Bangham, with colleagues Jeff Watkins and Standish, wrote the 1965 paper that effectively launched what would become the liposome "industry." Around that same time, Weissmann joined Bangham at the Babraham. Later, Weissmann, then an emeritus professor at New York University School of Medicine, recalled the two of them sitting in a Cambridge pub, reflecting on the role of lipid sheets in separating the cell interior from its exterior milieu. This insight, they felt, would be to cell function what the discovery of the double helix had been to genetics. As Bangham had been calling his lipid structures "multilamellar smectic mesophases," or sometimes "Banghasomes," Weissmann proposed the more user-friendly term liposome. [ 16 ] [ 17 ]


A liposome has an aqueous solution core surrounded by a  hydrophobic  membrane, in the form of a  lipid bilayer ;  hydrophilic   solutes  dissolved in the core cannot readily pass through the bilayer. Hydrophobic chemicals associate with the bilayer. This property can be utilized to load liposomes with hydrophobic and/or hydrophilic molecules, a process known as encapsulation. [ 18 ]  Typically, liposomes are prepared in a solution containing the compound to be trapped, which can either be an aqueous solution for encapsulating hydrophilic compounds like proteins, [ 19 ] [ 20 ]  or solutions in organic solvents mixed with lipids for encapsulating hydrophobic molecules.
Encapsulation techniques can be categorized into two types: passive, which relies on the stochastic trapping of molecules during liposome formation, and active, which relies on the presence of charged lipids or transmembrane ion gradients. [ 18 ]
A crucial parameter to consider is the "encapsulation efficiency," which is defined as the amount of compound present in the liposome solution divided by the total initial amount of compound used during the preparation. [ 21 ]
In more recent developments, the application of liposomes in  single-molecule experiments  has introduced the concept of "single entity encapsulation efficiency." This term refers to the probability of a specific liposome containing the required number of copies of the compound. [ 22 ]


To deliver the molecules to a site of action, the lipid bilayer can fuse with other bilayers such as the  cell membrane , thus delivering the liposome contents; this is a complex and non-spontaneous event, however, [ 23 ]  that does not apply to nutrients and drug delivery. By preparing liposomes in a solution of  DNA  or  drugs  (which would normally be unable to  diffuse  through the membrane) they can be (indiscriminately) delivered past the lipid bilayer. [ 24 ]  Liposomes can also be designed to deliver drugs in other ways. Liposomes that contain low (or high)  pH  can be constructed such that dissolved aqueous drugs will be  charged  in solution (i.e., the pH is outside the drug's  pI  range). As the pH naturally neutralizes within the liposome ( protons  can pass through some membranes), the drug will also be neutralized, allowing it to freely pass through a membrane. These liposomes work to deliver drug by  diffusion  rather than by direct cell fusion. However, the efficacy of this pH regulated passage depends on the physiochemical nature of the drug in question (e.g. pKa and having a basic or acid nature), which is very low for many drugs.


A similar approach can be exploited in the biodetoxification of drugs by injecting empty liposomes with a transmembrane pH gradient. In this case the vesicles act as sinks to scavenge the drug in the blood circulation and prevent its toxic effect. [ 25 ]
Another strategy for liposome drug delivery is to target  endocytosis  events. Liposomes can be made in a particular size range that makes them viable targets for natural  macrophage   phagocytosis . These liposomes may be  digested  while in the macrophage's  phagosome , thus releasing its drug. Liposomes can also be decorated with  opsonins  and  ligands  to activate endocytosis in other cell types.


Regarding pH-sensitive liposomes, there are three mechanisms of drug delivery intracellularly, which occurs via endocytosis. [ 26 ]  This is possible because of the acidic environment within endosomes. [ 26 ]  The first mechanism is through the destabilization of the liposome within the endosome, triggering pore formation on the endosomal membrane and allowing diffusion of the liposome and its contents into the cytoplasm. [ 26 ]  Another is the release of the encapsulated content within the endosome, eventually diffusing out into the cytoplasm through the endosomal membrane. [ 26 ]  Lastly, the membrane of the liposome and the endosome fuse together, releasing the encapsulated contents onto the cytoplasm and avoiding degradation at the lysosomal level due to minimal contact time. [ 26 ]


Certain anticancer drugs such as  doxorubicin  (Doxil) and  daunorubicin  may be administered encapsulated in liposomes. Liposomal  cisplatin  has received  orphan drug  designation for pancreatic cancer from EMEA. [ 27 ]  A study provides a promising preclinical demonstration of the effectiveness and ease of preparation of Valrubicin-loaded immunoliposomes (Val-ILs) as a novel nanoparticle technology. In the context of hematological cancers, Val-ILs have the potential to be used as a precise and effective therapy based on targeted vesicle-mediated cell death.  [ 28 ]


The use of liposomes for transformation or  transfection  of DNA into a host cell is known as  lipofection .


In addition to gene and drug delivery applications, liposomes can be used as carriers for the delivery of dyes to textiles, [ 29 ]  pesticides to plants, enzymes and nutritional supplements to foods, and cosmetics to the skin. [ 30 ]


Liposomes are also used as outer shells of some microbubble  contrast agents  used in  contrast-enhanced ultrasound .


Until recently, the clinical uses of liposomes were for  targeted drug delivery , but new applications for the oral delivery of certain dietary and nutritional supplements are in development. [ 31 ]   This new application of liposomes is in part due to the low absorption and  bioavailability  rates of traditional oral dietary and nutritional tablets and capsules.  The low oral bioavailability and absorption of many nutrients is clinically well documented. [ 32 ]  Therefore, the natural encapsulation of  lypophilic  and  hydrophilic  nutrients within liposomes would be an effective method of bypassing the destructive elements of the  gastric system  and  small intestines  allowing the encapsulated nutrient to be efficiently delivered to the cells and tissues. [ 33 ]


The term  nutraceutical  combines the words  nutrient  and  pharmaceutical , originally coined by Stephen DeFelice, who defined nutraceuticals as “food or part of a food that provides medical or health benefits, including the prevention and/or treatment of a disease”. [ 34 ]  However, currently, there is no conclusive definition of nutraceuticals yet, to distinguish them from other food‐derived categories, such as food (dietary) supplements, herbal products, pre‐ and probiotics,  functional foods , and fortified foods. [ 35 ]  Generally, this term is used to describe any product derived from food sources which is expected to provide health benefits additionally to the nutritional value of daily food. A wide range of nutrients or other substances with nutritional or physiological effects (EU Directive 2002/46/EC) might be present in these products, including  vitamins ,  minerals ,  amino acids ,  essential fatty acids ,  fibres  and various plants and herbal extracts. Liposomal nutraceuticals contain bioactive compounds with health-promoting effects. The encapsulation of bioactive compounds in liposomes is attractive as liposomes have been shown to be able to overcome serious hurdles bioactives would otherwise encounter in the gastrointestinal (GI) tract upon oral intake. [ 36 ]


Certain factors have far-reaching effects on the percentage of liposome that are yielded in manufacturing, as well as the actual amount of realized liposome entrapment and the actual quality and long-term stability of the liposomes themselves. [ 37 ]  They are the following: (1) The actual manufacturing method and preparation of the liposomes themselves; (2) The constitution, quality, and type of raw  phospholipid  used in the formulation and manufacturing of the liposomes; (3) The ability to create homogeneous liposome particle sizes that are stable and hold their encapsulated payload. These are the primary elements in developing effective liposome carriers for use in dietary and nutritional supplements.


The choice of liposome preparation method depends, i.a., on the following parameters: [ 38 ] [ 39 ]


Useful liposomes rarely form spontaneously. They typically form after supplying enough energy to a dispersion of (phospho)lipids in a polar solvent, such as water, to break down multilamellar aggregates into oligo- or unilamellar bilayer vesicles. [ 5 ] [ 24 ]


Liposomes can hence be created by  sonicating  a dispersion of amphipatic lipids, such as  phospholipids , in water. [ 8 ]  Low  shear rates  create multilamellar liposomes. The original aggregates, which have many layers like an onion, thereby form progressively smaller and finally  unilamellar liposomes  (which are often unstable, owing to their small size and the sonication-created defects). Sonication is generally considered a "gross" method of preparation as it can damage the structure of the drug to be encapsulated. Newer methods such as extrusion, micromixing [ 40 ] [ 41 ] [ 42 ]  and Mozafari method [ 43 ]  are employed to produce materials for human use. Using lipids other than  phosphatidylcholine  can greatly facilitate liposome preparation. [ 5 ]


Further advances in liposome research have been able to allow liposomes to avoid detection by the body's immune system, specifically, the cells of  reticuloendothelial system  (RES). These liposomes are known as " stealth liposomes ". They were first proposed by G. Cevc and G. Blume [ 44 ]  and, independently and soon thereafter, the groups of L. Huang and  Vladimir Torchilin [ 45 ]  and are constructed with PEG ( Polyethylene Glycol ) studding the outside of the membrane. The PEG coating, which is  inert  in the body, allows for longer circulatory life for the drug delivery mechanism. Studies have also shown that PEGylated liposomes elicit anti-IgM antibodies, thus leading to an enhanced blood clearance of the liposomes upon re-injection, depending on lipid dose and time interval between injections. [ 46 ] [ 47 ]  In addition to a PEG coating, some stealth liposomes also have some sort of biological species attached as a ligand to the liposome, to enable binding via a specific expression on the targeted drug delivery site. These targeting ligands could be  monoclonal antibodies  (making an  immunoliposome ),  vitamins , or specific  antigens , but must be accessible. [ 48 ]  Targeted liposomes can target certain cell type in the body and deliver drugs that would otherwise be systemically delivered. Naturally toxic drugs can be much less systemically toxic if delivered only to diseased tissues.  Polymersomes , morphologically related to liposomes, can also be used this way. Also morphologically related to liposomes are highly deformable vesicles, designed for non-invasive transdermal material delivery, known as  transfersomes . [ 49 ]


Liposomes are used as models for artificial cells.


Liposomes can be used on their own or in combination with traditional antibiotics as neutralizing agents of bacterial toxins. Many bacterial toxins evolved to target specific lipids of the host cells membrane and can be baited and neutralized by liposomes containing those specific lipid targets. [ 50 ]


A study published in May 2018 also explored the potential use of liposomes as "nano-carriers" of fertilizing nutrients to treat malnourished or sickly plants. Results showed that these synthetic particles "soak into plant leaves more easily than naked nutrients", further validating the utilization of nanotechnology to increase crop yields. [ 51 ] [ 52 ]


Machine learning  has started to contribute to liposome research. For example,   deep learning  was used to monitor a multistep  bioassay  containing sucrose-loaded and nucleotides-loaded liposomes interacting with a lipid membrane-perforating  peptide . [ 53 ]   Artificial neural networks  were also used to optimize formulation parameters of  leuprolide   acetate  loaded liposomes [ 54 ]
and to predict the particle size and the  polydispersity  index of liposomes. [ 55 ]


A  liposome  extruder  is a device that prepares cell membranes,  exosomes  and also generates nanoscale liposome formulations. [ 1 ] [ 2 ]  The liposome extruder employs the track-etched  membrane  to filter huge particles and achieve sterile filtration. [ 3 ] [ 4 ]


A  liposome  is made up of  phospholipid bilayers , with the liposome being a spherical vesicle. Phospholipid bilayers have both  hydrophobic  and  hydrophilic  properties, which are important characteristics of  cell membranes . [ 5 ]  The hydrophobic ends of phospholipid molecules are constrained [ clarification needed ] , often to each other, creating spherical liposomes that are smaller when the hydrophobic ends are exposed to a solution that is aqueous in nature. The preparation of liposomes results in the formation of the liposome extruder [ clarification needed ] . A liposome extruder is characterized by the uniform, narrow size distribution of its output, and has a particle-size control mechanism that is highly precise. Complex, toxic, injectable products such as the  antifungal  liposomal  Amphotericin B , or the liposomal  cytotoxic   anticancer agents   doxorubicin ,  paclitaxel ,  irinotecan ,  Adriamycin , and  cytarabine  contain liposomes which are prepared using the liposome extruder. [ 6 ]


The technology for extruding liposomes relies on the performance and structural characteristics of the  lipid bilayers  in the liposomal  phospholipids . [ how? ] [ clarification needed ] [ 7 ]  An external extrusion force pushes the vesicles of liposomes that are large through the polycarbonate membranes with pore sizes that are specific when the  transition temperature  of the phospholipids rises slightly due to the change in operating temperature [ further explanation needed ] . Re- polymerization  of the multiple compartments pr liposomes that are large in particle size occurs, [ 8 ] [ 9 ]  and smaller liposomes are created due to the rupturing of the membrane [ which? ]  pores. Extrusion of liposomes occurs at a uniform size, based on the pore size in the  polycarbonate   membrane . [ 10 ]  This happens when the big vesicles are passed through the  cell membrane  with a nanopore size specified in size several times [ 10 ]  due to the extrusion of polycarbonate membranes having uniform and vertical nanopore distribution on the surface of the membrane. [ 11 ] [ 12 ]


Liposome extruders are applied in the formulation of liposomes of homogeneous size distributions. [ 3 ] [ 13 ] [ 14 ] [ 15 ]


This type of liposome extruder is primarily used in research laboratories, as it can process mini-sample volumes between 0.25 ml and 2.5 ml. The hand-driven liposome extruders are further categorized into liposome extruders with a thermal-jacketed option and liposome extruders under ambient temperature. They are operated by manually by  pushing a plunger. Liposome extruders under ambient temperature can be fitted with a cooling jacket to regulate temperatures during liposome extrusion. [ 16 ] [ 17 ]


Jacketed liposome extruders are applied in laboratories and in pilot-scale research phases. They process volumes between 2 mL and 3 L. The jacketed extruders are fitted with barrels [ clarification needed ]  to regulate the temperatures of the samples. To drive this extruder, a compressed nitrogen cylinder is used. [ 18 ]


Online liposome extruders process volumes of between 2 ml and 20L. They are driven by a high-pressure electric pump, making them appropriate for use in pilot-scale liposome production. [ 2 ]


A multiple liposome extruder system is fitted with pressure and temperature sensors and a control panel to regulate liposome production. it processes capacities of between 1L and 200L. [ 19 ]


Lotion  is a low- viscosity  topical preparation intended for application to the  skin . By contrast,  creams  and  gels  have higher viscosity, typically due to lower water content. [ 1 ] [ 2 ]   Lotions are applied to external skin with bare hands, a brush, a clean cloth, or  cotton wool .


While a lotion may be used as a medicine delivery system, many lotions, especially  hand lotions  and  body lotions  and lotion for  allergies  are meant instead to simply smooth, moisturize, soften and, sometimes, perfume the skin. [ 3 ]


Some skincare products, such as  sunscreen  and  moisturizer , may be available in multiple formats, such as lotions, gels, creams, or sprays.


Dermatologists can prescribe lotions to treat or prevent skin diseases. [ 1 ]  It is not unusual for the same drug ingredient to be formulated into a lotion,  cream  and  ointment . Creams are the most convenient of the three but inappropriate for application to regions of hairy skin such as the scalp, while a lotion is less viscous and may be readily applied to these areas (many medicated  shampoos  are in fact lotions). Historically, lotions also had an advantage in that they may be spread thinly compared to a cream or ointment and may economically cover a large area of skin, but product research has steadily eroded this distinction.  Non-comedogenic  lotions are recommended for use on acne prone skin. [ 4 ]


Lotions can be used for the delivery to the skin of medications such as:


Since health care workers must wash their hands frequently to prevent disease transmission, hospital-grade lotion is recommended to prevent skin  dermatitis  caused by frequent exposure to cleaning agents in the soap. [ 5 ]  A 2006 study found that application of hospital-grade lotion after hand washing significantly reduced skin roughness and dryness. [ 6 ] [ failed verification ]


Care must be taken not to use consumer lotions in a hospital environment, as the  perfumes  and  allergens  may be a danger to those who are immunodeficient or with allergies. [ 7 ] [ 8 ]


Most cosmetic lotions are  moisturizing lotions , although other forms, such as  tanning lotion , also exist.


Cosmetic lotions may be marketed as anti-aging lotions, which can also be classified as a cosmetic in many cases, and may contain fragrances. The  Food and Drug Administration  voiced concern about lotions not classified as drugs that advertise anti-aging or anti-wrinkle properties. [ 7 ] [ 9 ]


Most lotions are oil-in-water  emulsions  using a substance such as  cetearyl alcohol  to keep the emulsion together, but water-in-oil lotions are also formulated. The key components of a skin care lotion, cream or gel emulsion (that is mixtures of oil and water) are the  aqueous  and oily phases, an  emulsifier  to prevent separation of these two phases, and, if used, the  drug  substance or substances. Various other ingredients such as  fragrances ,  glycerol ,  petroleum jelly ,  dyes ,  preservatives ,  proteins  and stabilizing agents are commonly added to lotions.


Manufacturing lotions and creams can be completed in two cycles:


A typical oil-in-water manufacturing process may be:


Depending on their composition, lotions can be comedogenic, meaning that they can result in the increased formation of  comedones  (clogged hair follicles). [ 10 ]  People who are prone to  acne  or forming comedones often prefer lotions that are designed to be non-comedogenic (not causing outbreaks). [ 10 ]


All topical products, including lotions, can result in the  percutaneous (through the skin) absorption  of their ingredients. Though this has some use as a route of drug administration, it more commonly results in unintended  side effects . For example, medicated lotions such as  diprolene  are often used with the intention of exerting only  local effects , but absorption of the drug through the skin can occur to a small degree, resulting in systemic side effects such as  hyperglycemia  and  glycosuria . [ 11 ]


Absorption through the skin is increased when lotions are applied and then covered with an  occlusive  layer, when they are applied to large areas of the body, or when they are applied to damaged or broken skin. [ 11 ]


Lotions containing some aromas or food additives may trigger an immune reaction or even cause users to develop new allergies. [ 12 ]


There is currently no regulation over use of the term "hypoallergenic", and even pediatric skin products with the label were found to still contain allergens. [ 13 ]  Those with  eczema  are especially vulnerable to an allergic reaction with lotion, as their compromised skin barrier allows preservatives to bind with and activate immune cells. [ 14 ]


The  American Academy of Allergy, Asthma, and Immunology  released a warning in 2014 that natural lotion containing ingredients commonly found in food (such as goats milk, cow's milk, coconut milk, or oil) may introduce new allergies, and an allergic reaction when those foods are later consumed. [ 12 ]  A 2021 study found that "frequent skin moisturization in early life might promote the development of food allergy, most likely through transcutaneous sensitization". [ 15 ]


Magnetic  nanoparticle -based drug delivery  is a means in which magnetic particles such as  iron oxide nanoparticles  are a component of a delivery vehicle for magnetic  drug delivery , due to the simplicity with which the particles can be drawn to (external)  magnetopuissant targets . [ 1 ] [ 2 ]  Magnetic nanoparticles can impart imaging and  controlled release  capabilities to drug delivery materials such as  micelles ,  liposomes , and polymers.


Molecular magnets  (single-molecule magnets) are a platform that incorporates insoluble (toxic) drugs into biocompatible carrier materials, without adding magnetic  iron oxide nanoparticles  which might adversely affect patients susceptible to  iron overdose . The drawbacks in conventional magnetic drug delivery methods can be overcome by switching from typical  iron oxide nanoparticles  to ones based on molecular magnets, such as  Fe(salen) -based " anticancer nanomagnet " with proven cancer-fighting ability. [ 3 ] [ 4 ] [ 5 ]  However, insoluble drugs including Fe(salen) also have some inherent drawbacks, such as poor water solubility, loss of magnetic activity in solvents, and potential cytotoxicity when accumulated in tissues and organs.


As an alternative synthetic method of magnetic drug delivery, a "non-iron oxide"-based smart delivery platform has been very recently developed by  self-assembly  of the Fe(salen) drugs into nano-cargoes encapsulated by a  smart polymer , exhibiting bio-safe multifunctional magnetic capabilities, including  MRI , magnetic field- and pH-responsive heat-releasing  hyperthermia  effects, and controlled release. [ 6 ]


Magnetic nanoparticle drug delivery  is the use of external or internal magnets to increase the accumulation of  therapeutic  elements contained in  nanoparticles  to fight pathologies in specific parts of the body. It has been applied in  cancer treatments ,  cardiovascular diseases , and  diabetes . Scientific researches revealed that magnetic drug delivery can be made increasingly useful in clinical settings.


The development of magnetic nanoparticle drug delivery started with  Paul Ehrlich 's concept of a "magic bullet". [ 1 ]  The concept was built during the 1970s with the application of the anticancer drug  doxorubicin  in animal models. The first successful clinical trial of the process occurred in 1996. [ 2 ]


The use of magnetic nanoparticles for drug delivery results in the accumulation of therapeutic elements at a disease site to increase their therapeutic effects as well as limit side-effects at non-target loci. There are many factors that act as variables to accumulation including blood circulation, adherence of therapeutic elements, diffusion of therapeutic elements, bodily response to increased concentrations of these particles, etc. [ 3 ]  Tumor hypoxia is one of the largest challenges regarding cancer drug delivery as tumors grow faster than  vasculature , making initial targeting increasingly important in treatment. This tumor environment drives considerable attention towards magnetic nanoparticles as treatment modalities allowing faster and efficient delivery of drugs and treatment. [ 4 ]


Fundamentally, pulsatile artificial capillaries made to mimic blood flow show that the flow force of the  capillaries  inhibits accumulation of nanoparticles on a magnet downstream, but the magnetic force of the upstream magnet overcomes the force of flow to result in larger accumulation. As a result, for near-surface disease states, magnets should be placed downstream of the disease locus, and for intra-surface disease states, magnets should be placed upstream of the disease locus to maximize accumulation. [ 3 ]


Magnetic nanoparticles for therapeutic applications are selected based on their properties determined by the nanoparticle composition which can be divided into three main groups - metal only,  metal alloy , or metal oxide nanoparticles. Some key properties of magnetic nanoparticles include a large specific surface area, desirable biocompatibility, presence without causing disease or eliciting  immune response , and superparamagnetism. [ 5 ]  Magnetic nanoparticles are influenced by an external magnetic field due to the magnetic moment found within the network unit. The external magnetic field is necessary for transport and activation of these nanoparticles. Therefore, when a drug is attached/encased in magnetic nanoparticles, these particles will be targeted using an external magnetic field to guide and concentrate the drug at desired disease locus. [ 6 ]


Design of magnetic nanoparticles for clinical application requires careful evaluation of the effects of surface modification, size, and shape on its magnetic properties. Ferromagnetic properties of nanoparticles have been used in magnetic drug delivery systems. This is important, as ferromagnetism is described as the coercivity of particles to form macro-materials on permanent magnets. The macro-materials include  iron ,  cobalt , and  nickel ; these elements retain their magnetic properties when a magnet is removed, which is why they accumulate on the permanent magnets. [ 3 ]  Iron oxides, such as Fe₂O₄ and Fe₃O₄ in particular, play a key role in magnetic nanoparticle drug delivery. The particle sizes typically range from 3 nm to 30 nm. Overall, these iron oxides display good magnetic properties, lower toxicity, and high stability against degradation. [ 6 ]


For example, a Fe3-δO4 core-shell is used as a carrier for drug delivery. The designed magnetic nanoparticle-based structure displayed biocompatibility, the formation of a covalent bond between the carrier and drug, and  glutathione -responsive drug release which prevents early drug release and increases bioavailability. Furthermore, the presence of magnetic nanoparticles in this drug delivery method allows for its response to external magnetic fields for functionalization. [ 7 ]  The combination of superparamagnetic iron oxide (SPIO) and polyethylene glycol (PEG) used as drug carriers for doxorubicin are influenced by external magnetism. In vivo SPIO-PEG-D under a magnetic field leads to greater tumor accumulation of therapeutic elements, shows lower tumor size, and reduces  cardiotoxicity  and  hepatotoxicity  in the magnetic field.  Doxorubicin  is known for being extremely toxic, and SPIO-PEG shows potential for use as a nanoparticle carrier for reduced toxicity in the periphery. [ 8 ]


Coating defines the biocompatibility of the therapeutic agent and its ability to travel in the body. When the agent is not biocompatible, it will quickly be excreted from the body, and there will be magnetic accumulation or off-target therapeutic effects. [ 4 ]  The use of organic or inorganic coating molecules increases the  half-life  of the nanocarrier by delaying its clearance by the  reticuloendothelial system   (RES). This delay occurs because the coating overcomes the pH, hydrophobicity, and surface charge of the magnetic nanoparticles. Additionally, coating allows molecules to covalently bind to specific molecules, such as ligands, proteins, or antibodies, which provides binding specificity to target tissues. [ 6 ]


A common structure of coating includes the core-shell structure. In this structure, metal oxide cores are coated with biocompatible materials which allows for increased control and biocompatibility. [ 6 ]  The most common coatings used for optimum response involve the use of  polysaccharides  like  dextran  and polymers like  polyethylene glycol . [ 4 ] [ 9 ]  Furthermore, carbon coatings have proved to be biocompatible and have high capacity for absorption into cells. Even  polyaniline  with anti-cancer agent  epirubicin  can be used for tumor exploration of the brain. Polyethyleneimine has displayed high cellular accumulation and low toxicity. This coating was found to have poor pharmacokinetic properties when used alone, but with magnetic field induction, it was found to accumulate on tumors at clinically significant rates. [ 4 ]  Silica coatings increase the external surface area to assist in binding and are heat resistant. There are various coatings used to prevent leaching of the magnetic core of the nanoparticles; these coatings have a significant salt concentration with a slightly alkaline (basic) pH. [ 1 ]


Polyethylene glycol (PEG) is an example of a hydrophilic coating that has been used as a biocompatible targeting modality. Hydrophilic PEG interacts beneficially with the physiological environment to improve biocompatibility by preventing opsonization on the surface of the particles, thus increasing circulation time from minutes to hours, or even days, for magnetic nanoparticles. MRI shows prolonged  PEG circulation and increased SPIO-PEG-D particle accumulation within the tumor with magnetic guidance. [ 8 ]


Coating not only provides hydrophilic and hydrophobic properties but can also contribute to temperature- and pH-dependent properties. Particular substances, such as PNG, provide these two properties, allowing unique and efficient delivery of drugs. This also enables greater control of release, as body temperature allows a greater amount of drug released, while physiological pH allows a lower amount of drug released. [ 10 ]  Other coating options for similar pH-dependent properties include the hydrogel chitosan that is crosslinked to a polymer coating. [ 11 ]  These coating choices have displayed positive results in delivery of anticancer drugs.


The small sizes of magnetic nanoparticles allow them to target a variety of targets of different sizes for different purposes. These sizes range from targeting a small cell (10-100 μm), a virus (20-45 nm), a protein (5-50 nm), or a gene (2 nm wide and 10-100 nm long). If these magnetic nanoparticles are coated correctly, they can interact with and enter body structures, allowing adequate delivery of a drug. Additionally, using magnetic nanoparticles in drug delivery has remote control capability. This occurs through the external magnetic field gradient that is associated with the magnetic field's permeability within human tissue. With the application of this remote control, accumulation and transfer of the magnetic nanoparticles is promoted, which has been especially useful in the delivery of anticancer drugs to specific tumor tissues. [ 6 ]


Another advantage of drug delivery using magnetic nanoparticles is the personability of magnet placement depending on disease state location. [ 3 ]  While this may also be a limitation, it can be effective if the resources can be used for personally tailored medicine reception. Additionally, a major advantage of magnetic nanoparticles is that they can be visualized with ultrasound and/or MRI imaging. [ 1 ] [ 8 ] [ 9 ]  Increase in cellular uptake of SPIO-PEG-D was linked to distinguishable darker differences in  MRI  and increased tumor visibility. [ 8 ]


Limitations of magnetic drug delivery can range from their inherent magnetic properties to interactions with bodily barriers. When magnetic nanoparticles are in the bloodstream, they have high solubility and ionic strength, allowing them to interact with plasma proteins, stimulating the immune system to further inhibit their function. Additionally, the proportion of the nanoparticle size to the target tissue has shown limitations in effective drug delivery, especially in the kidneys and the brain. Intracellular barriers include the removal of the magnetic nanoparticles from the target membrane by ligand-dependent endocytosis followed by separation via acidification in the endosome chamber. Other barriers to consider are the depth of the target tissue, vascular sources, body weight, the speed and amount of blood flow to the target tissue, distance from the field source, injection route, and tumor volume. However, the use of magnetic nanoparticles is more effective when used in near-surface tissues that have slower blood flow, allowing for diffusion and/or endocytosis of nanoparticles into the tissue. [ 6 ]


Another limitation involves the accumulation of nanoparticles only 5 mm away from an external magnet. [ 3 ]  An accumulation distance of 5 mm may not be sufficient in larger applications of magnetic drug delivery. This may be effective enough for sites in closer proximity to the surface of the body, but when the site of interest is deeper within tissue, then the advantage of using magnetic nanoparticles for delivery decreases exponentially. It has been proposed to implant magnets within the body to overcome this limitation. [ 4 ]  Magnet location placement can be upstream or downstream of the location of the disease for maximum accumulation. [ 3 ]


Another question arises from the subject of cellular uptake. While the use of a magnetic field may guide particles to therapeutic sites, it is not an indicator of cellular uptake of particles. This raises questions regarding the effect, if any, of the therapeutic element on the effector area. Generally, nanoparticles efficiently cross cell barriers; however, this can change in the presence of other processes. Promise has been shown with the use of PEG coating. Hydrophilic coatings have shown enhanced cellular uptake at tumor cells with the use of a magnetic field. [ 8 ]


Another concern arises regarding the biotoxicity of magnetic nanoparticles. It is difficult to say for certain that all magnetic nanoparticles are toxic due the large variety of magnetic particles that can be used. The nanoparticles size, biodegradability, composition, and dosage are a few of the properties impacting this concern. However, it has been shown that magnetic nanoparticles that are either inhaled to enter the lungs or are swallowed and enter the gastrointestinal tract have unsatisfactory impacts on the body. PEG, linear neutral polyether coatings have a tendency to lose their targeting capabilities in response to their "immune stealthing" function. [ 1 ]


Most magnetic nanoparticle applications in clinical settings are used for cancer therapies. Magnetic nanoparticles have the ability to target the specific locus of the tumor, use a decreased amount of drug to treat the tumor, and result in decreased off-target effects of the drug. [ 1 ]  The most common method of introducing magnetic nanoparticles into the body is through  intravenous  injection; from the site of injection, the nanoparticles travel through the bloodstream. They eventually migrate to the target site with the use of external or implanted magnetic forces. [ 12 ]


A pH/magnetic field dual responsive drug loaded nanomicelle was developed for targeted magnetothermal synergistic chemotherapy of cancer. In this drug delivery system, after the drug reaches the target site and tumor cell uptake is complete, an external magnetic field is applied causing a magnetothermal effect, raising the tumor cells' temperature and further promoting drug uptake. This nanocarrier system aims to improve drug stability, control drug release, and improve tumor targeting efficacy. This approach has shown increased treatment efficacy over traditional chemotherapy and has not demonstrated any noticeable biotoxicity. [ 13 ]


Cardiovascular disease treatment presents as another application of magnetic nanoparticle drug delivery. Atherosclerosis cardiovascular disease is a buildup of plaque in the inner lining of the arteries, and there are models on how magnetic nanoparticle drug delivery could be used as a treatment. However there have not been any in vivo or in vitro studies of magnetic nanoparticles being used to deliver drugs to the arteries to effectively reduce inflammation. [ 12 ]


Other potential applications of magnetic nanoparticles are brain imaging and drug delivery past the  blood-brain barrier  (BBB) using biodegradable magnetic iron oxide nanoparticles. The scope of this application is the treatment of central nervous system (CNS) disorders by functioning as contrast agents and drug carriers. To cross the BBB, these nanoparticles are designed by creating specificity to the BBB; this is achieved by designing the surface of the nanoparticles to be engrafted to ligands, antibodies, small molecules, cell-penetrating peptides, or conjugated RNA to target specific receptors situated along the BBB in order to facilitate entry. As opposed to methods of drug delivery that result in drugs being removed from the cerebrospinal fluid (CSF) or being degraded, magnetic nanoparticle delivery presents an opportunity to protect therapeutics as well as encourage more efficient delivery following the introduction of the nanoparticles. Magnetic nanoparticles can also be used in conjunction with imaging modalities like  ultrasound  to improve imaging. [ 9 ]


The use of nanoparticles in ophthalmic drug delivery is also being explored in clinical research. Magnetic nanoparticles inserted into rats'  corneas  or administered in an eye drop solution showed high adhesion to the target site. However, the exact mechanism by which the adhesion occurred is still being researched. When the rats were exposed to a bacterial substance that should induce  keratitis  of the cornea, the amount of inflammation in the treatment group of rats (received the eye drops after exposure) was inhibited. [ 14 ]  Magnetic nanoparticles have also been used in hyperthermic therapy of cancer, cell purification, biosensing, and immunocytochemical tests. [ 6 ]


In the  United States military , the  Mark I NAAK , or  MARK I Kit , ( "Nerve Agent Antidote Kit" ) is a dual-chamber  autoinjector : Two anti- nerve agent  drugs— atropine sulfate  and  pralidoxime chloride —each in injectable form, constitute the kit. The kits are only effective against the nerve agents  tabun  (GA),  sarin  (GB),  soman  (GD) and  VX .


Typically, U.S. servicemembers are issued three MARK I Kits when operating in circumstances where chemical weapons are considered a potential hazard. Along with the three kits are issued one  CANA  (Convulsive Antidote, Nerve Agent) for simultaneous use. (CANA is the drug  diazepam  or  Valium , an anticonvulsant.) Both of these kits are intended for use in "buddy aid" or "self aid" administration of the drugs prior to  decontamination  and delivery of the patient to definitive medical care for the condition.


A newer model, the  ATNAA  (Antidote Treatment Nerve Agent Auto-Injector), [ 1 ]  has both the atropine and the pralidoxime in one syringe, allowing for simplified administration.


The use of a Mark 1 or ATNAA kit inhibits the nerve agents' purpose, thereby reducing the number of fatal casualties in the advent of chemical warfare. The kits should only be administered if nerve agents have been absorbed or inhaled.


A  metered-dose inhaler  ( MDI ) is a device that delivers a specific amount of medication to the  lungs  in the form of a short burst of aerosolized medicine that is usually self-administered by the patient via inhalation. It is the most commonly used delivery system for treating  asthma ,  chronic obstructive pulmonary disease  (COPD) and other respiratory diseases. The medication in a metered dose inhaler is most commonly a  bronchodilator ,  corticosteroid  or a combination of both for treating asthma and COPD. Other medications less commonly used but also administered by MDI are mast cell stabilizers, such as  cromoglicate  or  nedocromil .


A metered-dose inhaler consists of three major components: the canister, which is produced in aluminum or stainless steel by means of  deep drawing , where the formulation resides; the metering valve, which allows a metered quantity of the formulation to be dispensed with each actuation; and an actuator (or mouthpiece) which enables the patient to operate the device and directs the aerosol into the patient's lungs. [ 1 ] [ 2 ]  The formulation comprises the drug, a liquefied gas propellant and, in many cases, stabilizing  excipients . The actuator contains the mating discharge nozzle and generally includes a dust cap to prevent contamination.


To use the inhaler, the patient presses down on the top of the canister, with their thumb supporting the lower portion of the actuator. Actuation of the device releases a single metered dose of the formulation, which contains the medication either dissolved or suspended in the propellant. Breakup of the volatile propellant into droplets, followed by rapid evaporation of these droplets, results in the generation of an aerosol consisting of micrometer-sized medication particles that are then inhaled. [ 3 ]


Metered-dose inhalers are only one type of  inhaler , but they are the most commonly used type. The replacement of  chlorofluorocarbons  propellants with  hydrofluoroalkanes  (HFA) resulted in the redesign of metered-dose inhalers in the 1990s. For one variety of  beclomethasone  inhalers, this redesign resulted in considerably smaller aerosol particles being produced and increased in potency by a factor of 2.6. [ 4 ]


Before the invention of the MDI, asthma medication was delivered using a fragile and unreliable squeeze bulb  nebulizer . [ 7 ]   The relatively crude nature of these devices also meant that the particles that they generated were relatively large, too large for effective drug delivery to the lungs. [ 2 ]   Nonetheless, these nebulizers paved the way for inhalation drug delivery, inspiring the MDI.


MDIs were first developed in 1955 by Riker Laboratories, now a subsidiary of  3M Healthcare . [ 7 ]   At that time, MDIs represented a convergence of two relatively new technologies, the  CFC  propellant and the Meshburg metering valve, originally designed for dispensing perfume. [ 8 ]  The initial design by Riker used a glass canister coated with vinyl plastic to improve its resilience. [ 7 ]   By 1956, Riker had developed two MDI-based products, the Medihaler-Ept containing  epinephrine  and the Medihaler-Iso containing  Isoprenaline . [ 2 ]   Both products are  agonists  that provide short-term relief from asthma symptoms and have now largely been replaced in asthma treatment by  salbutamol , which is more selective.


Metered-dose inhalers are sometimes used with add-on devices referred to as holding chambers or spacers, tubes attached to the inhaler that act as a reservoir or holding chamber and reduce the speed at which the aerosol enters the mouth. They serve to hold the medication that is sprayed by the inhaler. This makes it easier to use the inhaler and helps ensure that more of the medication gets into the lungs instead of just into the mouth or the air. Proper use of a spacer can make an inhaler more effective in delivering medicine. [ 9 ]


Spacers can be especially helpful to adults and children who find a regular metered dose inhaler hard to use. People who use corticosteroid inhalers should use a spacer to prevent getting the medicine in their mouth, where  oral yeast infections  and  dysphonia  can occur. [ 10 ]


The deposition of the content of drug formulation on the canister surface can result in a shorter shelf life of an MDI  inhaler . Applying a suitable surface coating to the components helps to extend this shelf life. Over the years, various coating processes have been developed that can be applied to both the canister and valve to protect the contents from deposition and degradation.
Gas plasma processing is an industrial technique carried out in a vacuum to coat the entire MDI  inhaler . It involves constant or pulsed gas excitation by radio frequency (RF) or the microwave field to produce an energetic plasma. This coating ensures that the drug formulation does not stick to the interior wall of the MD  inhaler  and results in the patient receiving the prescribed dose of medication, extending the product's shelf-life.


A metered dose inhaler contains enough medication for a certain number of actuations (or "puffs") printed on the canister.  Even though the inhaler may continue to work beyond that number of uses, the amount of medication delivered may not be correct. It is important to keep track of the number of times an inhaler is used so that it can be replaced after its recommended number of uses. For this reason, several regulatory authorities have requested that manufacturers add a dose counter or dose indicator to the actuator. Several inhalation products are now sold with a dose counter-actuator. Depending on the manufacturer and the product, inhalers are sold as a complete unit or the individual canister as a refill prescription.


While MDIs are commonly used in the treatment of lung-based disorders, their use requires dexterity to complete the required sequential steps to achieve the application of these devices. Incorrect completion of one or more steps in using an MDI can substantially reduce the delivery of the administered medication and, consequently, its effectiveness and safety. Numerous studies have demonstrated that between 50-100% of patients do not use their inhaler devices correctly, with patients often unaware that they are using their inhaled medication incorrectly. [ 11 ] [ 12 ]  Incorrect inhaler technique has been associated with poorer outcomes. [ 12 ] [ 13 ]  Incorrect maintenance and cleaning of metered dose inhalers is also an issue identified by many users, highlighting the need for clear guidance for patients prescribed MDIs. [ 14 ] [ 15 ]


One of the most crucial components of an MDI is its propellant. The propellant provides the force to generate the aerosol cloud and is also the medium where the active component must be suspended or dissolved. Propellants in MDIs typically make up more than 99% of the delivered dose, [ 16 ]  so the properties of the propellant dominate more than any other individual factor.  This is often overlooked in literature and in industry because so few propellants are used, and their contribution is often taken for granted.  Suitable propellants must pass a stringent set of criteria, and they must:


In the early days of MDIs, the most commonly used propellants were the  chlorofluorocarbons   CFC-11 ,  CFC-12  and  CFC-114 .


In 2008, the  Food and Drug Administration  announced that inhalers using  chlorofluorocarbons  as a propellant, such as  Primatene Mist , could no longer be manufactured or sold as of 2012. [ 19 ]  This followed from U.S. decision to agree to the 1987  Montreal Protocol  on Substances that deplete the ozone layer. [ 20 ]


Hydrofluorocarbon  propellants have replaced CFC propellants. [ 21 ]  Concerns about the use of  hydrofluorocarbon  propellants have, however, since arisen since these compounds are potent  greenhouse gases ; propellants released during the use of a single inhaler result in a greenhouse footprint equivalent to greenhouse gases released during a 180-mile car journey. [ 22 ]


Phospholipids  are important natural  surfactant  lipids. [ 23 ]  used to enhance penetration and bioavailability. [ 24 ]  Phospholipids reduce the high  surface tension  forces at the air-water interface within the  alveoli , thereby reducing the pressure needed to expand the lungs. Thus, commercially available formulations of phospholipids have been designed to spread rapidly over an air-aqueous interface, thereby reducing what is otherwise a very high surface tension of water.


For ease of identification, many MDI's are colour-coded


Microbial drug delivery  is an emerging form of drug administration characterized by the use of  commensal   microbes  that have been  genetically modified  to produce medications for  chronic diseases  in  humans . [ 1 ] [ 2 ] [ 3 ]  Only proteinaceous  drugs  can be produced by microbes, as  DNA  encodes for  protein . Research into microbial drug delivery refers to this  route of administration  as  topical , since the microbes release the drug directly to the surface of affected  tissues , namely the  gastrointestinal (GI) epithelium . [ 1 ] [ 2 ]  Microbial drug delivery is not currently used as a standard route of drug administration due to its experimental nature. During  clinical trials , it has been used to treat forms of  inflammatory bowel disease  (IBD). [ 2 ] [ 3 ]  The most prominently studied vehicles of microbial drug administration are the  bacterial   species ,  Lactococcus lactis  and  Bacteroides ovatus . [ 1 ] [ 2 ] [ 3 ]


The usage of  recombinant  microbes (i.e. microorganisms designed to contain DNA from two or more different species) has applications in treating chronic diseases. [ 1 ] [ 2 ] [ 3 ]  In 2006, Braat  et al . implemented microbial drug delivery with  L. lactis  in clinical trials, successfully treating  Crohn's disease  (CD), a form of IBD that causes  inflammation  and  ulceration  in the  intestines . In this study, a recombinant strain of  L. lactis  containing  complementary DNA  (cDNA) for the human  interleukin-10  (IL-10)  gene  was used to treat CD with IL-10, an anti-inflammatory  cytokine . [ 2 ] [ 3 ]  Patients consumed capsules containing the microbe to populate the intestines and received therapeutic doses of IL-10 directly from the recombinant bacteria. [ 3 ]  As this route of administration is experimental, it is currently not available as a standard treatment option.


In a 2013  animal study  with  B. ovatus  as the vehicle for microbial drug delivery, researcher Zaed Hamady suggested that recombinant strains of  B. ovatus  containing  transforming growth factor-beta  (TGF-β) and  keratinocyte growth factor -2 (KGF-2) are ready for clinical trials. [ 1 ]


The  L. lactis  mechanism of microbial drug delivery described in the 2006 study of Braat  et al.  uses a form of recombinant  L. lactis  (LL-Thy12) which has replaced the gene, Thy12, with the gene for human IL-10. Removal of Thy12, which encodes for the production of  thymidine , causes  L. lactis  to become dependent on dietary thymidine to maintain live colonies in the gut. [ 2 ] [ 3 ]  The addition of the IL-10 gene allows for the production of human IL-10 to decreases gut inflammation. [ 3 ]   Secretion  of IL-10 from  L. lactis  in the gut is considered to be a topical administration of the drug to the epithelium, permitting healing in local tissues damaged by inflammation. [ 2 ] [ 3 ]  The administration of IL-10 topically avoids  systemic effects , such as  immunosuppression  in non-target tissues. [ 2 ]  When using LL-Thy12, IL-10 secretion is dependent on the quantity of live LL-Thy12 in the GI tract. As the presence of dietary thymidine increases the quantity of LL-Thy12, the drug production increases proportionately. Reductions in dietary thymidine kill LL-Thy12, decreasing the production of IL-10. [ 2 ] [ 3 ]  There is a delay of approximately 72-hours between a change in thymidine dosage and the production of IL-10. [ 1 ]  Due to LL-Thy12’s dependence on thymidine, they will die upon exiting the body through  defecation . [ 3 ]


B. ovatus  has been used in animal studies as a mode of microbial drug delivery due to its  xylanase   operon . [ 1 ]  Operons exist in bacteria to control  gene expression  and are composed of a DNA sequence containing an  operator  followed by the genes of interest. The operator in the xylanase operon prevents  transcription  of genes when bound to a  repressor protein . The  B. ovatus  xylanase operon only functions in the presence of the starch,  xylan , which removes the repressor and enables production of whichever proteins correlate with the genes located after the operator. [ 1 ]  For microbial drug delivery, the genes after the operator include those inserted as part of the genetic modification.  Xylan is non- digestible  to human  gastric acid  or  digestive enzymes , so a predictable quantity of dietary xylan will reach the recombinant  B. ovatus  in the gut, hypothetically allowing for a precise quantity of drug to be produced by the recombinant  B. ovatus . [ 1 ]  In  mice , recombinant  B. ovatus  strains containing genes for  growth factors  TGF-β and KGF-2 within the xylanase operon have successfully treated  ulcerative colitis  (UC). [ 1 ]  The secreted drugs from  B. ovatus  are applied topically to the epithelial lining, affecting local tissues rather than acting systemically. Systemic administration of these growth factors could otherwise cause  tumors  and increased  vascularization  of tissues. [ 1 ]  When administered microbially, TGF-β and KGF-2 facilitate tissue repair only in the colon where they are released. [ 1 ]


Safety is a major factor in the efficacy of microbial drug delivery. Depending on the type of drug being administered, a certain level of control is required for effective and safe treatment of colonic diseases. [ 1 ]  The  L. lactis  system has a 72-hour delay between ingesting thymidine and activating IL-10 production, while the  B. ovatus  system allows the drug to be produced once xylan reaches the bacteria. [ 1 ]  Regarding IL-10 secretions in  L. lactis , the delay is acceptable for treatment of IBD, [ 1 ] [ 2 ] [ 3 ]  however any drug that requires a precise dosage and timing may necessitate  B. ovatus  for controlling drug output. [ 1 ]


The safety of microbial drug delivery is tied to the microbes’ commensal capability and instance of  pathogenesis . A highly pathogenic microbe would not be suitable for medical treatment due to an inherent  infection  risk.  L. lactis  is considered by the  Food and Drug Administration  (FDA) to be  generally recognized as safe  (GRAS), [ 4 ]  as it is commonly found in widely consumed  dairy  products, suggesting its safety in medical treatment. [ 2 ] [ 3 ]   B. ovatus  is naturally found in 10% of healthy human  colons , [ 5 ]  demonstrating safety in its compatibility with the human gut microbiota; [ 1 ]  however,  Bacteroides  species are known in some cases to cause infections, typically resulting from  surgery in the GI tract . [ 5 ]


Concerns regarding the containment of recombinant microbes in the gut have been addressed through safety mechanisms in both  L. lactis  and  B. ovatus . [ 1 ] [ 2 ] [ 3 ]  Containment refers to the inability of microbes to colonize the external environment, where they may have unknown consequences. LL-Thy12 will die upon removal from the body, as they depend on dietary thymidine for survival. [ 2 ] [ 3 ]   B. ovatus  is naturally an  obligate anaerobe , so any recombinant strain is expected to die in the presence of oxygen once removed from the body. [ 1 ] [ 5 ]


Microneedles (MNs) are medical tools used for microneedling, primarily in drug delivery, disease diagnosis, and collagen induction therapy. Known for their minimally invasive and precise nature, MNs consist of arrays of micro-sized needles ranging from 25μm to 2000μm. Although the concept of microneedling was first introduced in the 1970s, its popularity has surged due to its effectiveness in drug delivery and its cosmetic benefits.


Since the 2000s, there has been discoveries on new fabrication materials of MNs, like silicon, metal and polymer. Alongside with materials, a variety of MNs types (solid, hollow, coated, hydrogel) has also been developed to possess different functions. The research on MNs has led to improvements in different aspects, including instruments and techniques, yet adverse events are possible in MNs users.


Microneedle patches  or  Microarray patches  are micron-scaled medical devices used to administer  vaccines , drugs, and other therapeutic agents. [ 2 ]  While  microneedles  were initially explored for  transdermal  drug delivery applications, their use has been extended for the intraocular, vaginal, transungual, cardiac, vascular, gastrointestinal, and intracochlear delivery of drugs. [ 3 ] [ 4 ] [ 5 ]  Microneedles are constructed through various methods, usually involving  photolithographic  processes or micromolding. [ 6 ]  These methods involve  etching  microscopic structure into resin or silicon in order to cast microneedles. Microneedles are made from a variety of material ranging from  silicon ,  titanium ,  stainless steel , and  polymers . [ 7 ] [ 1 ]  Some  microneedles  are made of a drug to be delivered to the body but are shaped into a needle so they will penetrate the skin. The microneedles range in size, shape, and function but are all used as an alternative to other delivery methods like the conventional  hypodermic needle  or other  injection  apparatus. Stimuli-responsive microneedles are advanced devices that respond to environmental triggers such as temperature, pH, or light to release therapeutic agents. [ 8 ]


Microneedles are usually applied through even single needle or small arrays. The arrays used are a collection of microneedles, ranging from only a few microneedles to several hundred, attached to an applicator, sometimes a patch or other solid stamping device. The arrays are applied to the skin of patients and are given time to allow for the effective administration of drugs. Microneedles are an easier method for physicians as they require less training to apply and because they are not as hazardous as other needles, making the administration of drugs to patients safer and less painful while also avoiding some of the drawbacks of using other forms of  drug delivery , such as risk of infection, production of hazardous waste, or cost. [ 9 ]


The concept of microneedles was first derived from the use of large hypodermic needles in the 1970s, [ 10 ]  but it only became prominent in the 1990s as microfabrication manufacturing technology developed. [ 10 ]  Later, the concept of MNs finally came into experimentation in 1994 when  Orentreich  discovered the insertion of tri-beveled needles to the skin could possibly stimulates the release of  fibrous strand. [ 10 ] [ 11 ]   The investigation on MNs’ potential to improve transdermal drug delivery gradually raised public awareness of MNs. [ 10 ]  Since then, there has been massive research conducted on MNs, contributing to the development of different materials, types, and fabrication methods of MNs. Application and adverse events are explored. [ 12 ]  In the 2000s, clinical trials on MNs’ use in drug delivery began. [ 12 ]


Microneedles were first mentioned in a 1998 paper by the research group headed by  Mark Prausnitz  at the  Georgia Institute of Technology  that demonstrated that microneedles could penetrate the uppermost layer ( stratum corneum ) of the  human skin  and were therefore suitable for the  transdermal delivery  of therapeutic agents. [ 13 ]  Subsequent research into microneedle drug delivery has explored the medical and cosmetic applications of this technology through its design. This early paper sought to explore the possibility of using microneedles in the future for vaccination. Since then researchers have studied microneedle delivery of  insulin ,  vaccines ,  anti-inflammatories , and other pharmaceuticals. In dermatology, microneedles are used for scarring treatment with skin rollers. As mentioned before, microneedles have also been explored for local targeted drug delivery at other  drug delivery  sites, such as the gastrointestinal, ocular, vascular etc., of which, ocular, vaginal and gastrointestinal have shown increasingnly convincing outcomes where they serve as a more efficient, localised drug delivery system, without the drawbacks of systemic exposure/toxicity. [ 14 ] [ 15 ] [ 16 ]


The major goal of any microneedle design is to penetrate the skin's outermost layer, the  stratum corneum  (10-15μm). [ 17 ]  Microneedles are long enough to cross the stratum corneum but not so long that they stimulate nerves which are located deeper in the tissues and therefore cause little to no pain. [ 13 ]


Research has shown that there is a limit on the type of drugs that can be delivered through intact skin. Only compounds with a relatively low molecular weight, like the common allergen nickel (130  Da ), [ 18 ]  can penetrate the skin. Compounds that weigh more than 500 Da cannot penetrate the skin. [ 17 ]


Microneedles (MNs) consist of micro-sized needles arrays that are made of various materials exhibiting different characteristics and are suitable in the synthesis of different types of MNs. The selection of materials for formation of MNs greatly depends on the strength of skin penetration, manufacturing method, and rate of drug release. [ 12 ]


Silicon  is the first material used for the production of MNs. [ 12 ]  While the flexible nature of silicon allows easy manufacture of different sizes and types of MNs, silicon MNs can easily fracture during insertion in the skin. [ 19 ]  On the contrary, MNs made of metals like  stainless steel ,  titanium , and  aluminum , are non-toxic and possess strong mechanical properties to penetrate the skin without breakage. [ 12 ] [ 19 ]  Nevertheless, metal MNs may cause allergic effects in some patients and it creates non-biodegradable wastes. [ 19 ] [ 20 ]


Polymer  is also regarded as a promising material for MNs due to its good  biocompatibility  and low toxicity. [ 12 ] [ 19 ]  Water-soluble polymers are more commonly used within the big polymer group and MNs tip breaking is more likely compared to MNs made of silicon and metal. [ 12 ] [ 19 ]  Therefore, polymer is a more suitable material for dissolving MNs or hydrogel-forming MNs.


Since their conceptualization in 1998, several advances have been made in terms of the variety of types of microneedles that can be fabricated. The 5 main types of microneedles are solid, hollow, coated, dissolvable/dissolving, and  hydrogel -forming. [ 2 ]  The distinct characteristic of each type of MNs allow a variety of clinical applications, including diagnosis and treatment. [ 12 ]


Micro-sized needles in a microneedles (MNs) device can be as short as 25μm or even 2000μm in length depending on their types. [ 12 ]


Solid MNs are the first type of MNs fabricated and are the most commonly used. [ 21 ]  Hard solid MNs have sharp tips that pierce through and form pores on the  stratum corneum . [ 12 ] [ 21 ]  A drug patch will then be applied to the skin for drug to be absorbed slowly and passively through numerous micropores. [ 21 ]


This type of array is designed as a two part system; the microneedle array is first applied to the skin to create microscopic wells just deep enough to penetrate the outermost layer of skin, and then the drug is applied via  transdermal patch . Solid microneedles are already used by dermatologists in  collagen induction therapy , a method which uses repeated puncturing of the skin with microneedles to induce the  expression  and deposition of the  proteins   collagen  and  elastin  in the  skin . [ 22 ]


Solid MNs help increase the permeability and absorption of drugs. [ 21 ]


Hollow MNs are designed with a hole at the tip and a hollow capacity that store drugs. [ 21 ]  Upon MNs insertion, stored drug is directly injected into the  dermis  and this effectively facilitates the absorption of either large-molecular or large-dosage drug. [ 12 ] [ 21 ]  Yet, a portion of the drug can be leaked or clogged and it may hinders the overall drug administration. [ 12 ]  Since the delivery of the drug depends on the flow rate of the microneedle, this type of array could become clogged by excessive swelling or flawed design. [ 17 ]  This design also increases the likelihood of buckling under the pressure and therefore failing to deliver any drugs.


Coated MNs are fabricated by coating drug solution over solid MNs and the thickness of the drug layer can be adjusted depending on the amount of drug to be administered. [ 12 ] [ 23 ]  A benefit of coated MNs is that less amount of drug is needed as compared to other drug administration route. [ 12 ] [ 21 ] [ 23 ]  This is because the layer of drug will quickly dissolve and delivered into the  systemic circulation  directly across the skin. [ 21 ] [ 23 ]  The solid MNs which are removed afterwards may be contaminated by left-over drugs and the reuse of those MNs raise the concern of  cross-infection  between patients. [ 12 ] [ 23 ]


Coated microneedles are often covered in other  surfactants  or thickening agents to assure that the drug is delivered properly. [ 17 ]  Some of the chemicals used on coated microneedles are known irritants. While there is risk of local inflammation to the area where the array was, the array can be removed immediately with no harm to the patient.


Dissolving MNs are mostly composed of water-soluble drugs that enable the dissolution of MN tips when inserted into skin. [ 12 ] [ 23 ] [ 1 ]  This is a one-step approach which does not require the removal of MNs and is convenient for long-term therapy. [ 12 ] [ 21 ]  However, incomplete insertion and delay dissolution is observed with the use of dissolving MNs. [ 21 ]


This polymer would allow the drug to be delivered into the skin and could be broken down once inside the body. Pharmaceutical companies and researchers have begun to study and implement polymers such as  Fibroin , a silk-based protein that can be molded into structures like microneedles and dissolved once in the body. [ 24 ]


The primary material for the fabrication of hydrogel-forming microneedles (HFMs) is  hydrophilic  polymer that encloses drugs. [ 21 ] [ 25 ]  This material draws water from  interstitial fluid  in the stratum corneum and results in  polymer  swelling and release of drug. [ 21 ] [ 25 ]  Besides, the hydrophilic features of HFMs allow readily uptake of interstitial fluid that could be used for disease diagnosis. [ 25 ]


The most abundant transdermal drug administration route currently is via  hypodermic needles ,  transdermal patches , and topical creams. [ 21 ]  However, these routes have limited therapeutic effects because stratum corneum serves as a barrier that reduces the entry of  drug molecules into the systemic circulation and target tissues. [ 21 ]  The invention of MNs have retained the benefits of both hypodermic needles and transdermal patches while minimizing their cons. [ 12 ] [ 26 ]


Compared to hypodermic needles, MNs provide a pain-free administration. [ 11 ] [ 12 ]  MNs are able to penetrate through the  epidermis , but not any deeper to compress on nerve-ends to produce pain responses. [ 11 ] [ 12 ]  The superficial penetration also lessen the infection risk. [ 27 ]


Compared to transdermal patches, MNs are proven to be effective in producing micropores on the epidermis. The micropores facilitate the absorption of large molecules, like  calcein  and  insulin , by 4 times via  in-vitro  skin models. [ 11 ]  In addition, MNs' direct drug delivery to systemic circulation avoided the first-pass effect in the liver. [ 27 ]  Significantly increasing the drug  bioavailability , and the fast absorption into the systemic circulation also allowed a fast onset of action. Therefore, MNs could benefit diabetes treatment as common oral delivery would lead to a significant loss of insulin from degradation in the liver ( first-pass effect ) and insulin molecules are too large to be absorbed using common transdermal patches. [ 27 ]


Furthermore, the high precision of MNs also allows drug reaching to localized tissues precisely, for instance, intradermal layers for cancer or the eye for ophthalmic disorder. [ 26 ]


MNs are suitable for vaccination with their capability to deliver macromolecules and maintain a slow and sustained release of vaccine agents by using both coated and dissolving MNs. [ 26 ]  In addition, MNs' biodegradability minimizes biohazardous waste, unlike hypodermic needles. [ 12 ] [ 26 ]  The application of MNs in vaccination would benefit people who avoid vaccination due to  trypanophobia  (fear of needles in medical settings). [ 26 ] As of 2024, it has been found to generate an immune response similar to injection of measles and rubella vaccine. [ 28 ]


Disease diagnosis and monitoring of  therapeutic efficacy  is possible by detecting several  biomarkers  in body fluid. However, current tissue fluid extraction methods are pain-inducing, and it may take up to hours or days for samples to be analyzed in medical laboratories. [ 12 ]  MNs could collect body fluid in an almost painless manner, and it could provide immediate diagnosis when combined with a sensor.


MNs allow penetration through the epidermis but not long enough to compress nerves in deeper layers, and thus, they are minimally invasive and almost painless. MNs' precision also allow the extraction of fluid surrounding diseased tissues, which may contain higher concentration of different biomarkers and specific biomarkers that are not present in the systemic circulation. [ 29 ]  These fluids provide more clinically significant and accurate values than those extracted from the systemic circulation, subsequently lowering the chances of underestimation of disease severity, especially for localized diseases. [ 29 ]


Furthermore, MNs are capable of providing (near) real-time diagnosis, and it is easily administrated with simple procedures. [ 30 ]  Thus, MNs are potential candidates for  Point-of-care (PoC) testing  which could be conducted bedside. [ 30 ]


Hollow MNs and hydrogel MNs could be used to diagnose and monitor several diseases including  Cataracts ,  Diabetes ,  Cancer , and  Alzheimer’s disease . [ 12 ] [ 29 ]  For instance, hollow glass MNs and hydrogel MNs could extract skin interstitial fluid for the detection of glucose levels. [ 12 ] [ 29 ]


In the field of  dermatology , MNs are more commonly known as collagen induction therapy. The therapy induces dermis regeneration via repetitive perforation of the skin using sterilized MNs. [ 31 ]  The repetitive penetration through the stratum corneum forms micropores, and these physical traumas to the skin sequentially stimulate the  wound-healing  cascade and expression of  collagen  and  elastin  in the  dermis . [ 31 ]


By making use of the human natural regeneration properties, microneedling could be used alone to treat scars, wrinkles, and skin  rejuvenation , or in combination therapy with topical  tretinoin  and  vitamin C  for enhanced effect. [ 11 ] [ 31 ]  Recent research has expanded the possibilities of MNs to treat  pigmentation disorder ,  actinic keratosis , and promote hair growth in patients of  androgenetic alopecia  and  alopecia areata . [ 11 ] [ 31 ] [ 32 ]


MNs have been diverged into different forms, including Dermapen and Dermarollers. Dermarollers are hand-held rollers equipped with a total of 192 solid steel micro-sized needles arranged into 24 arrays, lengths ranging from 0.5-1.5mm. [ 31 ] [ 33 ]  With the growing popularity of microneedling, MNs have also been commodified into home care Dermarollers, which are similar to medical dermarollers, except that the needles are shorter (0.15mm). [ 33 ]  This is a more budget-friendly device that allows individuals to perform microneedling at home.


There are many advantages to the use of microneedles, the most prominent being the improved comfort of patients.  Needle phobia  can affect both adults and children, and sometimes can lead to fainting. The benefit of microneedle arrays is that they reduce anxiety that patients have when confronted with a hypodermic needle. In addition to improving psychological and emotional comfort, microneedles have been shown to be substantially less painful than conventional injections. [ 17 ]  Some studies recorded children's views on blood sampling with microneedles and found patients were more willing when prompted with a less painful procedure than traditional sampling with needles. Microneedles are beneficial to physicians as well, since they produce less hazardous waste than needles and are generally easier to use. Microneedles are also less expensive than needles as they require less material and the material used is cheaper than the materials in hypodermic needles.


Microneedles present a new opportunity for home and community-based healthcare. One of the biggest drawbacks of traditional needles is the hazardous waste that they produce, making disposal a serious concern for doctors and hospitals. For patients who require regular administration of medication at home, disposal can become an environmental concern is needles are placed in the trash. Dissolvable or swelling microneedles would provide those who are limited in their ability to seek hospital care with the ability to safely administer drugs in the comfort of their homes, although disposal of solid or hollow microneedles could still pose a  needle-stick  or  blood borne pathogen  infection risk. [ 1 ]


Another benefit of microneedles is their lower rates of  microbial  invasion into delivery sites. [ 1 ] [ 17 ]  Traditional injection methods can leave puncture wounds for up to 48 hours post-treatment. This leaves a large window of opportunity for harmful bacteria to enter into the skin. Microneedles only damage the skin to a depth of 10-15μm, making it difficult for bacteria to enter the bloodstream and giving the body a smaller wound to repair. [ 6 ]  Further research is required to determine the types of bacteria able to breach the shallow puncture site of microneedles.


There are some concerns about how physicians can be sure that all of the drug or vaccine has entered the skin when microneedles are applied. Hollow and coated microneedles both possess the risk that the drug will not properly enter the skin and will not be effective. Both of these types of microneedles can leak [ 34 ] [ 17 ]  onto a person's skin either by damage of the microneedle or incorrect application by the physician. This is why it is essential that physicians are trained how to properly apply the arrays.


Another concern is that incorrectly applied arrays could leave foreign material in the body. Although there is a lower risk of infection associated with microneedles, the arrays are more fragile than a typical hypodermic needle due to their small size and thus have a chance of breaking off and remaining in the skin. Some of the material used to construct the microneedles, such as titanium, cannot be absorbed by the body and any fragments of the needles would cause irritation.


There is a limited amount of literature available on the subject of microneedle drug delivery, as current research is still exploring how to make effective needles. In terms of design and manufacture, low drug loading is a key barrier towards reaching the clinics. [ 35 ]


Apart from procedural pain, some common post-treatment  adverse events  (AEs) of MNs include temporary discomfort,  erythema  (skin redness), and  edema . [ 11 ] [ 36 ]  Pinpoint bleeding, itching, irritation, and bruising are also possible in some cases. [ 11 ] [ 36 ]  However, most of the adverse side effects are not long-lasting and could be resolved spontaneously within 24 hours after the treatment, making MNs a rather safe tool. [ 36 ] [ 37 ]  Photoprotection and minimal exposure to chemicals irritants  are often advised for an effective recovery and lowered chance of skin inflammation. [ 36 ]


Severe risks may be possible if there are technical errors during the procedure. For example, the usage of non-sterile tools might result in post-inflammatory  hyperpigmentation , systemic  hypersensitivity , local infections, etc. [ 11 ]  Moreover, if excess pressure is used over a bony prominence, it could lead to “Tram-track scarring”. [ 36 ]  But this could be avoided by using smaller needles and prevent over-pressurizing on top of these areas. [ 36 ]  In addition, if the patient is allergic to the either the drug used or the material of MNs,  contact dermatitis  is possible. [ 11 ]  Therefore, clinicians should be cautious towards patients with high risks of allergy. [ 37 ]


Molecule-based magnets  ( MBMs ) or  molecular magnets  are a class of materials capable of displaying  ferromagnetism  and other more complex magnetic phenomena. This class expands the materials properties typically associated with magnets to include low density,  transparency ,  electrical insulation , and low-temperature fabrication, as well as combine magnetic ordering with other properties such as  photoresponsiveness . Essentially all of the common magnetic phenomena associated with conventional transition-metal magnets and  rare-earth magnets  can be found in molecule-based magnets. [ 1 ] [ 2 ]  Prior to 2011, MBMs were seen to exhibit "magnetic ordering with  Curie temperature  (T c ) exceeding room temperature". [ 2 ] [ 3 ]


The first synthesis and characterization of MBMs was accomplished by Wickman and co-workers in 1967. This was a diethyldithiocarbamate-Fe(III) chloride compound. [ 4 ] [ 5 ]


In February 1992, Gatteschi and  Sessoli  published on MBMs with particular attention to the fabrication of systems in which stable  organic radicals  are coupled to  metal ions . [ 6 ]  At that date, the highest Tc on record was measured by  SQUID magnetometer  as 30K. [ 7 ]


The field exploded in 1996 with the publication of the book "Molecular Magnetism: From Molecular Assemblies to the Devices". [ 8 ]


In February 2007, de Jong et al. grew thin-film  TCNE  MBM in situ, [ 9 ]  while in September 2007, photoinduced magnetism was demonstrated in a TCNE organic-based magnetic semiconductor. [ 10 ]


The June 2011 issue of  Chemical Society Reviews  was devoted to MBMs. In the editorial, written by Miller and Gatteschi, are mentioned  TCNE  and above-room-temperature magnetic ordering along with many other unusual properties of MBMs. [ 2 ]


The mechanism by which molecule-based magnets stabilize and display a net magnetic moment is different than that present in traditional metal- and ceramic-based magnets. For metallic magnets, the unpaired electrons align through  quantum mechanical  effects (termed exchange) by virtue of the way in which the electrons fill the orbitals of the  conductive band . For most oxide-based ceramic magnets, the unpaired electrons on the metal centers align via the intervening  diamagnetic  bridging oxide (termed  superexchange ). The magnetic moment in molecule-based magnets is typically stabilized by one or more of three main mechanisms: [ citation needed ]


In general, molecule-based magnets tend to be of low dimensionality. Classic magnetic alloys based on iron and other ferromagnetic materials feature  metallic bonding , with all atoms essentially bonded to all nearest neighbors in the  crystal lattice . Thus, critical temperatures at which point these classical magnets cross over to the ordered magnetic state tend to be high, since interactions between spin centers is strong. Molecule-based magnets, however, have spin bearing units on molecular entities, often with highly directional bonding. In some cases, chemical bonding is restricted to one dimension (chains). Thus, interactions between spin centers are also limited to one dimension, and ordering temperatures are much lower than metal/alloy-type magnets. Also, large parts of the magnetic material are essentially diamagnetic, and contribute nothing to the net magnetic moment. [ citation needed ]


In 2015  oxo-dimeric   Fe(salen) -based magnets ("anticancer nanomagnets") in a water suspension were shown to demonstrate intrinsic room temperature ferromagnetic behavior, as well as antitumor activity, with possible medical applications in  chemotherapy , [ 11 ] [ 12 ] [ 13 ] [ 14 ]   magnetic drug delivery ,  magnetic resonance imaging  (MRI), and magnetic field-induced local  hyperthermia therapy .


Molecule-based magnets comprise a class of materials which differ from conventional magnets in one of several ways. Most traditional magnetic materials are comprised purely of metals (Fe, Co, Ni) or metal oxides (CrO 2 ) in which the unpaired electrons spins that contribute to the net  magnetic moment  reside only on metal atoms in d- or f-type orbitals. [ citation needed ]


In molecule-based magnets, the structural building blocks are molecular in nature. These building blocks are either purely  organic molecules ,  coordination compounds  or a combination of both. In this case, the unpaired electrons may reside in d or f orbitals on isolated metal atoms, but may also reside in highly localized s and p orbitals as well on the purely organic species. Like conventional magnets, they may be classified as hard or soft, depending on the magnitude of the  coercive field . [ citation needed ]


Another distinguishing feature is that molecule-based magnets are prepared via low-temperature solution-based techniques, versus high-temperature metallurgical processing or electroplating (in the case of  magnetic thin films ). This enables a chemical tailoring of the molecular building blocks to tune the magnetic properties. [ citation needed ]


Specific materials include purely organic magnets made of organic radicals for example p-nitrophenyl nitronyl nitroxides, [ 15 ]  decamethylferrocenium tetracyanoethenide, [ 16 ]  mixed coordination compounds with bridging organic radicals, [ 17 ]   Prussian blue  related compounds, [ 18 ]  and  charge-transfer complexes . [ 19 ]


Molecule-based magnets derive their net moment from the cooperative effect of the spin-bearing molecular entities, and can display bulk  ferromagnetic  and  ferrimagnetic  behavior with a true  critical temperature . In this regard, they are contrasted with  single-molecule magnets , which are essentially superparamagnets (displaying a blocking temperature versus a true critical temperature). This  critical temperature  represents the point at which the materials switches from a simple paramagnet to a bulk magnet, and can be detected by ac susceptibility and  specific heat  measurements. [ citation needed ]


Mouthwash ,  mouth rinse ,  oral rinse , or  mouth bath [ 1 ]  is a liquid which is held in the mouth passively or swirled around the mouth by contraction of the perioral muscles and/or movement of the head, and may be  gargled , where the head is tilted back and the liquid bubbled at the back of the mouth.


Usually mouthwashes are  antiseptic  solutions intended to reduce the microbial load in the mouth, although other mouthwashes might be given for other reasons such as for their  analgesic ,  anti-inflammatory  or  anti-fungal  action. Additionally, some rinses act as saliva substitutes to neutralize acid and keep the mouth moist in  xerostomia  (dry mouth). [ 2 ] [ 3 ]  Cosmetic mouthrinses temporarily control or reduce bad breath and leave the mouth with a pleasant taste. [ 4 ]


Rinsing with water or mouthwash after brushing with a  fluoride toothpaste  can reduce the availability of salivary fluoride. This can lower the anti-cavity re-mineralization and antibacterial effects of fluoride. [ 5 ] [ 6 ] [ 7 ]  Fluoridated mouthwash may mitigate this effect or in high concentrations increase available fluoride, but is not as cost-effective as leaving the fluoride toothpaste on the teeth after brushing. [ 5 ]  A group of experts discussing post brushing rinsing in 2012 found that although there was clear guidance given in many public health advice publications to "spit, avoid rinsing with water/excessive rinsing with water" [ 8 ]  they believed there was a limited evidence base for best practice. [ 9 ]


Common use involves rinsing the mouth with about  20–50  ml   (0.7–1.7  US fl oz )  of mouthwash. The wash is typically swished or gargled for about half a minute and then spat out. Most companies suggest not drinking water immediately after using mouthwash. In some brands, the  expectorate  is stained, so that one can see the bacteria and debris. [ 10 ] [ 11 ] [ 12 ]
Mouthwash should not be used immediately after brushing the teeth so as not to wash away the beneficial fluoride residue left from the toothpaste. Similarly, the mouth should not be rinsed out with water after brushing. Patients were told to "spit don't rinse" after toothbrushing as part of a  National Health Service  campaign in the UK. [ 13 ]  A fluoride mouthrinse can be used at a different time of the day to brushing. [ 8 ]


Gargling is where the head is tilted back, allowing the mouthwash to sit in the back of the mouth while exhaling, causing the liquid to bubble. Gargling is practiced in Japan for perceived prevention of viral infection. One commonly used way is with  infusions  or  tea . In some cultures, gargling is usually done in private, typically in a  bathroom  at a sink so the liquid can be rinsed away. [ 14 ]


Serious harm and even death can quickly result from ingestion due to the high alcohol content and other substances harmful to ingestion present in some brands of mouthwash. [ 15 ]  Zero percent alcohol mouthwashes do exist, as well as many other formulations for different needs (covered in the above sections).


These risks may be higher in toddlers and young children if they are allowed to use toothpaste and/or mouthwash unsupervised, where they may swallow it. Misuse in this way can be avoided with parental admission or supervision and by using child-safe forms or a children's brand of mouthwash.


Surrogate alcohol  use such as ingestion of mouthwash is a common cause of death among homeless people during winter months, because a person can feel warmer after drinking it. [ 16 ]


The most-commonly-used mouthwashes are commercial antiseptics, which are used at home as part of an  oral hygiene  routine. Mouthwashes combine ingredients to treat a variety of oral conditions. Variations are common, and mouthwash has no standard formulation, so its use and recommendation involves concerns about  patient safety . Some manufacturers of mouthwash state that their antiseptic and antiplaque mouthwashes kill the  bacterial plaque  that causes  cavities ,  gingivitis , and  bad breath . It is, however, generally agreed that the use of mouthwash does not eliminate the need for both  brushing  and  flossing . [ 17 ] [ 18 ] [ 19 ]  The  American Dental Association  asserts that regular brushing and proper flossing are enough in most cases, in addition to regular dental check-ups, although they approve many mouthwashes. [ 20 ]
For many patients, however, the mechanical methods could be tedious and time-consuming, and, additionally, some local conditions may render them especially difficult. Chemotherapeutic agents, including mouthwashes, could have a key role as adjuncts to daily home care, preventing and controlling supragingival plaque, gingivitis and oral malodor. [ 21 ]


Minor and transient side effects of mouthwashes are very common, such as  taste disturbance , tooth staining,  sensation of a dry mouth , etc. Alcohol-containing mouthwashes may make dry mouth and halitosis worse, as they dry out the mouth. [ 22 ] [ 23 ]  Soreness, ulceration and redness may sometimes occur (e.g.,  aphthous stomatitis  or  allergic contact stomatitis ) if the person is allergic or sensitive to mouthwash ingredients, such as preservatives, coloring, flavors and fragrances. Such effects might be reduced or eliminated by diluting the mouthwash with water, using a different mouthwash (e.g. saltwater), or foregoing mouthwash entirely.


Prescription mouthwashes are used prior to and after oral surgery procedures, such as  tooth extraction , or to treat the pain associated with  mucositis  caused by  radiation therapy  or  chemotherapy . They are also prescribed for  aphthous ulcers , other  oral ulcers , and other mouth pain. [ 24 ]  "Magic mouthwashes" are prescription mouthwashes  compounded  in a  pharmacy  from a list of ingredients specified by a doctor. [ 25 ] [ 26 ]  Despite a lack of evidence that prescription mouthwashes are more effective in decreasing the pain of oral  lesions , many patients and prescribers continue to use them. There has been only one  controlled study  to evaluate the  efficacy  of magic mouthwash; it shows no difference in efficacy between the most common magic-mouthwash formulation, on the one hand, and commercial mouthwashes (such as  chlorhexidine ) or a  saline / baking soda  solution, on the other. Current guidelines suggest that saline solution is just as effective as magic mouthwash in pain relief and in shortening the healing time of oral mucositis from cancer therapies. [ 24 ]


The first known references to mouth rinsing is in  Ayurveda [ 27 ]  for treatment of gingivitis. [ 28 ]  Later, in the  Greek  and  Roman  periods, mouth rinsing following mechanical cleansing became common among the upper classes, and  Hippocrates  recommended a mixture of salt,  alum , and vinegar. [ 29 ]  The Jewish  Talmud , dating back about 1,800 years, suggests a cure for gum ailments containing "dough water" and olive oil. [ 30 ]  The ancient Chinese had also gargled salt water, tea and wine as a form of mouthwash after meals, due to the antiseptic properties of those liquids. [ 31 ]


Before Europeans came to the Americas, Native North American and Mesoamerican cultures used mouthwashes, often made from plants such as  Coptis trifolia . [ 32 ]  Peoples of the Americas used salt water mouthwashes for sore throats, and other mouthwashes for problems such as  teething  and mouth ulcers. [ 32 ]


Anton van Leeuwenhoek , the famous 17th century  microscopist , discovered living organisms (living, because they were mobile) in deposits on the teeth (what we now call  dental plaque ). He also found organisms in water from the canal next to his home in Delft. He experimented with samples by adding vinegar or brandy and found that this resulted in the immediate immobilization or killing of the organisms suspended in water. Next he tried rinsing the mouth of himself and somebody else with a mouthwash containing vinegar or brandy and found that living organisms remained in the dental plaque. He concluded—correctly—that the mouthwash either did not reach, or was not present long enough, to kill the plaque organisms. [ 33 ]
In 1892, German  Richard Seifert  invented mouthwash product  Odol , which was produced by company founder  Karl August Lingner  (1861–1916) in  Dresden . [ 34 ]


That remained the state of affairs until the late 1960s when Harald Loe (at the time a professor at the  Royal Dental College  in  Aarhus , Denmark) demonstrated that a  chlorhexidine  compound could prevent the build-up of dental plaque. The reason for chlorhexidine's effectiveness is that it strongly adheres to surfaces in the mouth and thus remains present in effective concentrations for many hours. [ 35 ]


Since then commercial interest in mouthwashes has been intense and several newer products claim effectiveness in reducing the build-up in dental plaque and the associated severity of gingivitis, in addition to fighting bad breath. Many of these solutions aim to control the volatile sulfur compound–creating anaerobic bacteria that live in the mouth and excrete substances that lead to bad breath and unpleasant mouth taste. [ 11 ] [ 10 ] [ 36 ] [ 37 ] [ 38 ]  For example, the number of mouthwash variants in the United States of America has grown from 15 (1970) to 66 (1998) to 113 (2012). [ 39 ]


Research in the field of  microbiotas  shows that only a limited set of microbes cause tooth decay, with most of the bacteria in the human mouth being harmless. Focused attention on cavity-causing bacteria such as  Streptococcus mutans  has led research into new mouthwash treatments that prevent these bacteria from initially growing. While current mouthwash treatments must be used with a degree of frequency to prevent this bacteria from regrowing, future treatments could provide a viable long-term solution. [ 40 ]


A clinical trial and laboratory studies have shown that alcohol-containing mouthwash could reduce the growth of  Neisseria gonorrhoeae  in the pharynx. [ 41 ] [ 42 ]  However, subsequent trials have found that there was no difference in gonorrhoea cases among men using daily mouthwash compared to those who did not use mouthwash for 12 weeks. [ 43 ] [ 44 ]


Alcohol is added to mouthwash not to destroy bacteria but to act as a carrier agent for essential active ingredients such as menthol, eucalyptol and thymol, which help to penetrate plaque. [ 45 ]  Sometimes a significant amount of  alcohol  (up to 27% vol) is added, [ 46 ]  as a carrier for the  flavor , to provide "bite". [ 47 ] [ unreliable medical source? ]  Because of the alcohol content, it is possible to fail a  breathalyzer  test after rinsing, although breath alcohol levels return to normal after 10 minutes. [ 48 ]  In addition, alcohol is a  drying agent , which encourages bacterial activity in the mouth, releasing more malodorous volatile sulfur compounds. Therefore, alcohol-containing mouthwash may temporarily worsen  halitosis  in those who already have it, or, indeed, be the sole cause of halitosis in other individuals. [ 49 ]  Alcohol in mouthwashes may act as a  carcinogen  (cancer-inducing agent) in some cases  (see:  Oral cancer § Alcohol ) . [ 50 ]  Many newer brands of mouthwash are alcohol-free, not just in response to consumer concerns about oral cancer, but also to cater for religious groups who abstain from alcohol consumption.


In painful oral conditions such as  aphthous stomatitis , analgesic mouthrinses (e.g.  benzydamine  mouthwash, or "Difflam") are sometimes used to ease pain, commonly used before meals to reduce discomfort while eating.


Benzoic acid  acts as a buffer. [ 45 ]


Betamethasone  is sometimes used as an anti-inflammatory, corticosteroid mouthwash. It may be used for severe inflammatory conditions of the oral mucosa such as the severe forms of aphthous stomatitis. [ 51 ] : 209


Cetylpyridinium chloride  containing mouthwash (e.g. 0.05%) is used in some specialized mouthwashes for halitosis. [ 52 ]  Cetylpyridinium chloride mouthwash has less anti-plaque effect than chlorhexidine and may cause staining of teeth, or sometimes an oral burning sensation or  ulceration . [ 53 ]


Chlorhexidine digluconate  is a chemical antiseptic and is used in a 0.05–0.2% solution as a mouthwash. [ 54 ] [ 11 ] [ 45 ] [ 55 ]  There is no evidence to support that higher concentrations are more effective in controlling dental plaque and gingivitis. [ 56 ]  A randomized clinical trial conducted in Rabat University in  Morocco  found better results in  plaque  inhibition when chlorohexidine with alcohol base 0.12% was used, when compared to an alcohol-free 0.1% chlorhexidine mouthrinse. [ 57 ]


Chlorhexidine has good  substantivity  (the ability of a mouthwash to bind to hard and soft tissues in the mouth). [ 53 ]  It has anti-plaque action, and also some anti-fungal action. [ 53 ]  It is especially effective against Gram-negative  rods . [ 53 ]  The proportion of  Gram-negative  rods increase as  gingivitis  develops, so it is also used to reduce gingivitis. [ 56 ] [ 58 ]  It is sometimes used as an adjunct to prevent dental caries and to treat  periodontal disease , [ 53 ]  although it does not penetrate into periodontal pockets well. [ 59 ]  Chlorhexidine mouthwash alone is unable to prevent plaque, so it is not a substitute for regular toothbrushing and flossing. [ 59 ]  Instead, chlorhexidine mouthwash is more effective when used as an adjunctive treatment with toothbrushing and flossing. [ 56 ]  In the short term, if toothbrushing is impossible due to pain, as may occur in  primary herpetic gingivostomatitis , chlorhexidine mouthwash is used as a temporary substitute for other oral hygiene measures. [ 59 ]  It is not suited for use in  acute necrotizing ulcerative gingivitis , however. [ 59 ]  Rinsing with  chlorhexidine  mouthwash before and after a tooth extraction may reduce the risk of a  dry socket . [ 60 ]  Other uses of chlorhexidine mouthwash include prevention of oral candidiasis in  immunocompromised  persons, [ 59 ]  treatment of  denture-related stomatitis , mucosal ulceration/erosions and  oral mucosal  lesions, general burning sensation [ 56 ]  and many other uses. [ 59 ]


Chlorhexidine mouthwash is known to have minor adverse effects. [ 60 ]  Chlorhexidine binds to  tannins , meaning that prolonged use in persons who consume coffee, tea or red wine is associated with extrinsic staining (i.e. removable staining) of teeth. [ 53 ]  A systematic review of commercial chlorhexidine products with anti-discoloration systems (ADSs) found that the ADSs were able to reduce tooth staining without affecting the beneficial effects of chlorhexidine. [ 61 ]  Chlorhexidine mouthwash can also cause taste disturbance or alteration. [ 56 ]  Chlorhexidine is rarely associated with other issues like overgrowth of enterobacteria in persons with  leukemia , desquamation, irritation, and  stomatitis  of oral mucosa, [ 53 ] [ 60 ]  salivary gland pain and swelling, and hypersensitivity reactions including anaphylaxis. [ 53 ]


Hexetidine [ 45 ]  also has anti-plaque, analgesic, astringent and anti-malodor properties, but is considered an inferior alternative to chlorhexidine. [ 62 ]


In dilute concentrations,  chlorine dioxide  is an ingredient that acts as an antiseptic agent in some mouthwashes. [ 63 ] [ 64 ]


In traditional  Ayurvedic medicine , the use of oil mouthwashes is called "Kavala" ("oil swishing") or "Gandusha", [ 27 ] [ 65 ]  and this practice has more recently been re-marketed by the  complementary and alternative medicine  industry as " oil pulling ". [ 27 ]  Its promoters claim it works by "pulling out" "toxins", which are known as  ama  in Ayurvedic medicine, and thereby reducing  inflammation . [ 66 ]  Ayurvedic literature claims that oil pulling is capable of improving oral and systemic health, including a benefit in conditions such as  headaches ,  migraines ,  diabetes mellitus ,  asthma , [ 27 ]  and  acne , as well as  whitening teeth . [ 67 ]


Oil pulling has received little study and there is little evidence to support claims made by the technique's advocates. [ 65 ]  When compared with chlorhexidine in one small study, it was found to be less effective at reducing oral bacterial load, [ 68 ] [ 69 ]  and the other health claims of oil pulling have failed scientific verification [ 65 ]  or have not been investigated. [ 65 ]  There is a report of  lipid pneumonia  caused by accidental inhalation of the oil during oil pulling. [ 70 ] [ 71 ] [ 72 ]


The mouth is rinsed with approximately one tablespoon of oil for 10–20 minutes then spat out. [ 65 ] [ 67 ]   Sesame oil ,  coconut oil  and  ghee  are traditionally used, [ 67 ]  but newer oils such as  sunflower oil  are also used. [ 67 ]