric population have become sensible topics, which need to be further explored. As a widely used drug, data from studies properly conducted in the pediatric population, and not derived from adult studies, are needed. Moreover, the efficacy and safety of higher doses due to increases in MIC should be studied. Among the least represented topics, PK/PD, antibiotic stewardship, and dosing and infusion strategies, especially in neonates, represent a critical gap of knowledge, with a florid literature pointing out a lack of studies in the pediatric population since at least 30 years. This underlines the need for randomized-controlled trials to evaluate the clinical impact, safety, and acceptability of continuous infusion of vancomycin compared to intermittent infusion as a main challenge in the neonatal and pediatric population.To conclude, top-cited articles about vancomycin use in children and neonates were almost equally distributed among journals of the “infectious diseases” and “pediatrics” areas. The most productive journal was


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. Microfluidics application for core–shell drug carrier particles synthesis and the advantages of using this technique compared to conventional bulk methods. 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.2 The core–shell particles can have different core shapes, shell thickness, and surface morphology.3The 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.2,4,5Over 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.6 The development of characterization techniques has led to the production of structures for these different core–shell nanocomposites.7Nanoparticles (NPs) synthesis is a challenging process, and due to their usage in the advanced materials, new techniques have been made for these nanoparticles' synthesis.8,9Because 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 fields.2A 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 significantly influence their applications. It has long been a significant 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.2,10Recently, there are many improvements in making core–shell drug carrier particles due to their specific characteristics. Microfluidics has been developed and is a promising solution for the above problems.2.11 In most microfluidic devices, nanoscale fluids pass through micro-dimensional channels.12 In these microfluidic systems, the pressure and flow must be adjustable.13,14Microfluidics is a science of studying the fluid manipulation on micro/nanoscale, increasing the surface area-to-volume ratio.15–17 Microfluidic devices are usually fabricated with polydimethylsiloxane (PDMS) polymer, glass, silicone, and polytetrafluoroethylene in the desired shape and dimensions.18–20Several kinds of materials, such as inorganic materials, metals, polymers, and plastics, are applicable for microfabrication. Microstructures and semiconductor devices have been fabricated using silicon and glass.17,21,22 It is also used in bioassays and targeted drug delivery systems (DDS) using implantable microfluidic devices.23 The microstructure is generally fabricated by soft lithography.24PDMS is the most common material used to fabricate microfluidic devices because of the ease of fabrication, optical transparency, gas permeability, low chemical reactivity, and inexpensiveness.20 There are a few drawbacks, considering the simplicity of glass-based microfluidics. First, the device geometry is limited, and device fabrication's technicality can be complicated, making reproducibility of devices a problem.25Glass capillary microfluidic devices are typically made by pulling capillaries through a fine tip with an accurate size orifice, co-axially assembling them inside a wider square or circular capillary, and eventually gluing such capillaries onto a glass slide.26Microfluidics is an interdisciplinary science that can be used in many scientific fields, including the pharmaceutical industry, biomedical and chemical sensors, drug delivery, cell growth, and the food industry.27–29The main advantages of using microfluidic systems are high efficiency, integration capability, mass production, reduced response time, and parallel operations. These mentioned properties show the importance and breadth of research in the field of microfluidic.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 fluids 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 fluids in this volume. These properties are also widely used to design chips and perform specific functions such as moving fluid inside a channel or mixing fluids.9,36The presence of individual structures inside the microfluidic device, such as ducts, valves, mixers, and pumps, enables the device to allow one or more types of fluid to enter; move along the channels; if necessary, store them in a part of the chip for a while; mix them to create a specific reaction. Eventually, the original products and wastes are transferred to the outside of the device by the outputs. Also, it is worth mentioning that microfluidic systems made up of these components usually are not more than a few centimeters in size.37,38There is a lot of research and diagnostic tests in biology, chemistry, and medicine in which samples and soluble substances can be evaluated, so microfluidic devices have a wide range of applications in these areas. In microfluidic devices, each part of the chip can act as a part of the laboratory, and so these lab chips are called lab-on-chip.39,40A lab-on-chip is a device used instead of a laboratory process, usually on a scale of square centimeters or even millimeters in size . It will42,43 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.10,44,45Another factor that has led to the use of lab-on-chips devices in recent years is the use of small amounts of fluid in these chips, which reduces costs and time of process.3.46 The development of appropriate drug carriers in biomedical applications to reduce the side effects is desirable and has beneficial therapeutic effects.47–49 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.50,51Pharmaceutical systems use targeted transfer technology or control the release of therapeutic agents.51,52Drug delivery is the mechanism or process of delivering a pharmaceutical substance that involves releasing a bioactive agent at the optimal and required rate.53–55 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.5,54–56 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.5,54,57Cancer is a leading cause of death, and despite tremendous efforts to fight cancer and the existence of multiple therapy modalities, cancer treatment still is a significant problem.5,56,58Recent 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.4.59,60 They protect the drug against harsh conditions and provide the possibility of release under specific temperature or pH conditions; that's why these micro and nano-capsulation methods have gained more attention.60–62Core–shell particles were initially introduced to make production methods in the field of biotechnology more effective. Nowadays, with the advent of encapsulation technologies using core–shell particles, medicines can stay active for longer periods of time.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.65,66Core-shelling can be defined 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 nano-capsules has become very important in the pharmaceutical industry in the past few years. Therefore, a lot of research has been done in this specific field.1Some types of core–shells particles are shown in 4.14.1.167 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.31,63The protection of drug components can be considered as one of the primary reasons for encapsulation.4.1.270 This method creates an appropriate delay.71 There are two different types of release: delayed and stable.56,61,65Core–shell particles are useful for drug delivery in the right place at the right time.72,73 The other example of the delayed-release is using core–shell nanoparticles prepared using microfluidic chips for oral delivery of chemotherapeutics for colon cancer. They would only be released in the colon.54The first 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.74The 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.2The appropriate selection of shell material for therapeutic delivery can improve controlled release, preservation, and responsiveness to stimuli.4.1.375 For example, chemotherapy drugs can cause hair loss, fatigue, and many other problems. When they are used in the core–shell type can significantly 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.46,56,58Most medications have several side effects.4.24.2.1N-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 specific area.61,65 Drugs can be used as a core, and PNIPAAm can be used as a shell.Nowadays, some polymers have specific 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-4.2.276,77 According to previous reports, most tumors have a pH between 5.7 and 7.8, and the pH of the fluid 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.65,78Many polymers which are used for drug delivery have specific 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.4.2.379,80Multiple 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 specified 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.2,81As 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 specific parts in the human body.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.82One 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-et al.83 made core–shell nanogels with PNIPMAM shell and gold nanoparticles as the core for sustained and triggered release of doxorubicin (DOX).Deshpande 65Microparticles 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.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.11An encapsulated atorvastatin loaded porous silicon (PSi) NPs with a reactive oxygen species (ROS) was applied for diabetic wound healing.65Core–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.et al.85 for the sustained and controlled release of anticancer drugs with paclitaxel as a model drug. Paclitaxel's typically controlled release profile enables the use of NPs for the delivery of anticancer drugs. Sustained-release includes the ability to consistently fight cancer cells, resulting in a decline in cancer cells' viability.A DLPC shell and PLGA core were developed by Liu 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.Thi 4.386The core part can be gas, liquid, or solid, and the shell is usually solid, but its nature depends on the targeted application.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.2Hollow microparticles have attracted increasing attention because of their specific properties such as higher surface area, lower density, and certain superior optical properties than bulk materials.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 89Core–shell microcapsules with an aqueous core could be applied to encapsulate and protect incompatible substances or active ingredients and drug delivery.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. Solidification 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 after the shell's breakage or degradation, the solid core structure solves this problem because it can release from the carriers only after the degradation of polymer layers.2Shell materials are commonly classified 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.In the following, the most commonly used core and shell materials will be described.4.3.12 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 often used due to their unique properties, such as flexibility, 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 significant 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.2An organic polymer or any other organic compound of high density may be used as the shell material.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 microfluidic 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 microfluidics device. Also, ethylene glycol dimethacrylate monomer was polymerized under UV light used to generate a rigid core.There are various physically rigid polymeric materials such as polystyrene, PLGA, and isotactic polypropylene (iPP) used to produce solid core particles.4.3.254,56,59 In fields 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 modified 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.2,96Silica 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.1,97In high-performance liquid chromatography, solid silica-core/porous-shell particles could be used for the separation with a high flow 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.4.3.3Metals and their oxides are also used for encapsulation.2Compared 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, and ZnO nanoparticles have been considered in drug delivery.5,98–100Metal and metal oxides are mostly used as cores and for drug delivery. Because with the help of a magnetic field, 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, TiO4.44.4.1101 Magnetic core–shell carriers have gained a lot of interest because of their physicochemical and structural properties. Localized treatment and stability under external magnetic fields 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.102In the 1970s, Widder's theory of magnetic drug delivery was introduced.103The core–shell drug carrier particles produced using magnetic nanoparticles could be led to the specific neighborhoods for releasing the drug in the body using an external magnetic field. For example, after nanocarriers' injection in magnetically induced systems, an extracorporeal magnetic field 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 .104 The magnetic core is used to release the drug to a specific 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.104–106 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 108Due 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.4.4.2et al.109 synthesized Au-impregnated polyacrylonitrile (PAN)/polythiophene (PTH) core–shell nanofibers, 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.5,110Wang 110 Mixing silver nanoparticles with polymer and making nanocomposites is one of their most-used application method.5,111Silver nanoparticles have antibacterial properties, and this feature is the basis of their application.4 as a reducing agent.5,111Silver nanoparticles with anti-fungal and anti-inflammatory effects are environmentally friendly, non-thermal, heat-resistant, and highly corrosion-resistant. As an example, in 2015, hydrogel granules of chitosan/silver nanocomposite were produced in the presence of NaBH131,132Gold 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 significant applications as sensors, solar cells, and in the field of pharmaceutical and tissue engineering. Gold nanoparticles and chitosan bound to glycolic acid were reported to be synthesized for pharmaceutical and engineering applications.133While 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.5,131,132Compared 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 configuration. Participation as a significant 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.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@SiO2 nanostructures are very effective against E. coli.134The antibacterial effect of novel core–shell nanostructures based on copper and silver metals against 3O4@copper(ii) metal–organic framework Cu3(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 Fe3O4@Cu-BTC antibacterial activity by promoting the successful isolation and transfer of photoexcited electron–hole pairs.135Also, recently, Fe4.4.3etc., 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.137–139 This material has a low-density capability, a very high electrical conductivity, and excellent strength. Recently, the application of graphene oxide in biomedical fields, 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 significant for effective release to achieve appropriate drug loading and biocompatibility.138,140,141Research on carbon nanomaterials containing carbon nanotubes, graphite, graphene, 140,141Meanwhile, 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 significantly improved the loading capacity and cellular uptake. Therefore to increase the delivery efficiency of CpG ODNs, GO–CS nanocomposites will serve as efficient nanocarriers.4.4.465,142,143Some 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 specific 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.117In 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).5Also, 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.5.65,144 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 influence the release profile, 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.50Microparticles 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 flexible sizes, compositions, and internal structures is needed to fulfill these demands.50,144New technologies, like microfluidics, can solve these problems. For the production of effective drug carrier particles, microfluidic devices offer specific advantages. Compared to bulk methods, microfluidic technology allows the production of highly stable, uniform, monodispersed particles with higher encapsulation efficiency by effectively regulating the fabricated chip's geometries and the flow rates of multiphase fluids.68,123,145 Microfluidics-templated emulsions facilitate the controlled drug release by producing highly uniform microparticles with well-controlled sizes, shapes, and compositions.65In traditional bulk synthesis methods, both the inertial and viscous effects govern mass transport in fluids, associated with nonlinearities that give rise to numerous instabilities, such as turbulence. In contrast, the inertial effect becomes negligible in microfluidics. This feature allows microfluidics to synthesize nanoparticles in a highly regulated and reproducible manner that has been difficult to achieve in traditional macroscale methods.et al.146 to use the capillary instability-driven break-up of a liquid jet made up of two immiscible fluids for producing polymer particles with various shapes and morphologies. The stated strategy allows the emulsification process to be precisely controlled, leading to monodispersed droplets with controlled morphologies ranging from 20 to 200 μm in size.144Microfluidics can be used for polymer synthesis with precise forms or chemicals for drug delivery application. For example, a technique developed by Nie 51In addition, some conventional delivery methods, including painful and harmful injections, can benefit from microscale technologies by fabrication of microneedles or needle-free injection devices. In order to improve the comfort and quality of life of patients, microfluidic systems have recently been developed for transdermal administration of drugs.12Also, microfluidics' 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.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, microfluidic systems have been successfully used. These systems, which utilize a needle or an array of microneedles, transfer the drug across the skin (epidermis) barrier.51Microfluidic systems can be used for the direct delivery of active molecules, in addition to the potential of producing complex drug carriers.12,20,49–51,65,144,145 are not reviewed here. In the following section, we will focus on core–shell drug carrier particles production in microfluidic devices.Recent advances in developing and utilizing such platforms for drug delivery systems have been discussed elsewhere65In addition to basic solid microparticles, microfluidic devices offer a flexible approach to producing more complex functional microparticles with core–shell particles with multicompartmental structures for co-encapsulation and synergistic release of specific 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 sustained-release, triggered release, and combined release of both release styles can be accomplished based on their advanced shell functions and internal structures.86By 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.1 In the following section, we will describe microfluidic devices' application for core–shell drug carrier particle production and discuss various microfluidic systems that have been utilized for core–shell drug carrier particle preparation, characterization, and application.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.6.11,12,20,148Microfluidics' adaptation to the development of micro-sized structures has become more important since the first 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 fluids' properties in the microfluidic channels, control over the entire production chain is possible. Therefore, these systems might be used for the production of single or double emulsions.24,32,63,142In recent years, a lot of research has been done about the application of microfluidic 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 significant advantages of this method. In microfluidic devices, drug-loaded particles' volume and permeability can be controlled more straightforwardly than other methods, making microfluidics more suitable for the fabrication of pharmaceutical drug carrier particles. So far, many microfluidic chips have been designed for the formation of core–shell nanoparticles drug carriers.20 Core–shell particles for drug delivery application are mainly fabricated by droplet microfluidics.12,20,49–51,65,144,145The microfluidic method significantly reduces material costs and improves drug encapsulation efficiency. The most important advantage of using microfluidic devices is uniform core–shell droplets size. The polydispersity index (PDI) of these particles is usually less than 1%, which can be adjusted by the fluids' physical properties.6.1149 A single emulsion is a droplet of one liquid dispersed in an immiscible fluid that forms the continuous phase.25 The common single emulsion includes oil-in-water (O/W) and water-in-oil (W/O) emulsions.20Droplet microfluidics 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-flowing, and flow-focusing constrictions.5,150,151 The droplets can be generated from a single emulsion of two partially miscible or immiscible fluids or multiple emulsions (mostly the double emulsion) of three or more immiscible fluids.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.20It 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 microfluidic devices.49,152 Double and multiple emulsions are frequently produced by a combination of two or more flow geometries.5 The most common geometries in 2D are T- and Y-junctions, while for the 3D design, flow-focusing, co-flow, and various combinations of the previous designs used for the production of double emulsions.11Usually, if multi emulsion core–shell droplets are needed, a sequential process of producing a single emulsion should be continued to place the primary emulsified droplet in the secondary droplet.The vital point in droplet-based microfluidics 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.We can classify microfluidic methods into single-step and sequential methods for double or multiple emulsion particle fabrications despite the different geometries of droplet microfluidic devices. First, we will introduce important dimensionless numbers associated with droplet-microfluidics. Then we will describe different geometries of droplet-based microfluidics, and then we will discuss single-step and sequential methods for core–shell particle preparation.6.1.1u is the fluid's velocity, l is the characteristic length, ρ is the fluid's density, μ is the fluid's viscosity, σ is the surface tension, and D is the mass diffusion coefficient.The most important dimensionless numbers in droplet microfluidics are Reynolds number (Re), Péclet number (Pe), Weber number (We), and capillary number (Ca) .12 The Weber number, defined by 11,12Two forms of instability in the fluid's behavior in a droplet-based microfluidic device are described: dripping and jetting regimen . The tra−2), the droplet formation is not influenced by the shear stress. In order to form a thread and finally 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 1.11The capillary number described by 153 The two-fluid system's behavior can be expressed according to the outer fluid's capillary number and the inner one's Weber number, i.e., the outer fluid'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 fluid stream breaks simultaneously when the inner and middle fluids' rates are equal, leading to the creation of a double emulsion presenting one internal drop. The outer fluid flow rate governs the transitions in the double or multiple emulsion devices between the two regimes; dripping happens while the outer fluid is slower, and vice versa for jetting.12Dripping and jetting regimen happens when the inner fluid is pumped into the secondary immiscible fluid, like in the formation of single emulsion droplets. Parameters related to fluids such as their viscosities, surface tensions, densities, flow rate, and the ratio between flow rates and the device characteristics such as geometry and surface chemistry control the formation of the droplet.20 We can control the droplet formation by understanding these theories, and droplet sizes can be perfectly controlled with passive methods by tuning the microfluidic device geometry, interfacial tension and viscosity of liquid phases, flow rates, and pressure, or with active methods by electrical forces, magnetic force, temperature, and acoustic force.5,12,143,154,155As mentioned, co-flow, flow-focusing, and T-junction, under a dripping or jetting regimen, are the most common geometries in droplet microfluidics. The junction shape defines the interface between the two immiscible flows. The droplet will be generated when the drag force is higher than the viscose force.6.1.220,156 When fluids with different velocities are introduced side by side, hydrodynamic focusing evolves. Hydrodynamic flow-focusing systems are generally easy to manufacture and operate and capable of generating particles with a uniform size distribution. Flow-focusing particles are usually <1 μm, which is too small for long-term payload release applications.25,145The dispersed phase and continuous phase flow through two sides of the channel in flow-focusing droplet microfluidic devices and meet before the inner capillary orifice. The droplets are formed at the orifice . The phy6.1.325 The co-flow geometry describes a structure in which the dispersed phase in the inner capillary flows in the same direction through an orifice of specified dimension into a continuous flow from the outer capillary  emulsions or water-in-oil-in-water (W/O/W) double emulsion can be generated in hydrophilic channels. In contrast, water-in-oil (W/O) or oil-in-water-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 micro-heaters. In contrast, passive control can be regulated by flow rate controlling.50,160 The advantage of T-junction is to produce better monodisperse droplets.20The simplest and most used microfluidic geometry is T-junction . The ort161–163A 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 specific designs, they can produce multi emulsion core–shell particles.6.1.520As 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 .20164 A conventional double emulsion microfluidic device in a single-step method is made of two round capillaries with the orifices facing each other where the round capillaries are inserted into a square capillary , 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 microfluidic device  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,20Through a sequential process in two steps , a doubl171 except that 3D devices remove the wettability constraints imposed by 2D devices. The droplets in 3D microfluidic 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.2,164The basis for the generation of core–shell droplets is the same in both 2D and 3D devices,165A microfluidic double emulsion geometry  has beenet al.174 developed a hierarchical and flexible microfluidic 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  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 flow-focusing, double flow-focusing, co-flowing, T-junction, and dual-coaxial geometry to prepare G/L/L emulsion.6.2et al.176 showed the application of focused surface acoustic wave (FSAW) microfluidics with one or two focused interdigital transducers (FIDTs) and a bonded polydimethylsiloxane (PDMS) microfluidic channel on a lithium niobate (LiNbO3) substrate  (P(DDMA-co-TPM)) shell is from silica nanoparticles. In this method, in combination with in situ photopolymerization, the droplet-based microfluidic method generates highly monodisperse organic microparticles from P(DDMA-co-TPM) in a simple way  and the polymeric coating material (polylactic-glycolic-acid) was injected into the microfluidic 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 field on the laminar flow that was developed in the microfluidic 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.179Recently a novel fabrication technique for core–shell structure nanoparticles was created by combining microfluidic 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  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 microfluidics when the double emulsions were generated, the hydrophilic actives could be trapped with high efficiency in the cores. During the solidification of the microparticle shells with other actives, the cores' rupture or fusion could be avoided. During microfluidic emulsification, the microparticles' size and components can be easily and precisely controlled by adjusting the flow 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.2Li et al.182 developed a doxorubicin-loaded core–shell structured microsphere through a coaxial electro-hydrodynamic atomization process. A PLGA core and a poly (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.Xu 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 profiles were affected by varying the outer and inner flow ratio. In addition, the performance of different microspheres in cytotoxicity, cellular apoptosis were analyzed in vitro. Also, tumor inhibition against subcutaneous U87 glioma xenograft was performed in vivo. The benefits and potential applications of this kind of multi-drug release system in the treatment of brain tumors were demonstrated.Nie et al.183 defined a flexible 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 fluorescent 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.Ho 6.4in vivo is one real obstacle to the clinical-scale application of nanoparticles.145 This section presents microfluidic techniques capable of characterizing drug delivery nanoparticles.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 6.4.1184 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 Microfluidic 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 flow microfluidic 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 microfluidic channel, small angle X-ray scattering (SAXS) was used. Although recent developments in label-free particle characterization, particle detection remains a challenge for integrating high-throughput microfluidic 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.145The most fundamental feature of drug delivery nanoparticles is particle size, a major determinant of bio-distribution and retention in target tissues.6.4.2145The 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 surface-bound 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 defined 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 filtration.et al.186 developed an integrated microfluidic 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 microfluidic device into a PDMS chip. The method of drug absorption and cytotoxicity assessment may be achieved simultaneously with the use of combination systems.Microfluidic-based liquid chromatography (LC) has attracted a lot of attention because of its improved sensitivity, reduced sample utilization, and ability to multiplex measurements. Gao 187,188 and microfluidic-based LC-MS analysis189,190 have been introduced.With a low amount of reagent usage, integrated devices may provide a means of high-throughput drug analysis. In addition, many microfluidic-based nanospray emitters7.In this review, various kinds of core–shell microparticles are first 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 field if metal or metal oxide is used.This review also provides an overview of microfluidic 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. Microfluidic 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 microfluidic 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. Microfluidic devices are classified based on their geometry, and they could be designed to generate core–shell particles using single-step or sequential emulsification methods.On the other hand, nanoparticles can be easily made in nanoscale by applying microfluidic devices, which is very difficult or impossible to achieve in the other methods. In some cases, particles made with microfluidic devices reach a few hundred nanometers in diameter, making this method popular. The microfluidic 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 microfluidic chips are the perfect choice for making core–shell drug carriers particle.There are no conflicts to declare.


To evaluate the clinical effects and safety of glucocorticoids for patients with nonarteritic anterior ischemic optic neuropathy (NAION).  The databases MEDLINE, Embase, PubMed, Cochrane Database, and Web of Science were used to search for the relevant studies, and full-text articles that reported on the evaluation of glucocorticoids vs. no-treatment or placebo for patients with NAION. Review Manager 5.4 was used to estimate the pooled effects of the results among selected studies. Forest plots, funnel plots, and Begg's rank correlation were also performed on the included articles. P = 0.02), VF , and RNFL  in NAION patients and had a high improvement rate of VA . No significant publication bias was observed in our study. Discussion. Our research preliminarily confirmed the effectiveness of glucocorticoids for NAION treatment, but more high-quality RCTs focusing on the hormone adverse reactions should be performed to verify our conclusions. A total of 983 patients were contained in the 9 studies that satisfied the eligibility criteria. The meta-analysis showed that, compared with the control group, the glucocorticoid group had significantly improved the VA (MD: -0.25, 95% CI ,  Ischemic optic neuropathy (ION) is a vascular disease . It occuThe pathological mechanism of NAION is still unclear , 9. SomeGlucocorticoids are anti-inflammatory and can reduce edema . They caLiterature has shown that the application of glucocorticoids in the treatment of NAION can achieve better curative effects , 18. We We used comprehensive databases  to search for previous studies that investigated the effects of glucocorticoids on the clinical outcomes in patients with ION. The literature search was performed from inception up to November 30th, 2021, using the following keywords and MeSH terms: (1) glucocorticoids; (2) ION; (3) corticosteroid; and (4) optic neuropathy. Numerous combinations of words and strings were applied with Boolean operators “AND” and “OR” to broaden the search. Our literature search was carried out without any consideration for publication status limitations or language restrictions. The reference lists of the retrieved studies and review articles were examined manually to identify further relevant studies not identified by the search strategy.Researches compared patients who received glucocorticoids and other therapyThe study contained patients with IONThe study contained indicators evaluating efficacy between glucocorticoids and other therapyThe study was available in full textA study was included if it satisfied the following criteria:Researches did not meet the inclusion criteriaThe outcomes of interest were not reported or were impossible to useThe document was a review, abstract, letter, or a duplicate publicationThe exclusion criteria were as follows:Data extraction was conducted independently by two reviewers (Zhou and Zhang), and the disagreements were resolved in consultation with a third reviewer. The number of patients in each study group was recorded. We also extracted data for study location, study design, intervention mode, patients' characteristics (age and gender), year of outset, and time of follow-up.To qualitatively evaluate the quality of the included studies, the Cochrane Collaboration's tool was used to assess the quality of randomized controlled trials (RCTs), and the Newcastle–Ottawa Scale (NOS) was used to assess the quality of nonrandomized trials.I2 statistics were used to test the heterogeneity. An I2 value of 0%-50% indicated that heterogeneity was not relevant/important; 30%-50% suggested moderate heterogeneity; 50%-90% represents substantial heterogeneity; and 75%-100% represented considerable heterogeneity. A fixed effects model was applied in the absence of heterogeneity, while a random effect model was used when heterogeneity was observed. If there were more than 5 studies included in the meta-analysis, the data would be evaluated for publication bias by viewing the symmetry of the funnel plot and using the Begg rank correlation method.The review manager  was used to estimate the pooled results in the selected studies. Chi-square test and The search yielded 1263 titles. After removal of duplicates, 1027 articles were identified. After manually inspecting the titles and abstracts, 920 articles were excluded. From these, 98 articles were further excluded due to various reasons including that they had a different study design, insufficient data available, or because they were review articles. Ultimately, 9 studies included in our present meta-analysis strictly met our selection criteria –27.  FigThe detailed characteristics of these 9 eligible studies are summarized in After identifying the included articles, the abstract and full text of each article were carefully read and the publication's quality was evaluated according to Cochrane Collaboration's tools and NOS Tables  and 3. FP = 0.02; I2 = 89%, P < 0.00001).The pooled analysis indicated that, compared with the control group, the glucocorticoid group resulted in a significant improvement in the visual acuity  with a mean difference (MD) of -0.25 . The results showed that the glucocorticoid group had a better improvement in evaluation of visual field than the control group  , as insignificant heterogeneity was found among the included studies ( = 0.02) .P = 0.02, fixed effects model), without significant heterogeneity  , 6 studies involving 303 patients reported it. Meta-analysis showed that compared to the control group, the glucocorticoid group had a higher decrease of RNFL  .P = 0.0005, fixed effects model), with insignificant heterogeneity among the included studies   .Since there were not enough literature reports on the comparison of adverse reactions between the two groups, we could not make a combined analysis. We made a descriptive analysis about adverse reactions, and the specific results were shown in P value of the Egger test was not statistically significant . This indicated that there was no significant publication bias in our meta-analysis.The funnel plots for all four outcomes are shown in Optic nerve edema is an important factor in the decline of visual function, and the timely application of glucocorticoids in a timely manner can help to eliminate edema, reduce the crowded state of optic disc, improve the blocking state of axial plasma flow, reduce the crowded pressure of capillaries at the optic nipple, improve the blood flow state, and improve the degree of nerve ischemia, so as to reduce some damage to visual function in a certain sense , 28, 29.P = 0.02), VF , and RNFL  in NAION patients.Our study systematically evaluated the therapeutic effect of glucocorticoids on NAION patients with VA, VF, RNFL, and adverse reactions as outcome indicators. A total of 9 studies were included in this paper. The results of meta-analysis showed that the application of glucocorticoids could improve VA (MD: -0.25, 95% CI , Chen et al. conducted a meta-analysis of the literature on the treatment of NAION with corticosteroids, and they found that corticosteroids did not significantly improve the vision of NAION patients . HoweverThe adverse reactions of glucocorticoid drugs used in the treatment of NAION deserve clinicians' attention, such as monitoring blood glucose changes, nausea, indigestion, headaches, and weight gain, Anxiety and depression are easily overlooked, and intraocular hypertension is the most common adverse reactions , 37. By This study had some limitations. First, among the included studies, 7 were nonrandomized studies and only 2 were RCTs. As the “gold standard” for clinical efficacy evaluation, RCTs have more objective guiding significance, which may reduce the reliability of the results of this study. Second, there were few reports of adverse reactions in the original studies included in the meta-analysis, so it was impossible to accurately evaluate the safety of glucocorticoids in NAION treatment.Our meta-analysis found that the application of glucocorticoids in the treatment of NAION was safe and effective and can effectively improve VA and VF of NAION patients. However, the effect of glucocorticoids on the improvement of vision in NAION patients should be verified by more large sample RCTs and should focus on its hormone adverse reactions.


Marine organisms are known to produce a wide variety of natural products that are unique in terms of diversity, structural, and functional properties .Marine organisms living in extreme environments experience conditions close to the limit of life, e.g., polar and hot regions, deep sea, hydrothermal vents, marine areas of high pressure or high salinity. They have evolved unique strategies for surviving in these harsh conditions, as well as biosynthesizing novel bioactive compounds, which are potentially useful for pharmaceutical, cosmeceutical, nutraceutical, and biotechnological applications . Researchttps://www.mdpi.com/journal/marinedrugs/special_issues/Extreme_Environments accessed on 4 November 2021), includes 10 research articles and 2 reviews, providing a wide overview of the chemical biodiversity offered by different marine organisms inhabiting extreme environments to be used for biotechnological and pharmaceutical applications. The six articles in this Special Issue are focused on the polar regions, which represent an untapped source of marine natural products and are still largely unexplored compared to more accessible sites. Many of these articles refer to Antarctica, which is the coldest and most inaccessible continent on the Earth, where extreme temperatures, light and ice have selected biological communities with a unique suite of bioactive metabolites. The marine organisms of Arctic and Antarctic environments are a reservoir of natural compounds, exhibiting huge structural diversity and significant bioactivities that could be used in human applications.This Special Issue, as a continuation of the previous Special Issue, “Bioactive Molecules from Extreme Environments”  acerata, Haliclona (Rhizoniera) dancoi, Hemimycale topsenti and Hemigellius pilosus that led to the identification of two different chemical classes of molecules, suberitenone A and B and mycalols. The fraction containing the marine mycalol and its analogues, which have already been reported to possess anticancer activity on anaplastic thyroid carcinoma cells [As molluscs, sponges are known to produce a series of marine natural products with interesting biological activities that could be applied to biomedical applications. Riccio et al.  reportedma cells ,7, was iAspergillus insulicola HDN151418, which was isolated from an unidentified Antarctic sponge. Sclerotiotides M and N showed antimicrobial activity against a panel of pathogenic strains. The majority of marine bioactive compounds derive from microorganisms as an invaluable source for novel chemistry and sustainable production of bioactive compounds, bypassing the limit for the re-collection of marine resources using destructive practices . HoweverDi Lorenzo et al.  reported4 at low temperatures (22 °C) by using five Antarctic bacterial strains isolated from a consortium associated with the Antarctic ciliate Euplotes focardii. All copper nanoparticles display antimicrobial activity against various types of Gram-negative and Gram-positive bacteria and fungi pathogen microorganisms, including Escherichia coli, Staphylococcus aureus, and Candida albicans. The ability of these bacteria to synthesize copper nanoparticles may represent a mechanism of defense against this heavy metal. In fact, Antarctica is not completely free from contaminants that could reach the Southern Ocean via long-range atmospheric transport from other continents. Metal nanoparticle synthesis using microorganisms is an eco-friendly and sustainable strategy alternative to chemical and physical approaches, which is particularly promising in the bioremediation of the contaminated environment and in the production of antibiotics against various types of pathogenic microorganisms. Most research work in this field has been carried out on silver and gold nanoparticles. Another work on silver nanoparticles from Antarctic bacteria is given in the first book [John et al.  describerst book .Paenibacillus sp. SVB7, which was isolated from the Svalbard archipelago in the Arctic Ocean. Svalbamides A and B are structurally unique as they contain 3-amino-2- pyrrolidinone amino acid, which is rarely reported in natural products, and 3-hydroxy-8-methyldecanoic acid was occasionally found in natural products from Paenibacillus and related bacteria. Svalbamides A and B may function as potential chemopreventive agents, as they induced quinone reductase activity in murine hepatoma cells.Du et al.  describeIn addition to the polar regions, extreme are also environments of deep sea, hydrothermal vents, hot/arid regions, etc and other articles review these environments in this Special Issue. Dermacoccus abyssi MT 1.1T, from a Mariana Trench sediment in 2006, which was collected at a depth of 10,898 m from the Challenger Deep by the remotely operated submersible Kaiko in 1998. In the past, seven highly colored dermacozines A–G and 4 derivatives dermacozines H–J were isolated from this promising strain [Juhasz et al.  reportedg strain ,17,18. DBacillus amyloliquefaciens, a thermotolerant marine strain S185 isolated from offshore the South Sea, China. This marine strain displayed a strong antifungal activity against Fusarium oxysporum f. sp. cubense (Foc), which is responsible for a severe fungal disease in banana plants (Panama disease), due to its capacity to produce the antifungal compound iturin A5. This strain is able to grow between 20–50 °C, adapting to variable conditions of pH, salts and temperature. Due to these features, it is a promising candidate for a cost-effective and sustainable biocontrol application for Panama disease in the future. Singh and et al.  describePenicillium griseofulvum MCCC 3A00225, a deep sea-derived fungus isolated from the Indian Ocean sediment. The Penicillium species is recognized as the richest source for biologically important and structurally unique secondary metabolites. All isolates were tested for in vitro anti-food allergic bioactivities in immunoglobulin (Ig) E-mediated rat basophilic leukemia (RBL)-2H3 cells. One of these compounds, (-)-cyclopenol, significantly decreased the degranulation release with an IC50 value of 60.3 μM, compared to that of 91.6 μM of the positive control, loratadine.Xing et al.  reportedMuriellopsis sp (MCH35), which is isolated from an arid region of the north of Chile, Antofagasta, where it is exposed to high solar radiation. Among microorganisms as a prolific source of bioactive molecules, microalgae are the most diversified photosynthetic organisms with high adaptability to various environmental conditions [Muriellopsis sp. (MCH35) represents a potential candidate for lutein production under intense UV irradiation for biotechnological applications.Ruiz-Domínguez et al.  studied nditions . Microalnditions , variousnditions , and agenditions . Since sRimicaris sp. inhabiting the deep-sea hydrothermal vent in Manus Basin (Papua New Guinea). Shrimps belonging to the family Alvinocarididae are particularly abundant in the deep waters of Atlantic, Pacific, and Indian Oceans, especially in hydrothermal vents and cold seeps. Crustin, a cationic peptide of 7–22 kDa, belongs to the class of antimicrobial peptides (AMPs), a class of evolutionarily conserved molecules that exist in almost all organisms and play an important role in the innate immunity of organisms. They directly kill bacteria, fungi, viruses, and parasites, targeting the inner and/or outer membranes of microorganisms in a non-receptor-specific manner, with a rate of resistance several orders of magnitude lower than that of conventional antibiotics. Wang et al.  reportedMarine Drugs for their support and kind help.As Guest Editor of the second edition of this Special Issue, I dedicate this Issue to the memory of Prof. Guido di Prisco, my mentor, who passed away in September 2019. He spent his life studying the structure, function, and evolution of the hemoglobins of polar fishes and inspired my interest in life in Antarctic and Arctic environments. I am also grateful to all the authors who contributed to making this an exceptional Special Issue with new discoveries/research on bioactive molecules from extreme conditions. The papers included in this second Special Issue, as well as in the first Special Issue, highlight the increasing interest in these extreme habitats, which are perceived as important sources for drug discovery. I want to thank all the reviewers and I hope that this collection will provide a unique and valuable reference source for researchers interested in extreme environments and help the scientific community inspire the next generation to further research dedicated to this field.