Injector pens are an alternative to the manufacture of medication for injection in vials containing either liquid or a powder to which a  diluent  such as sterile water is added. When a vial is used as a means of storage, the end-user must use a syringe to "draw up" or remove the medication from the vial to prepare it for administration. The end user must then perform a series of actions to insert the needle of the syringe under the skin, and depress the plunger on the syringe to inject the dose. This requires dexterity which may make it difficult to accurately or completely administer the appropriate doses of medications. [ 2 ]  Injector pens remove some of the complications of syringes by allowing the pen to be "pushed" against the skin at a 90-degree angle (removing the need to inject at a proper angle as is the case with syringes), as well as by replacing a long, thin plunger of a syringe with a simple button which is depressed and held to inject the dose. [ 2 ]


Many  insulin analogs  and  GLP-1 agonists  for diabetes treatment are available as injector pens. [ 2 ]  As with insulin vials, some insulin pens are made with higher concentrations including U-200, U-300, and U-500. Different concentration insulin products may not have the same  pharmacokinetic  properties as other strengths. [ 10 ]  The higher concentrations are used to lessen the volume of the injection, and allow the same dose of insulin to be injected with less force. [ 10 ]  In some cases, these medications may be combined into one pen to be administered daily, for example  insulin degludec with liraglutide [ 6 ]  and  insulin glargine with lixisenatide . [ 11 ]  Combination products are available in fixed-dose ratios and are generally dosed by units of insulin, which will administer a proportional amount of the GLP-1 agonist as well. [ 12 ]


Another class of medication commonly available as an injector pen is  monoclonal antibodies . Due to the molecular size of monoclonal antibodies, they must be administered via injection. Examples of monoclonal antibodies available or studied as injector pens include  adalimumab , [ 13 ]   secukinumab , [ 14 ]  and  alirocumab . [ 15 ]   CGRP antagonists  which are monoclonal antibodies, used for the prevention of migraines, are also available as injector pens. [ 16 ]  Other monoclonal antibodies designed for home use may also be manufactured as injector pens. [ 17 ] [ 18 ]


Some medications are formulated as injector pens to quicken the onset of action of the medication. This includes  epinephrine , which when used to treat  anaphylaxis  must work as soon as possible. [ 19 ]  Contrary to most other injector pens, epinephrine injector pens are designed to administer the medication via  intramuscular injection . [ 19 ]  Another medication formulated as an injector pen to ensure quick onset of action is  glucagon  for hypoglycemia. [ 20 ]  Other medications normally administered orally are also available or have been studied as injector pens, either due to different  pharmacokinetic  properties when administered via injection, or for those who cannot take oral medications. This includes  methotrexate  for  juvenile idiopathic arthritis [ 21 ]  and  sumatriptan  for treatment of migraines. [ 22 ]


Most injector pens are designed for subcutaneous injection just under the skin, but some are designed for injection into muscle. The desired injection site and the skin profile at the injection site will determine what needle length is appropriate for a person to use. [ 23 ]  For products with included needles, such as epinephrine pens, different brands may have different included needle lengths, which must be taken into account. [ 19 ]


Multiple studies have shown that many people prefer the use of injector pens over other forms of injectable medication, such as vial and syringe. [ 2 ]  Injector pens in general have also been shown to be at least as effective therapeutically as other injection methods. [ 2 ]  One study of the use of injector pens for insulin administration found that the chance a person initiated on insulin continued therapy for at least 12 months was higher with insulin pens than with vial and syringe administration. [ 2 ]  The same study found that the increase in adherence to therapy resulted in increased short-term pharmacy costs (i.e. for the pens/needles) but resulted in an overall decrease in healthcare costs related to diabetes. [ 2 ]  Insulin pens have also been shown to provide a higher quality of life than traditional injection methods. [ 2 ]  A 2011 systematic review which examined preference of insulin pens over vial and syringe administration found that in almost all studies and surveys a majority of people preferred insulin pens. [ 24 ]


The effectiveness of an injector pen can also depend on the technique used to inject. After fully pressing the plunger button to activate the pen, the button must continue to be held for about 10 seconds to ensure the dose is administered before removing the pen needle from the skin and finally releasing the button. [ 23 ]  Failure to use the pen as instructed may result in medication leakage and administration of a lower dose than was intended. [ 23 ]  Another administration problem which may impact effectiveness of an injector pen is  lipohypertrophy  of the subcutaneous tissue near the injection site. For this reason, it is recommended to rotate the injection site every administration. [ 23 ]


The first injector pen was introduced in 1985, by  Novo Nordisk  to administer insulin products. [ 25 ]  After their introduction, insulin pens had a slow adoption in the United States, with only 2% of insulin being injected via pen in 1999. A major barrier to adoption in the United States was the increased up-front cost of insulin pens compared to traditional injections. [ 26 ]  Pen adoption in the United States accelerated after studies showed that the higher up-front cost of insulin pens was offset by the increase in compliance, which decreased overall healthcare costs. [ 27 ]  Historically, pen needles were manufactured in lengths up to 12.7mm. Over time, pen needles designed for insulin pens have become shorter, and a 4mm long needle is considered sufficient for most people to administer subcutaneously correctly. [ 23 ]


In 1989, an injector pen form of  human growth hormone  was licensed in New Zealand. [ 28 ]  In the US, a pen form of  octreotide  was approved by the FDA in 2020, under the brand name  Bynfezia . [ 29 ]


Intranasal drug delivery  occurs when particles are inhaled into the nasal cavity and transported directly into the nervous system. Though pharmaceuticals can be injected into the nose, some concerns include injuries, infection, and safe disposal. Studies demonstrate improved  patient compliance  with inhalation. Treating brain diseases has been a challenge due to the  blood brain barrier . Previous studies evaluated the efficacy of delivery therapeutics through intranasal route for brain diseases and mental health conditions. Intranasal administration is a potential route associated with high drug transfer from nose to brain and drug  bioavailability . [ 1 ]


Drug delivery  is a process of administering therapeutics to treat human diseases. The first drug delivery system is often dated to the 1950s, when Smith Kline & French Laboratories introduced the Spansule technology. [ 2 ]  Between 1950s and 1980s, there were four drug release systems developed for oral and transdermal applications: dissolution, diffusion, osmosis, and ion-exchange controlled release. [ 3 ]  Later in the 1980s, the  Lupron Depot  technology further advanced the field by offering zero-order and long-term release systems. The intranasal route gained interest towards the end of the 20th century with treating cardiovascular and respiratory diseases. During the late 1980s, William Frey II studied the intranasal route for treating brain diseases. Ever since, it has become a potential route for nose-to-brain delivery. [ medical citation needed ] [ 4 ]


The nasal cavity is highly vascularized, allowing efficient transfer of molecules directly to the nervous system. Compared to other administration routes, nasal drug delivery increases bioavailability and reduces systemic exposure risks. The nasal cavity’s slightly acidic environment and enzymes can affect drug degradation, making delivery systems with neutral to acidic pH ideal. The respiratory region, with its large surface area and high vascularization, is the primary site for drug absorption into systemic circulation. Targeting the olfactory region enhances nose-to-brain drug delivery, as particles can travel via the olfactory nerve to the brain. This route offers potential for treating brain diseases and mental health conditions. [ 5 ]


The blood-brain barrier (BBB) is a semipermeable membrane that separates the blood from the brain’s interstitial fluid. It is formed by tight junctions between endothelial cells, astrocytes, and pericytes in the brain’s capillaries, and has high electrical resistance. The BBB is crucial for protecting the brain from pathogens and toxic substances, maintaining homeostasis, and preventing alterations to neuronal functions. However, some diseases can damage the BBB, causing leakage. Research suggests that increasing intake of vitamins and antioxidants, as well as reducing stress, can help restore the BBB. Due to its selective nature, the BBB restricts the passive diffusion of solutes, large and hydrophilic molecules, and immune factors, making it challenging to deliver pharmaceuticals directly to the brain. [ 6 ]


Neurodegenerative diseases  occur from loss of neuronal structure and function. This progressive degeneration of neurons is irreversible.  Alzheimer's  is a neurodegenerative disease that begins with short-term memory loss progressing to loss of control over heartbeat and breathing. It has been over 100 years since Alois Alzheimer first presented the world disease to the world in 1906. There is evidence for the efficacy of intranasal delivery to treat Alzheimer's. Intranasal delivery of insulin showed greater memory improvement in patients with Alzheimer's than in healthy individuals. [ 7 ]  Increased microglial activation inflammation are characteristics of Alzheimer's. Animal studies show intranasal administration of pro-resolving lipid mediators decreased both factors, slowing  pathogenesis  of this disease. [ 8 ]  Delivering a novel peptide via intranasal route reduced amyloid beta plaques, a defining trait of Alzheimer's and enhanced cognitive functions. [ 9 ]  Intranasal delivery of anti-Alzheimer's drug dispersed through hydrogel in rabbits demonstrated higher bioavailability compared to oral tablets. [ 10 ]  MiR132 is an RNA molecule that regulates neuronal morphology and maintains survival. This molecule is downregulated with Alzheimer's. A study administered PEG-PLA  nanoparticles  loaded with this miRNA to mice through the nasal route. This novel therapy showed increased expression of miR132 and improved memory function. [ 11 ]  To strengthen the effectiveness of intranasal delivery, there are studies to develop permeation enhancers to better improve drug transport across the blood brain barrier. [ 12 ]


Abnormal cell growth and formation of mass in the brain tissue or nearby regions may cause brain cancer. Constant headaches, seizures, and blurred vision are common symptoms.  Glioblastoma  (GBM) is the most fast-growing and deadliest brain tumor. Though the main cause of glioblastoma remains unknown, it originates when  astrocytes  mutate and multiply uncontrollably forming tumors in the frontal and temporal lobes of the brain. The challenge with current therapeutics is to initiate tumor cell apoptosis with no toxic effects to healthy brain tissue. Nanoparticles loaded with chemotherapeutics delivered through the intranasal route show promising results in treating glioblastoma.  PLGA -based nanoparticles loaded with  paclitaxel  or  doxorubicin  conjugated with a  RGD sequence  targeted the glioblastoma microenvironment and reduced tumor volume through cell death. [ 13 ] [ 14 ]  MicroRNA-21 (miR-21) inhibits pro-apoptotic genes increasing progression of glioblastoma. Self-assembling nanoparticles produced with anti-tumor peptides were administered intranasally and reduced miR-21 levels increasing tumor cell apoptosis. [ 15 ]


Infection, head injury, or strokes can cause sudden bursts of neuronal activity leading to abnormal behaviors, muscle movement, and mood changes. This condition is known as seizure.  Epilepsy  is characterized by recurring seizures. Some possible causes of epilepsy include imbalance or disruption of  neurotransmitters , strokes, or brain injury. Intranasal delivery of  carbamazepine  nanoparticles increase antiepileptic drug bioavailability. [ 16 ]  Administering a self-assembling hydrogel with neuroactive drugs to treat Parkinson's disease appears to be biocompatible, low in toxicity, and have a good recovery capacity. Nasal delivery of this gel demonstrated increased drug concentration in the brain. [ 17 ]   Oxytocin  is a hormone which is observed to alleviate anxiety symptoms in people with autism. Intranasal administration indicated efficient transfer of pharmacologically active oxytocin from nasal cavity to brain. [ 18 ]


Similar to Alzheimer's,  Parkinson's  is the most common neurodegenerative disease associated with balance and coordination issues, muscle stiffness, and tremors. During the early 1800s, James Parkinson medically defined this disease. A study observed improvement in locomotor abilities in rats with Parkinson's after intranasal delivery of conjugated mitochondrial systems. [ 19 ]  Another study demonstrated delivery of neuroactive drugs in a hydrogel increased residence times in the nasal cavity and concentration in the brain. [ 20 ]  Administering therapeutics combined with nanocarriers is shown to directly transfer drugs to the target cells and enhance accumulation. The observed effects include improved neuronal signaling and locomotion. [ 21 ]  Furthermore, intranasal delivery of biodegradable nanoparticles surface-modified with  lactoferrin  increase accumulation in the brain and cellular uptake. [ 22 ]


Characterized by loss of  neuroplasticity , depression is a common mood disorder causing persistent negative emotions and changes in lifestyle. Intranasal delivery of  relaxin-3  mimetics demonstrated significant anti-depressant activity in behavior paradigms of rat models. [ 23 ]   Delivering a  thermoresponsive  hydrogel loaded with berberine intranasally exhibited high bioavailability in hippocampus and anti-depressant activity. [ 24 ]


Anxiety can impair hippocampus function which increases risk of depression and dementia.  Anxiolytic  effects were observed in animal models post-intranasal delivery of a loaded polymeric nanoparticles. [ 25 ]  Another study indicated intranasal delivery of  neuropeptide Y  lowered anxiety in rats. [ 26 ]


Anorexia nervosa  (AN) is a common eating disorder characterized by low intake of food from fear of weight gain. Several complications are associated with this chronic disorder such as fatigue, insomnia, and low blood pressure. Intranasal administration of oxytocin in patients with AN significantly lowered food anticipation and eating concern. [ 27 ]


Uncontrolled and continuous use of a substance, drugs or alcohol, is known as substance use disorder. Substances can interfere with neuronal signaling and potentially disrupt the brain circuit. Addiction to these substances impairs thinking, behavior, and other biological functions. Intranasal delivery of insulin is associated with improvement in brain metabolic activities and alleviate impulsivity. [ 28 ]   Opioid  addiction is prevalent and associated with many substance abuse deaths. A study observed high biodistribution in the brain and reduction in opioid overdose in rats administered with  naloxone -loaded lipid nanoparticles. [ 29 ]


Witnessing a devastating or terrifying situation can lead to  post-traumatic stress disorder  (PTSD). This mental health condition triggers anxiety, depression, and extreme fear with memories. Intranasal administration of temperature-sensitive hydrogels loaded with PTSD medications showed enhanced brain targeting effects and tissue distribution. [ 30 ]  Similarly, another study observed anti-PTSD effects with intranasal administration of loaded hydrogels. [ 31 ]


Schizophrenia  is a chronic mental health condition caused by changes in brain chemistry and structure. Genetics and environment are hypothesized to play a key role in development of this disorder. Research suggests impaired gene expression or chemical imbalance may impact this condition. Anxiety can increase risk of schizophrenia and symptoms include hallucinations, disorganized speech, and abnormal behavior. Davunetide (NAP) is a segment of activity-dependent neuroprotective protein (ADNP). ADNP is reported be downregulated with schizophrenia. A study observed decreased hyperactivity in mice when treated with NAP via the intranasal route. [ 32 ]


Migraine  occurs with episodes of intense headache causing nausea and throbbing pain. Stress and hormonal changes can be a trigger migraine. A nasal spray containing sumatriptan demonstrated a significant reduction of migraine pain. Further clinical studies of intranasal administration of  sumatriptan  (ST) can help evaluate efficacy and safety of such delivery systems. [ 33 ]  Since its approval by the FDA in 2021, dihydroergotamine mesylate has been administered through nasal sprays to treat migraines. [ 34 ] [ 35 ]


Nanoparticles are drug delivery systems ranging from 1–1000 nm in diameter. Lipid-based and polymer-based nanocarriers are commonly used for nose-to-brain delivery as they exert high stability, solubility, and adherence. [ 36 ]  Exosomes and dendrimers are other potential nanocarriers. Nanosystems can be synthesized either using physical or chemical methods. A few physical methods include evaporation-condensation reaction and laser ablation. Irradiation, microemulsion, and chemical reduction are common chemical techniques to develop nanoparticles. Sonication, electroporation, and incubation are common methods to load drugs into nanocarriers.


Coating these nanosystems with mucoadhesive agents, stimulus-sensitive materials, or antibodies can enhance biocompatibility, clearance rates, specificity, and bioavailability. Penetration and absorption enhancers can significantly increase the overall efficacy of the system. Imaging studies along with measurement of drug transfer efficiency and bioavailability can further support the role of these drug delivery systems.


Lipid-based nanoparticles (LNP) can deliver molecules with low toxicity and controlled release. Liposomes, solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), and nanoemulsions are examples.


Liposomes are made up of phospholipids forming spherical vesicles. This property enables liposomes to exhibit high biocompatibility and biodegradability. Studies report potential application of liposomes to treat brain diseases due to increased retention and absorption in nasal cavity, and high brain biodistribution. [ 37 ]  A previous study developed a  cationic  liposome loaded with mRNA and green fluorescent protein  (GFP) . Intranasal delivery of this formulation in murine models demonstrated high brain biodistribution and expression of mRNA-GFP. [ 38 ]


Solid lipid nanoparticles (SLNs) are made up of solid lipids forming a matrix and stabilized by  surfactants . They exhibit high physical stability and remain in solid state at different temperatures. Based on a study, intranasal delivery of SLNs loaded with  rivastigmine tartrate  (RT) exhibited no toxicity, stability, and improved bioavailability. [ 39 ]  Sometimes burst release may occur due to rigidity and less flexibility in shape.


Nanostructured lipid carriers (NLC) are synthesized by a mixture of solid and aqueous lipids. NLC's are developed from SLNs, thus referred to as second generation LNPs. Intranasal administration of NLC loaded with  curcumin  (CRM) increased biodistribution and concentration in brain after emerging as a potential system for brain cancer. [ 40 ]


Small colloidal systems made of  micelles  containing oil, aqueous phases, and emulsifiers are called nanoemulsions. Intranasal delivery of gel nanoemulsion loaded with  temozolomide  is observed to exhibit sustained release and better permeation from nose to brain to treat glioblastoma. [ 41 ]


Polymer-based nanoparticles can be made from either natural or synthetic sources. Nanospheres and nanocapsules are polymeric nanoparticle systems. Natural polymers can be found in the environment or human body. On the other hand, synthetic polymers do not occur naturally and are artificially developed polymers with chemical modifications. Natural polymer-based nanoparticles can be made up of chitosan,  hyaluronic acid , alginate, and gelatin. Natural polymers exhibit excellent biocompatibility and biodegradability, and low toxicity. Synthetic polymer-based nanoparticles can consist of poly (glycolic acid) (PGA), poly (lactic acid) (PLA), and poly(L-lactide-co-glycolide) (PLGA).


A study evaluated chitosan nanoparticles loaded with an anti-epileptic drug,  phenytoin  (PHT), to treat epilepsy. Observations suggested high stability, sustained release, and bioavailability when these particles where administered via the intranasal route. [ 42 ]  Similarly, administering PLGA nanoparticles loaded  lamotrigine  (LTG), polymer-based nanoparticle, showed better permeation through BBB and higher bioavailability. [ 43 ]


Exosomes are vesicular structures containing genetic information. Recently, exosomes are being utilized as drug carriers. These systems are observed to be stable, specific, and safe. Moreover, delivery of exosomes shows less immunogenic affects. Further surface modifications and conjugation with liposomes enhances the therapeutic effects. Based on a previous study, intranasal delivery of exosomes loaded with a  Stat3  inhibitor reduced brain inflammation and slowed brain tumor growth. [ 44 ]


Dendrimers are polymeric macromolecules with a branched network similar to a tree structure. Generally, they are spherical and homogeneous. Surface charge and molecule chemistry can play crucial role with drug interaction and release. Poly(amidoamine) ( PAMAM ) dendrimers are the most commonly used system. A study investigated potential application of dendrimer-based formulation of  haloperidol . Intranasal administration showed improved targeting, and solubility as well as high concentrations in the brain. [ 45 ]  Drugs can be loaded in dendrimers through formulation and nanoconstruct. [ 46 ]


For drug delivery systems to bypass the blood brain barrier, modifications of physiochemical properties can enhance safety and efficacy. Size, surface charge, and  lipophilicity  play a major role in substance bypassing the blood brain barrier. Smaller, positively charged, or more lipophilic molecules enhance efficacy of nose-to-brain delivery. Decrease in delivery system size increases permeation. As the membrane is negatively charged, a particle with positive surface charge interacts electrostatically which enhances  bioadhesion . Carriers with more lipophilicity exert better  mucoadhesion  and residence time. Drug system pH, solubility, and hydrogen bonding potential are other physiochemical properties which should be evaluated.


An  intrauterine device  ( IUD ), also known as an  intrauterine contraceptive device  ( IUCD  or  ICD ) or  coil , [ 3 ]  is a small, often T-shaped  birth control  device that is inserted into the  uterus  to prevent  pregnancy . IUDs are a form of  long-acting reversible contraception  (LARC). [ 4 ]


Users are more satisfied with  contraceptive implants  such as IUDs than any other birth control method. [ 5 ]


IUDs are safe and effective in adolescents as well as those who have not previously had children. [ 6 ] [ 7 ]  Once an IUD is removed, even after long-term use, fertility returns to normal rapidly. [ 8 ]   Copper  devices have a failure rate of about 0.8%, while hormonal ( levonorgestrel ) devices fail about 0.2% of the time within the first year of use. [ 9 ]  In comparison,  male sterilization  and  male condoms  have a failure rate of about 0.15% and 15%, respectively. [ 10 ]  Copper IUDs can also be used as  emergency contraception  within five days of unprotected sex. [ 11 ]


Although  copper IUDs  may increase menstrual bleeding and result in painful cramps, [ 12 ]   hormonal IUDs  may reduce menstrual bleeding or stop  menstruation  altogether. [ 13 ]  However, women can have daily spotting for several months after insertion, and it can take up to three months for there to be a 90% decrease in bleeding with hormonal IUDs. [ 14 ]  Cramping can be treated with  NSAIDs . [ 15 ]  More serious potential complications include expulsion (2–5%) and rarely perforation of the uterus (less than 0.7%). [ 13 ] [ 15 ]  IUDs do not affect  breastfeeding  and can be inserted immediately after delivery. [ 13 ]  They may also be used immediately after an  abortion . [ 16 ] [ 17 ]


The use of IUDs increased within the United States from 0.8% in 1995 to 7.2% from the period of 2006 to 2014. [ 18 ] [ 19 ]  The use of IUDs as a form of birth control dates from the 1800s. [ 1 ]  A previous model known as the  Dalkon shield  was associated with an increased risk of  pelvic inflammatory disease  (PID). However, current models do not affect PID risk in women without  sexually transmitted infections  during the time of insertion. [ 20 ]


IUDs primarily work by preventing  fertilization . [ 21 ]  The progestogen released from hormonal IUDs mainly works by thickening the cervical mucus, preventing sperm from reaching the fallopian tubes. Hormonal IUDs may also sometimes prevent ovulation. [ 22 ] [ 23 ]


Copper IUDs do not contain any hormones, but release copper ions, which are toxic to sperm. They also cause the uterus and fallopian tubes to produce a fluid that contains white blood cells, copper ions, enzymes, and  prostaglandins , which is also toxic to sperm. [ 22 ]  The very high effectiveness of copper-containing IUDs as emergency contraceptives implies they may also act by preventing  implantation  of the  blastocyst . [ 24 ] [ 25 ]


The types of intrauterine devices available, and the names they go by, differ by location. In the United States, there are two types available: [ 26 ]


The  WHO   ATC  labels both copper and hormonal devices as IUDs. In the United Kingdom, there are more than 10 different types of copper IUDs available. In the United Kingdom, the term  IUD  refers only to these copper devices. Hormonal intrauterine contraception is labeled with the term  intrauterine system  (IUS). [ 27 ] [ 28 ]


levonorgestrel


-Prevents ovulation at times


-Emergency contraception


-Lighter periods after 3 months; some users experience  amenorrhea


Most copper IUDs have a  T-shaped frame that is wound around with pure electrolytic copper wire and/or has copper collars (sleeves). The arms of the frame hold the IUD in place near the top of the uterus. The  Paragard  TCu 380a measures 32 mm (1.26") horizontally (top of the T), and 36 mm (1.42") vertically (leg of the T). Copper IUDs have a first year failure rate ranging from 0.1 to 2.2%. [ 34 ]  They work by damaging sperm and disrupting their motility so that they are not able to join an egg. Specifically, copper acts as a spermicide within the uterus by increasing levels of copper ions, prostaglandins, and white blood cells within the uterine and tubal fluids. [ 12 ] [ 35 ]  The increased copper ions in the cervical mucus inhibit the sperm's motility and viability, preventing sperm from traveling through the cervical mucus, or destroying it as it passes through. [ 36 ]  Copper can also alter the endometrial lining, and while studies show that while this alteration can prevent implantation of a fertilized egg (" blastocyst "), it cannot disrupt one that has already been implanted. [ 37 ]


Advantages of the copper IUD include its ability to provide  emergency contraception  up to five days after unprotected sex. It is the most effective form of emergency contraception available. [ 38 ]  It works by preventing fertilization or implantation but does not affect already implanted embryos. [ 37 ]  It contains no hormones, so it can be used while breastfeeding, and fertility returns quickly after removal. [ 39 ]
Copper IUDs also last longer and are available in a wider range of sizes and shapes than hormonal IUDs. [ 14 ]  Disadvantages include the possibility of heavier menstrual periods and more painful cramps. [ 12 ]


IUDs that contain gold or silver also exist. [ 27 ] [ 40 ]  Other shapes of IUD include the so-called U-shaped IUDs, such as the Load and Multiload, and the frameless IUD that holds several hollow cylindrical minuscule copper beads. It is held in place by a suture (knot) to the  fundus of the uterus . It is mainly available in China and Europe. A framed copper IUD called the  IUB SCu300  coils when deployed and forms a three-dimensional spherical shape. It is based on a  nickel titanium  shape memory alloy core. [ 41 ]  In addition to copper, noble metal, and progestogen IUDs, women in China can get copper IUDs with  indomethacin . This non-hormonal compound reduces the severity of menstrual bleeding, and these coils are popular. [ 42 ]


Inert IUDs do not have a  bioactive  component. They are made of inert materials like  stainless steel  (such as the stainless steel ring (SSR), a flexible ring of steel coils that can deform to be inserted through the cervix) or  plastic  (such as the Lippes Loop, which can be inserted through the cervix in a  cannula  and takes a trapezoidal shape within the uterus). They are less effective than copper or hormonal IUDs, with a side effect profile similar to copper IUDs. Their primary mechanism of action is inducing a local  foreign body reaction , which makes the uterine environment hostile both to  sperm  and to  implantation  of an embryo. [ 43 ]  They may have higher rates of preventing pregnancy after fertilization, instead of before fertilization, compared to copper or hormonal IUDs. [ 44 ]


Inert IUDs are not yet approved for use in the United States, UK, or Canada. In China, where IUDs are the most common form of contraception, copper IUD production replaced inert IUD production in 1993. [ 45 ]  However, as of 2008, the most common IUD used by immigrants presenting to Canadian clinics for removal of IUDs placed in China was still the SSR. Because the SSR has no string for removal, it can present a challenge to healthcare providers unfamiliar with IUD types not available in their region. [ 46 ]


Hormonal IUDs (referred to as intrauterine systems in the UK) work by releasing a small amount of  levonorgestrel , a  progestin . Each type varies in size, amount of levonorgestrel released, and duration. The primary mechanism of action is making the inside of the uterus uninhabitable for sperm. [ 47 ]  They can also thin the endometrial lining and potentially impair implantation, but this is not their usual function. [ 48 ] [ 49 ]  Because they thin the endometrial lining, they can also reduce or even prevent menstrual bleeding. As a result, they are used to treat  menorrhagia  (heavy  menses ), once pathologic causes of menorrhagia (such as  uterine polyps ) have been ruled out. [ 50 ]  In a 10-year study, the levonorgestrel coil was found to be as effective as oral medicines (tranexamic acid, mefenamic acid, combined oestrogen–progestogen or progesterone alone); the same proportion of women had not had surgery for heavy bleeding and had similar improvements in their quality of life. [ 51 ] [ 52 ]


The progestin released by hormonal IUDs primarily acts locally; use of Mirena results in much lower systemic progestin levels than other very-low-dose  progestogen only contraceptives . [ 53 ]


Regardless of IUD type, there are some potential side effects that are similar for all IUDs. Some of these side effects include bleeding pattern changes, expulsion,  pelvic inflammatory disease  (especially in the first 21 days after insertion), and rarely uterine perforation. A small probability of pregnancy remains after IUD insertion, and when it occurs, there is a greater risk of  ectopic pregnancy . [ 54 ]


IUDs with progestogen confer an increased risk of  ovarian cysts , [ 55 ]  and IUDs with copper confer an increased risk of heavier periods.  Mirena  lists among its side effects mental health changes including nervousness, depressed mood, or mood swings. [ 56 ]


Menstrual cup  companies recommend that women with IUDs who are considering using menstrual cups should consult with their gynecologists before use. There have been rare cases in which women using IUDs dislodged them when removing their menstrual cups, however, this can also happen with tampon use. [ 57 ]  Despite reports, as of 2023, there is no scientific agreement on whether using a menstrual cup increases the risk of IUD expulsion; more rigorous studies are needed. [ 58 ]


Unlike condoms, the IUD does not protect against sexually transmitted infections. [ 59 ]


Modern IUDs do not lead to infertility or make it harder for a woman to become pregnant, and fertility typically returns within days of removal. Some prior studies found an association between infertility and the  Dalkon Shield , an early IUD design which is no longer available. [ 60 ]


Modern IUDs do not cause increased infection, though the earlier Dalkon Shield may have, because it contained multifilament strings, which provided bacteria a space to grow and move up the string. IUDs manufactured after 2008 use monofilament strings in order to prevent this from happening. [ 61 ]  However, as with any medical intervention, IUDs can lead to increased risk of infection immediately after the insertion.


According to the  U.S. Medical Eligibility Criteria for Contraceptive Use , published by the  CDC , women and adolescents under the age of 20 and women who have not given birth are classified in category 2 for IUD use, mainly due to "the risk for expulsion from nulliparity and for STDs from sexual behavior in younger age groups." According to the CDC, benefits generally outweigh the risks, and IUDs are recommended for young and nulliparous women, although more careful attention may be required. Women over age 20 and those who have previously given birth are placed in category 1, meaning no special concerns are placed on use. [ 62 ] [ 63 ]


Some women experience  amenorrhea , or lack of menstruation while using an IUD. Menstruation occurs when a woman has not become pregnant and the uterus sheds its lining in preparation for the next cycle. IUDs tend to thin the lining of the uterus, leading to less menses by volume or a lack of menstruation altogether. There is a condition known as  polycystic ovarian syndrome  (PCOS) which causes women to miss their periods and can lead to an increased risk of endometrial cancer. [ 64 ]  However, an IUD causes the endometrial lining of a uterus to thin, which is the opposite of what occurs with PCOS.


The main mechanisms of action of IUDs occur prior to fertilization, by preventing sperm from ever reaching the egg. [ 65 ]  The copper-bearing IUD acts as a spermicide, killing or impairing sperm so they cannot reach the egg. IUDs that contain progestin cause the cervical mucus to thicken, which stops sperm from entering the uterus.


It is difficult to predict what a woman will experience during IUD insertion or removal. Some women describe the insertion as cramps, some as a pinch, and others do not feel anything. Only 9% of  nulliparous  women considered the procedure painless, 72% moderately painful, and 17% experience substantial pain with insertion that needs active management. [ 66 ]  Approximately 11% of parous women feel similar pain. [ 67 ]  In such cases,  NSAIDs  can be effective when given in response to post-insertion pain, but have no significant effect when given prophylactically. [ 67 ]  Topical lidocaine has been found as an effective pain management drug when applied before the procedure. [ 68 ]  The use of intrauterine lidocaine (paracervical block) is underutilized in the United States as an effective method to reduce pain associated with insertion. [ 69 ]


IUD insertion can occur at multiple timepoints in a woman's reproductive lifespan:


During the insertion procedure, health care providers use a  speculum  to find the  cervix  (the opening to the uterus), pinch the cervix to stabilize it open with a  tenaculum , [ 75 ]  and then use an insertion device to place the IUD in the uterus. The insertion device goes through the cervix. The procedure itself, if uncomplicated, should take no more than five to ten minutes. [ 76 ]


A  suction cervical stabilizer  can be used in place of the standard tenaculum to hold the cervix open during the IUD insertion procedure. [ 77 ]  Suction cervical stabilizers, such as The Carevix™ Suction Cervical Stabilizer,  [ 78 ]  may reduce pain associated with the insertion procedure.  [ 79 ]


For immediate postpartum insertion, the IUD is inserted following the removal of the  placenta  from the  uterus . The uterus is larger than baseline following birth, which has important implications for insertion. After vaginal deliveries, insertions can be done using placental forceps, a longer inserter specialized for postpartum insertions, or manually, where the provider uses their hand to insert the IUD in the uterus. After cesarean deliveries, the IUD is placed in the uterus with forceps or manually during surgery prior to suturing the uterine incision. [ 74 ] [ 71 ] [ 80 ]


Generally, the removal is uncomplicated and reported to be not as painful as the insertion because there is no instrument that needs to go through the cervix. [ 81 ]  This process requires the health care provider to find the cervix with a speculum and then use ring forceps, which only go into the vagina, to grasp the IUD strings and then pull the IUD out.


IUD placement and removal can be taught both by manufacturers and other training facilities. [ 82 ]


The history of intrauterine devices dates back to the early 20th century. Unlike modern intrauterine devices, early interuterine (from Latin  inter- , meaning "between", as opposed to  intra- ) devices crossed both the vagina and the uterus, causing a high rate of pelvic inflammatory disease. The first IUD was developed in 1909 by the German physician Richard Richter, of Waldenburg. His device was made of silkworm gut and was not widely used. [ 83 ]


Ernst Gräfenberg , another German physician (after whom the  G-spot  is named), created the first Ring IUD,  Gräfenberg's ring , made of silver filaments. His work was suppressed during the Nazi regime, when contraception was considered a threat to Aryan women. [ 83 ]  He moved to the United States, where his colleagues H. Hall and M. Stone took up his work after his death and created the stainless steel Hall-Stone Ring. A Japanese doctor named Tenrei Ota also developed a silver or gold IUD called the Precea or Pressure Ring. [ 83 ]


Jack Lippes helped begin the increase of IUD use in the United States in the late 1950s. In this time,  thermoplastics , which can bend for insertion and retain their original shape, became the material used for first-generation IUDs. Lippes also devised the addition of the monofilament nylon string, which facilitates IUD removal. His trapezoid shape Lippes Loop IUD became one of the most popular first-generation IUDs. In the following years, many different shaped plastic IUDs were invented and marketed. [ 83 ]  These included the infamous  Dalkon Shield , whose poor design caused bacterial infection and led to thousands of lawsuits. Although the Dalkon shield was removed from the market, it had a lasting, negative impact on IUD use and reputation in the United States. [ 84 ]   Lazar C. Margulies  developed the first plastic IUD using thermoplastics in the 1960s. [ 85 ]  His innovation allowed insertion of the IUD into the uterus without the need to dilate the  cervix . [ 86 ]


The invention of the copper IUD in the 1960s brought with it the capital T-shaped design used by most modern IUDs. U.S. physician Howard Tatum determined that the 'T' shape would work better with the shape of the uterus, which forms a 'T' when contracted. He predicted this would reduce rates of IUD expulsion. [ 83 ]  Together, Tatum and Chilean physician Jaime Zipper discovered that copper could be an effective spermicide and developed the first copper IUD, TCu200. Improvements by Tatum led to the creation of the TCu380A ( ParaGard ), which is currently the preferred copper IUD. [ 83 ]


The hormonal IUD was also invented in the 1960s and 1970s; initially the goal was to mitigate the increased menstrual bleeding associated with copper and inert IUDs. The first model, Progestasert, was conceived of by Antonio Scommegna and created by Tapani J. V. Luukkainen, but the device only lasted for one year of use. [ 84 ]  Progestasert was manufactured until 2001. [ 87 ] [ unreliable medical source? ]  One commercial hormonal IUD which is currently available, Mirena, was also developed by Luukkainen and released in 1976. [ 83 ]  The manufacturer of the Mirena,  Bayer AG , became the target of multiple lawsuits over allegations that Bayer failed to adequately warn users that the IUD could pierce the uterus and migrate to other parts of the body. [ 88 ]


In  China , the use of IUDs by state health services was part of the government's efforts to limit birth rates. From 1980 to 2014, 324   million women were inserted with IUDs, in addition to the 107   million who had  tubal ligation . Women who refused could lose their government employment and their children could lose access to  public schools . [ citation needed ]  The IUDs inserted in this way were modified such that they could not be removed in a doctor's office (meant to be left indefinitely), and  surgical removal  is usually needed. [ 89 ]  Until the mid-1990s, the state-preferred IUD was a  stainless steel  ring, [ 90 ] [ 91 ]  which had a higher rate of  complications  compared to other types of IUD. It gave rise to the  idiom   shànghuán  ( 上环 ), meaning "insert a loop". Nowadays, the IUDs include T and V shapes, the former being the most common and easiest to remove.


To implement the  two-child policy , the government announced that IUD-removals would be paid for by the government. [ 89 ]  IUD removals are free for women "who are allowed to have another child" (see  one-child policy ) or "who cannot continue to have the IUD for health reasons." [ 92 ]


In the United States, the price of an IUD may range from $0 to $1,300. [ 93 ]   [ clarification needed ]  The price includes medical exams, insertion, and follow-up visits.
Under the Affordable Care Act, most insurance plans are required to cover all forms of birth control, including IUDs, although they may not cover all IUD brands. [ 94 ]


Among birth control methods, IUDs, along with other  contraceptive implants , result in the greatest satisfaction among users. [ 6 ]


A study found that female family planning providers choose LARC methods more often (41.7%) than the general public (12.1%). [ 95 ]


Mechanism of action Copper-releasing IUCs When used as a regular or emergency method of contraception, copper-releasing IUCs act primarily to prevent fertilization. Emergency insertion of a copper IUC is significantly more effective than the use of ECPs, reducing the risk of pregnancy following unprotected intercourse by more than 99%. 2,3  This very high level of effectiveness implies that emergency insertion of a copper IUC must prevent some pregnancies after fertilization. Emergency contraceptive pills To make an informed choice, women must know that ECPs—like the birth control pill, patch, ring, shot, and implant, 76 and even like breastfeeding 77 —prevent pregnancy primarily by delaying or inhibiting ovulation and inhibiting fertilization, but may at times inhibit implantation of a fertilized egg in the endometrium. However, women should also be informed that the best available evidence indicates that ECPs prevent pregnancy by mechanisms that do not involve interference with post-fertilization events. ECPs do not cause abortion 78  or harm an established pregnancy. Pregnancy begins with implantation according to medical authorities such as the US FDA, the National Institutes of Health 79  and the American College of Obstetricians and Gynecologists (ACOG). 80 Ulipristal acetate (UPA).  One study has demonstrated that UP can delay ovulation. 81 ... Another study found that UPA altered the endometrium, but whether this change would inhibit implantation is unknown. 82 p. 122: Progestin-only emergency contraceptive pills.  Early treatment with ECPs containing only the progestin levonorgestrel has been shown to impair the ovulatory process and luteal function. 83–87 p. 123: Combined emergency contraceptive pills.  Several clinical studies have shown that combined ECPs containing ethinyl estradiol and levonorgestrel can inhibit or delay ovulation. 107–110


How does EC work? In 2002, a judicial review ruled that pregnancy begins at implantation, not fertilisation. 8  The possible mechanisms of action should be explained to the patient as some methods may not be acceptable, depending on individual beliefs about the onset of pregnancy and abortion. Copper-bearing intrauterine device (Cu-IUD). Copper is toxic to the ovum and sperm and thus the copper-bearing intrauterine device (Cu-IUD) is effective immediately after insertion and works primarily by inhibiting fertilisation. 9–11  A systematic review on mechanisms of action of IUDs showed that both pre- and postfertilisation effects contribute to efficacy. 11 If fertilisation has already occurred, it is accepted that there is an anti-implantation effect, 12,13 Levonorgestrel (LNG). The precise mode of action of levonorgestrel (LNG) is incompletely understood but it is thought to work primarily by inhibition of ovulation. 16,17 Ulipristal acetate (UPA). UPA's primary mechanism of action is thought to be inhibition or delay of ovulation. 2


Mechanism of action The contraceptive action of all IUDs is mainly in the intrauterine cavity. Ovulation is not affected, and the IUD is not an abortifacient. 58–60  It is currently believed that the mechanism of action for IUDs is the production of an intrauterine environment that is spermicidal. Nonmedicated IUDs depend for contraception on the general reaction of the uterus to a foreign body. It is believed that this reaction, a sterile inflammatory response, produces tissue injury of a minor degree but sufficient to be spermicidal. Very few, if any, sperm reach the ovum in the fallopian tube. The progestin-releasing IUD adds the endometrial action of the progestin to the foreign body reaction. The endometrium becomes decidualized with atrophy of the glands. 65  The progestin IUD probably has two mechanisms of action: inhibition of implantation and inhibition of sperm capacitation, penetration, and survival.


Intravesical drug delivery  is the  delivery of medications  directly into the  bladder  by  urinary catheter . This method of drug delivery is used to directly target diseases of the bladder such as  interstitial cystitis  and  bladder cancer , but currently faces obstacles such as low drug retention time due to washing out with urine and issues with the low permeability of the bladder wall itself. Due to the advantages of directly targeting the bladder, as well as the effectiveness of  permeability enhancers , advances in intravesical  drug carriers , and  mucoadhesive , intravesical drug delivery is becoming more effective and of increased interest in the medical community.


Delivering drugs directly to the target bladder site allows for maximizing drug delivery while minimizing  systemic effects .
Delivering the treatment directly to the site allows for more effective dosages to be given since high concentrations of drug in the bladder can be reached. [ 1 ]  This becomes especially important when patients have a  urinary bladder disease  that is  drug resistant . The delivery of drugs directly to the bladder is a large improvement over systemic delivery which only allows a small fraction of the drug to reach the bladder, causing lower concentrations of drug leading to systemic treatments being ineffective. [ 1 ]  The smaller fraction of drug reaching its target with systemic delivery means more drugs must be administered which can lead to problems with systemic  toxicity . This is not the case when drug is administered directly to the bladder.


The layer of the bladder which comes into contact with urine, the urothelium (the  transitional epithelium  of the bladder, is a mostly impermeable barrier which stops molecules in the urine from being reabsorbed and prevents molecules from being secreted directly into the bladder as well. [ 1 ]   The bladder’s impermeability means that any drug delivered intravesical will not absorb into the bloodstream well through the bladder wall, causing fewer systemic effects. This impermeability also causes treatment of bladder diseases to be more difficult to treat as drugs do not absorb well into the bladder wall. Intravesical drug delivery has been identified as an ideal way to treat most urinary disorders, including bladder tumors and  bladder cancers ,  interstitial cystitis , and  urinary incontinence . [ 1 ] [ 2 ]
 [ 3 ] [ 4 ] [ 5 ]  There is currently a lack of interest in treating  urinary tract infections  using intravesical delivery.


While intravesical delivery shows distinct advantages over systemic drug delivery it has several problems to overcome. When giving a drug intravesically it is  diluted  by urine and washed out when urine is voided. [ 1 ] [ 2 ] [ 3 ]  Additionally, the low permeability of the urothelium which lines the bladder creates a hurdle that must be overcome if the bladder wall needs to be treated. [ 3 ]  These issues create the need for more frequent dosing, which causes urinary catheter site irritation and compliance issues with treatments. [ 2 ]
Intravesical drug dilution occurs as urine accumulates in the bladder, lowering the concentration of drug in the bladder as overall volume increases. The  voiding  of drug with urine when using traditional drug formulations in the bladder has become a hurdle to overcome as well, since  residence time  of the drug inside the bladder is directly tied to the treatment’s  efficacy . [ 1 ]  Creating  formulations  which adhere to the bladder wall has been targeted as one way to improve intravesical dug efficacy,. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]  The low adherence of drugs to the bladder wall and low permeability into the bladder wall contributes to low drug retention in the bladder. [ 1 ]  When modifying drug formulations for intravesical delivery gels or  viscosity  increasing formulations are sometimes used to increase retention, though this can cause issues with  urethra obstruction , an additional hurdle in intravesical drug delivery. [ 2 ]
Permeability issues with the bladder wall can be attributed to the urothelium, the lining of the bladder wall made up of  umbrella cells , intermediate cells, and basal cells.,. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]  The impermeability can be attributed to the umbrella cells which form tight junctions with each other to make up the innermost layer of the urothelium and have the ability to change shape to adapt to the bladder’s varying size. [ 1 ] [ 2 ]  The umbrella cells are covered in a dense layer of plaques which further prevents the absorption of particles through the urothelium and a layer of  mucin  composed of  glycosaminoglycans  (GAGs) which prevents both hydrophobic and negatively charged molecules from adhering to the bladder wall. [ 1 ] [ 4 ]  Overcoming the impermeability of the mucin layer and the urothelium is a large focus of many intravesical drug formulations, and is key to an efficacious intravesical treatment [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]


The main ways researchers are currently overcoming the problems in intravesical drug delivery are through developing formulations using  mucoadhesives ,  nanoparticles ,  liposomes , polymeric  hydrogel , expandable delivery devices, and electromotive drug administration. [ 1 ] [ 2 ] [ 3 ]  These methods each serve to improve retention time, drug permeability through the urothelium, or some combination of the two.


Enhancing Drug retention can be achieved through changing formulation and delivery device. Often drug retention and permeability enhancement are tied, as drugs which permeate the urothelium will suffer fewer effects from urine dilution and voiding. Two of the most common methods to improve drug retention are by using a  mucoadhesive  formulation or using polymeric  hydrogels  that form in the bladder, or  in situ  gelling hydrogels. [ 1 ] [ 2 ] [ 3 ]


Mucoadhesive formulations can be made with both  biopolymers  and  synthetic polymers , and usually contain polymers that are  hydrophilic  and can form many  hydrogen bonds  with the  GAG-mucin . [ 1 ]  Positively charged molecules typically make far better mucoadhesive as the mucin layer is negatively charged. [ 6 ]  By forming these bonds, the mucoadhesive, and the drug it carries, can maintain sustained contact with the bladder wall, enhancing retention of the drug in the bladder. Among mucoadhesive materials  Chitosan  often stands out due to its  biocompatibility ,  biodegradability , and permeability enhancing factors. [ 3 ]  In experiments with chitosan, it has been shown that the mucoadhesive properties of a molecule likely increase as the  molecular weight  is increased. [ 7 ]  Studies have also found that the modification of chitosan formulations with  thiomers , which can form covalent bonds with mucus, can significantly improve the mucoadhesion of the chitosan formulations [ 8 ]


Polymeric  hydrogels  for intravesical drug delivery take advantage of characteristics of the bladder or urine to gel, or may use external manipulation to cause the hydrogel to form. [ 1 ] [ 9 ]  These gels can take advantage of pH or temperature differences, or external input like  UV  lasers, to form gels inside the bladder after instillation of the formulation in liquid form. [ 9 ]  If these gels are made to be mucoadhesive they stick to the bladder wall and do not wash out or cause urethral obstruction. Polymeric hydrogels have also been formulated to float on top of the urine to avoid wash out and obstruction without having to adhere to the bladder wall. [ 10 ]  Drawbacks of using polymeric hydrogel formulations include the concern of urethral obstruction, the varying conditions of the urine which make pH or ionic controlled gelling formulations less controlled, and the  bladder wall inflammation  which can occur with mucoadhesive polymeric hydrogels. [ 2 ]


Enhancing drug permeability can be done through physical or chemical methods, and is also achieved through  nanoparticle  and  liposome   drug carriers . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]  Physical methods include electromotive drug administration, radiofrequency-induced chemotherapeutic effect, and conductive hyperthermic  chemotherapy , but electromotive drug administration seems to be the most prevalent in recent research and clinical trial focus. [ 1 ] [ 2 ] [ 3 ] [ 5 ] [ 11 ]  Chemical methods revolve around adding a chemical agent to enhance drug uptake and increase permeability. To enhance drug permeability through physical or chemical methods both the  mucin layer  and the  umbrella cells  of the urothelium must undergo a structural or chemical change. [ 1 ]


Electromotive drug administration utilizes a small  electric current  flowing across the bladder wall between two  electrodes , one on the skin and one placed inside the bladder via  catheterization , to enhance permeability of  aqueous  solutions. [ 1 ] [ 2 ] [ 3 ]  Electromotive drug administration best enhances  ionized  formulations, which diffuse poorly using standard  passive diffusion . [ 3 ]  This allows it to potentially assist in the delivery of many drugs that usually perform poorly in the bladder without having to change their formulations heavily. Across multiple studies and clinical trials electromotive drug administration has been shown to increase the uptake of many drugs, showing potential use in  bladder cancer ,  urinary incontinence ,  urinary cystitis  and pain management. [ 1 ] [ 2 ] [ 3 ] [ 5 ]  Cost of  local anesthesia  for bladder distention using electromotive drug administration in combination with  lidocaine  has been shown to be cheaper and more practical than  general anesthesia  or  spinal anesthesia . [ 5 ]


To enhance the permeability of the bladder wall, specifically the urothelium, to drugs administered locally to the bladder four chemical agents are most commonly used:  DMSO ,  protamine sulphate ,  Hyaluronidase , and  chitosan . DMSO is already widely used to directly treat urinary cystitis due to its  anti-inflammatory  and  antibacterial  properties. [ 1 ] [ 3 ]  DMSO can penetrate tissues without causing any damage to them. [ 1 ] [ 3 ]  This property of DMSO made it of particular interest as a chemical enhancer and it has been shown to increase the uptake of several chemotherapeutics used intravesically. [ 12 ]  Protamine sulphate causes disruption to the mucus layer of the urothelium and can cause large disruption of bladder permeability which can be modified by adding  defibrotide . [ 1 ] [ 3 ]  Hyaluronidase breaks down  Hyaluronic acid , a GAG molecule important to the  mucin layer , causing enhanced permeability of the mucin layer to drugs administered concurrently with hyaluronidase. [ 1 ]  Conversely, hyaluronic acid can be used to treat  interstitial cystitis  as it helps to repair damaged mucin layers. [ 3 ]  Chitosan is thought to function as a permeability enhancer by binding to the mucin layer and negatively affecting tight junctions between  umbrella cells  in the urothelium. [ 1 ]  It has been shown that chitosan increases bladder wall permeability but its effectiveness as a permeability enhancer decreases as calcium ion concentration increases. [ 13 ]  Chemically enhancing bladder permeability can lead to negative side effects such as  incontinence , pain, and uncontrolled leakage of molecules other than intended drug from the urine into the bladder wall. [ 1 ]


Nanoparticle  and  liposome   drug carrier  formulations allow for increased drug uptake, especially in the case of liposomes which allow for greater uptake via  endocytosis . [ 1 ] [ 2 ] [ 3 ] [ 5 ]  Liposomes generally must be shielded via modification with a  Polyethylene glycol  molecule to overcome issues with instability and  aggregation  in urine. [ 4 ]  Nanoparticle and Liposome drug carriers can be loaded into a  in situ  forming hydrogel to gain the advantages of mucoadhesive properties [ 4 ]  Empty liposomes by themselves have been noted to improve interstitial cystitis, most likely due to formation of a lipid film on damaged urothelium. [ 3 ] [ 5 ]  The variety of types of nanoparticles which can be made to carry drugs in intravesical formulations, combined with the tunability of many of these particles in regards to drug loading and release rates makes nanoparticles and liposomes a highly versatile and useful tool in intravesical drug delivery. [ 1 ]


A  jet injector  is a type of medical  injecting   syringe  device used for a method of drug delivery known as  jet injection . A narrow, high- pressure  stream of liquid is made to penetrate the outermost layer of the skin (stratum corneum) to deliver medication to targeted underlying tissues of the  epidermis  or dermis ("cutaneous" injection, also known as classical " intradermal " injection), fat ("subcutaneous" injection), or muscle ("intramuscular" injection).


The jet stream is usually generated by the pressure of a piston in an enclosed liquid-filled chamber. The piston is usually pushed by the release of a compressed metal spring, although devices being studied may use piezoelectric effects and other novel technologies to pressurize the liquid in the chamber.  The springs of currently marketed and historical devices may be compressed by operator muscle power, hydraulic fluid, built-in battery-operated motors, compressed air or gas, and other means. Gas-powered and hydraulically powered devices may involve hoses that carry compressed gas or hydraulic fluid from separate cylinders of gas, electric air pumps, foot-pedal pumps, or other components to reduce the size and weight of the hand-held part of the system and to allow faster and less-tiring methods to perform numerous consecutive vaccinations.


Jet injectors were used for mass  vaccination , and as an alternative to needle syringes for  diabetics  to inject  insulin . However, the  World Health Organization  no longer recommends jet injectors for vaccination due to risks of disease transmission. [ 1 ]  Similar devices are used in other industries to inject grease or other fluid.


The term " hypospray ", although better known from its usage in the 1960s television show  Star Trek , is attested in the medical literature as early as 1956. [1]


A jet injector, also known as a jet gun injector, air gun, or pneumatic injector, is a medical instrument that uses a high-pressure jet of liquid medication to penetrate the skin and deliver medication under the skin without a needle. Jet injectors can be single-dose or multi-dose.


Throughout the years jet injectors have been redesigned to overcome the risk of carrying contamination to successive subjects. To try to stop the risk, researchers placed a single-use protective cap over the reusable nozzle. The protective cap was intended to act as a shield between the reusable nozzle and the patient's skin. After each injection the cap would be discarded and replaced with a sterile one. These devices were known as protector cap needle-free injectors or PCNFI. [ 2 ]  A safety test by Kelly and colleagues (2008) [ 3 ]  found a PCNFI device failed to prevent contamination. After administering injections to  hepatitis B  patients, researchers found hepatitis B had penetrated the protective cap and contaminated the internal components of the jet injector, showing that the internal fluid pathway and patient-contacting parts cannot safely be reused.


Researchers developed a new jet injection design by combining the drug reservoir, plunger and nozzle into a single-use disposable cartridge. The cartridge is placed onto the tip of the jet injector and, when activated, a rod pushes the plunger forward. This device is known as a disposable-cartridge jet injector (DCJI). [ 2 ]


The International Standards Organization recommended abandoning the use of the name "jet injector", which is associated with a risk of cross-contamination and rather refer to newer devices as "needle-free injectors". [ 4 ]


Since the late 1970s, jet injectors have been increasingly used by diabetics in the United States. These devices have all been spring-loaded. At their peak, jet injectors accounted for 7% of the injector market. Currently, the only model available in the United States is the Injex 23.  In the United Kingdom, the Insujet has recently entered the market. As of June 2015, the Insujet is available in the UK and a few select countries. [ citation needed ]


Researchers from the  University of Twente  in the Netherlands patented a Jet Injection System, comprising a microfluidic device for jet ejection and a laser-based heating system. A continuous laser beam – also called a continuous-wave laser – heats the liquid to be administered, which is launched in a droplet form across the epidermis and slows down into the tissue below. [ 5 ]


Since the jet injector breaks the barrier of the skin, there is a risk of blood and biological material being transferred from one user to the next. Research on the risks of cross-contamination arose immediately after the invention of jet injection technology.


There are three inherent problems with jet injectors:


Splash-back refers to the jet stream penetrating the outer skin at a high velocity, causing the jet stream to ricochet backward and contaminate the nozzle. [ 6 ]


Instances of splash-back have been published by several researchers. Samir Mitragrotri visually captured splash-back after discharging a multi-use nozzle jet injector using high-speed  microcinematography . [ 7 ]  Hoffman and colleagues (2001) also observed the nozzle and internal fluid pathway of the jet injector becoming contaminated. [ 8 ]


Fluid suck-back occurs when blood left on the nozzle of the jet injector is sucked back into the injector orifice, contaminating the next dose to be fired. [ 6 ]


The CDC has acknowledged that the most widely used jet injector in the world, the Ped-O-Jet, sucked fluid back into the gun. "After injections, they [CDC] observed fluid remaining on the Ped-O-Jet nozzle being sucked back into the device upon its cocking and refilling for the next injection (beyond the reach of alcohol swabbing or acetone swabbing)," stated Dr. Bruce Weniger. [ 9 ]


Retrograde flow happens after the jet stream penetrates the skin and creates a hole, if the pressure of the jet stream causes the spray, after mixing with tissue fluids and blood, to rebound back out of the hole, against the incoming jet stream and back into the nozzle orifice. [ 6 ]


This problem has been reported by numerous researchers. [ 10 ] [ 11 ] [ 8 ] [ 12 ] [ 13 ]


Hepatitis B  can be transmitted by less than one nanolitre [ 14 ]  so makers of injectors must ensure there is no cross-contamination between applications. The  World Health Organization  no longer recommends jet injectors for vaccination due to risks of disease transmission. [ 1 ]


Numerous studies have found cross-infection of diseases from jet injections.  An experiment using  mice , published in 1985, showed that jet injectors would frequently transmit the viral infection  lactate dehydrogenase elevating virus  (LDV) from one mouse to another. [ 15 ]  Another study used the device on a calf, then tested the fluid remaining in the injector for blood. Every injector they tested had detectable blood in a quantity sufficient to pass on a virus such as hepatitis B. [ 14 ]


From 1984 to 1985, a weight-loss clinic in Los Angeles administered  human chorionic gonadotropin  (hCG) with a Med-E-Jet injector. A CDC investigation found 57 out of 239 people who had received the jet injection tested positive for hepatitis B. [ 16 ]


Jet injectors have also been found to inoculate bacteria from the environment into users. In 1988 a podiatry clinic used a jet injector to deliver  local anaesthetic  into patients' toes. Eight of these patients developed infections caused by  Mycobacterium chelonae . The injector was stored in a container of water and disinfectant between use, but the organism grew in the container. [ 17 ]  This species of bacteria is sometimes found in tap water, and had been previously associated with infections from jet injectors. [ 18 ]


Laser-assisted drug delivery  (LADD) is a drug delivery technique commonly used in the dermatology field that involves lasers. As skin acts as a protective barrier to the environment, the absorption of topical products through the epidermis is limited; thus, different drug delivery modalities have been employed to improve the efficacy of these treatments. The use of lasers in LADD has been shown to enhance the penetration of drugs transdermal, leading to a higher absorption rate, limited systemic effects, and reduced duration of treatment. Although this technique has evolved in the past decade due to its efficacy through scientific research and clinical practice, there remain some limitations regarding the safety aspect that needs to be taken into consideration.


Skin is the largest organ in the human body that acts as the primary protective barrier against the external environment. It provides protection against ultraviolet light, trauma, pathogens, microorganisms, and toxins, sensory perception, temperature regulation, and immunity. [ 1 ]  There are primarily three layers of skin, which include the outer epidermis, followed by the dermis and subcutaneous tissue, or hypodermis. [ 1 ]  Skin is used as the target for drug delivery as it is a convenient route of drug administration, and the large area allows for different placements on the skin for transdermal delivery [ 1 ]


Transdermal delivery is a non-invasive method commonly assisted in transporting topical products into intact and healthy skin. The substances initially penetrate through the stratum corneum, which is the outermost layer of the epidermis, then diffuse into the deeper epidermis and dermis layers for a systemic effect. [ 2 ]  Although transdermal drug delivery presents several advantages as compared to other conventional modalities such as oral and parenteral routes, [ 2 ] [ 3 ] [ 4 ] [ 5 ]  the complexity of the skin barrier limits the methodology to reach its full potential.


Various technologies have been developed to enhance the permeability of transdermal drugs, which can be divided into passive or chemical and active or physical methods. The passive approach involves the optimization of drug and vehicle interaction that could modify the stratum corneum structure or the addition of penetration enhancers for better absorption rates. [ 2 ]  Some of the limitations of this approach include lag time in drug release, low efficiency, and skin irritation. [ 2 ]  The active approach involves ultrasound, electrical stimulation, thermal approach, and mechanical approach. [ 2 ]  These techniques facilitate the transportation of drugs by using energy as a driving force. Within the thermal approach, laser-assisted drug delivery is a common and effective method that has been used to increase the efficiency of transdermal drug delivery by selectively destroying the chromophores of interest using light waves.


There are different types of lasers used in LADD, and they can be categorized into four main groups: (1) fully ablative lasers, (2) ablative fractional lasers (AFL), (3) non-ablative fractional lasers (NAFL), and (4) non-ablative dermal remodeling lasers. [ 6 ]  Common fully ablative lasers, including carbon dioxide (CO₂, wavelength peak 10,600 nm) and erbium-doped yttrium aluminum garnet (Er:YAG, wavelength peak 2940 nm), target water as their chromophore where all water-containing tissues within the epidermis are ablated. [ 7 ]  With its high wavelength peak, CO₂ laser has a high absorption rate of water and adipose tissues; whereas the wavelength of Er:YAG allows for the precise ablation of water and minimizes heat generation. [ 8 ]  The mechanism of AFL is similar to fully ablative lasers but when used fractionally, they create multiple vertical columns on the skin surface, which are also called microscopic treatment zones (MTZ) and allow for a more quantitatively controllable usage in LADD. [ 8 ]  NAFL are also fractionated lasers that produce MTZ, but as they are non-ablative, there is no ablation of the epidermis and instead, they use light energy to damage the dermis layer. [ 9 ]  Non-ablative dermal remodeling lasers include all types of lasers with a chromophore that is different from water as used in the previous groups. Common lasers within this group are neodymium-doped YAG laser (Nd: YAG, wavelength peak 1064 nm and 1320 nm), pulsed dye laser (wavelength ranges from 585 to 600 nm), and intense pulsed laser (IPL, wavelength ranges from 500 to 1200 nm). [ 9 ]  In general, with its high efficiency and rapid recovery time, AFL is the more common modality used for LADD, especially in the dermatology field. [ 10 ]


Lipophilic substances have shown to have a greater ability to cross the epidermis, thus, the efficiency of LADD is more remarkable when using hydrophilic substances. [ 6 ] [ 11 ]  Liquid and gel formulations of drugs also are proven to cross the channels created from the fractional lasers more easily as compared to oily formulations such as creams or ointments. [ 6 ]  Common drugs used in LAPP include but are not limited to 5-aminolaevulinic (5-ALA), 5-aminolevulinate (MAL), methotrexate (MTX), imiquimod, 5-fluorouracil (5-FU), timolol, triamcinolone acetonide (TAC), bimatoprost, tretinoin, pimecrolimus, poly-L-lactic acid (PLLA), analgesics, minoxidil (MXD), diphencyprone (DPCP), vitamin C, small interfering RNA (siRNA), vaccine, and antibodies. [ 12 ]


The efficiency of LADD with the selected laser settings is dependent upon the different characteristics associated with individual patients. The dermatological condition, the properties of the skin, and the surface area are taken into consideration to determine the eligibility of the patients for certain lasers and provide optimal treatments for each patient. For example, hydrated skin has a higher affinity for absorption of oily substances; skin atrophy that is associated with solar elastosis is more likely to produce pathological scarring under high laser intensity; hair areas have a higher absorption rate; older patients are more prone to adverse effects such as atrophy, erosion, ulceration, and will require longer recovery time. [ 6 ]  Not all patients are candidates for LADD as this method is intensified as compared to conventional topical treatment. [ 13 ]


A vast majority of pre-clinical work on LADD focuses on AFL based on its translational characteristics in clinical settings. These studies utilized mostly either porcine or murine skin as their disease model.


Within the dermatology field, porcine skin has been used as a disease model for testing the efficacy of LADD  in vivo . Haedersdal et al. pre-treated porcine skin with CO 2 -AFL before the application of MAL photodynamic therapy (PDT), creating single MTZs that increased porphyrin fluorescence uniformly up to 1.5 mm from the ablated channels. [ 14 ]  This demonstrated that for MAL, pre-treatment of AFL with MTZs spacing at 3-mm intervals, covering less than 1% surface of the area, was useful for the entire lesion. [ 7 ]  Similarly, Bachhav et al. showed that the increased numbers of MTZs from Er:YAG laser did not affect the absorption of lidocaine into either the epidermis or dermis, and thus, higher fluences of laser were not proportionally correlated to the absorption rate. [ 15 ]  AFL pre-treatment of porcine skin also has also shown to enhance the delivery of MAL at deeper layers of the skin, [ 15 ]  increase surface fluorescence from MAL as compared to non-AFL pre-treated skin, [ 16 ]  and induce higher fluorescence of 5-ALA as compared to MAL for deeper structure. [ 17 ]


Besides porcine skin, murine skin has also been used for testing the efficacy of LADD. A study performed on murine skin has shown that the penetration of 5-FU through skin increased 36 to 133-fold after pre-treatment with fully ablative Q-switched ruby, CO 2 , or Er:YAG lasers. [ 18 ]  Likewise, delivery of imiquimod in both murine and porcine skin increased up to 65-fold and 127-fold, after one and four passes of low-fluence fractional Er:YAG laser, respectively. [ 19 ]  As a result, with LADD, a dose of 0.4% imiquimod was equivalent to a topically applied dose of 5% imiquimod, [ 19 ]  which implied that a lower dosage of drug could be used with similar clinical outcomes. Besides topical drugs, Chen et al. showed that the treatment of fractional CO 2  on murine skin increased 8- to 15-fold the delivery of ovalbumin vaccine, along with an enhanced production of ovalbumin specific antibodies at 2 weeks. [ 20 ]


LADD has been implemented in clinical practice to support the absorption of topical agents into the skin, representative drugs include 5-ALA, MAL, 5-FU, corticosteroid, vitamin, and lidocaine.


LADD has been used in adjunction to photodynamic therapy (PDT) as a pre-treatment, which has shown to enhance the absorption of these drugs into the skin. 5-ALA and MAL are common photosensitizers that are used in PDT to treat different skin diseases such as actinic keratoses (AK), Bowen’s disease, and superficial cell carcinoma. [ 12 ]


Lim et al. (2014) utilized nonablative fractional laser Er:YAG to pre-treat twelve treatment areas on the back of 10 healthy males, followed by the incubation of 5-ALA. [ 21 ]  The results showed that pre-treated areas had higher level of porphyrin fluorescence as compared to non-pretreated areas, which indicated that LADD enhanced 5-ALA skin penetration. In another study, Jang et al. (2013) pre-treated 29 AK patients with an ablative CO 2  fractional laser, followed by 5-ALA-PDT treatment with varying incubation times. [ 22 ]  The pre-treatment of laser showed improvement of clinical outcomes even with the short incubation time, with 70.6% of the AK lesions had a complete clinical response to PDT.


In a randomized study, Choi et al. used both conventional MAL-PDT and a combination of AFL (Er:YAG) and MAL-PDT to treat 93 AK patients. [ 23 ]  The group treated with a combination of LADD and PDT showed higher clinical response rate of 91.7% as compared to conventional MAL-PDT group with clinical response rate of 65.6% after three months, and results were persistent after a twelve-month follow-up. In another randomized study with 21 patients with Bowen’s disease, the clearance rate of the lesions after 3 months was higher with pre-treatment of one session of ablative fractional Er:YAG followed by MAL-PDT (93.8%) as compared to two sessions of conventional MAL-PDT (73.1%), and with lower recurrence rates (6.7% versus 31.6%). [ 24 ]


5-FU is a common drug which is used to treat cancer and certain skin diseases, such as AK and certain types of nonmelanoma skin cancers. In a case study of 28 patients, including 16 superficial basal cell carcinomas and 14 squamous cell carcinomas  in situ , pre-treatment of a single pass of CO 2 -AFL followed by a single application of 5-FU showed histological clearance of 100% squamous cell carcinomas  in situ  and 71% of the superficial basal cell carcinomas. [ 25 ]  In a case report study, a patient with multiple Bowen’s disease lesions was selected for a half-side study, one was treated with Er:YAG laser followed by a topical treatment of 5-FU and the other was treated with only 5-FU cream. [ 26 ]  The legions treated with LADD showed accelerated clinical and histologic response as compared to conventional 5-FU, with no recurrences of lesions after 9 months. In another study, Wenande et al. (2021) showed that CO 2 -AFL enhanced the efficiency of cisplatin and 5-FU treatment for 20 patients with basal cell carcinoma, with 94.7% patients showed clinical clearance. [ 27 ]


Triamcinolone acetonide (TAC) is a common corticosteroid used as a therapeutic strategy for hypertrophic scars and keloids. [ 28 ]  In a case study, Waibel et al. used CO 2 -AFL to assist topical TAC delivery to treat 15 patients with hypertrophic and restrictive cutaneous scars. The results showed that significant improvement of the scars was observed after 6 months, with the most impacts on texture. [ 29 ]  Similarly, in a pilot study, either CO 2 -AFL or radiofrequency was used in adjunction with ultrasound-assisted TAC to treat alopecia areata, a disease associated with hair loss. [ 30 ]  All patients showed complete response after the treatment and specifically, the use of LADD with CO 2 -AFL showed complete response of patients after a single session as compared to a required of three and six sessions for radiofrequency.


Vitamin C and E are important substances that show antioxidant effects against UV radiation. Transdermal delivery after topical application of these vitamins has been facilitated with LADD. Lee et al. (2003) showed that the application of either nonablative fractional Er:YAG or CO 2  lasers improved the transdermal penetration of vitamin C significantly. [ 31 ]  In a split face comparison study regarding UV-induced skin aging, Trelles et al. treated 14 patients with conventional CO 2 -AFL on one side and CO 2 -AFL along with the application of vitamin C and E on the other side. [ 32 ]  As a result, the combination of LADD and vitamins demonstrated a 79% reduction in fine lines as compared to a 69% reduction for AFL-treated side without the delivery of vitamins.


Local anesthesia is used widely for dermatological surgeries via topical products or injections. As topical agents have a long incubation time for drug penetration and injections are associated with pain, LADD has been applied to the field for advancing the efficacy of anesthesia. Lidocaine is a local anesthetic cream used to prevent and treat pain. Increase dermal absorption and transdermal bioavailability of lidocaine were seen when using in conjunction with LADD, specifically AFL. Yun et al. demonstrated that 5% lidocaine cream applied after Er:YAG-AFL for a full resurfacing procedure showed significant lower pain score after the first pass of resurfacing, but there were only half of the patients were able to tolerate the second pass. [ 33 ]  Nevertheless, this indicated that LADD showed an enhancement of lidocaine penetration through the stratum corneum. Similarly, in a double-blind randomized controlled trial with 320 healthy volunteers, the patients were either pre-treated with Er:YAG-AFL followed by 4% lidocaine or treated with topical 4% lidocaine alone before cannulation. [ 34 ]  The results showed a 62% reduction in pain with the use of LADD as compared to conventional topical lidocaine.


When applying LADD in clinical settings, safety is an imperative factor that needs to be considered. As mentioned above, there are different lasers with distinct properties that could be implemented for patients. However, radiation of any type will damage human tissue to some extent. Some potential adverse events that are laser-induced include erythema, edema, scabbing, blistering, and pigmentary changes, especially at higher intensity and densities. [ 35 ] [ 36 ] [ 37 ]  Regarding intralesional therapies for scarring, telangiectasia, hypopigmentation, and skin atrophy have been observed in multiple studies as side effects of LADD. [ 35 ] [ 38 ] [ 39 ] [ 40 ] [ 41 ]  In LADD application for management of pigmentary condition, there are some pigment-related adverse effects such as worsening of melasma, [ 42 ] [ 43 ]  and hyperpigmentation in vitiligo. [ 44 ] [ 45 ]  While LADD improves the dermal infiltration of different medications, the skin also has heightened local reaction when exposed to the substances and external environment. [ 46 ]  In several studies about AFL-assisted delivery of MAL-photodynamic therapy, there are intensified local cutaneous responses, including burning sensation, pain, edema, pruritus, purpura, and transient pigmentary changes. [ 47 ] [ 48 ] [ 49 ] [ 50 ] [ 51 ] [ 52 ]  Furthermore, exposing the underlying dermis and vasculature to the outside environment also increases the risk of infection. [ 26 ]  AFL-assisted delivery of 5-FU, steroids, and MAL have shown elevated bacterial infections. [ 53 ] [ 54 ] [ 28 ] [ 55 ] [ 56 ]  In general, most LADD safety concerns are related to local reactions similar to that of laser therapy, and are generally well-tolerated with some exceptions. [ 57 ]


Current studies support the use of LADD in adjunction with topical products in treating dermatological diseases, but these studies are limited in sample size and lack of long-term follow-up outcomes. Larger randomized controlled trials with a wide variety of topical drugs are required to validate the efficacy and side effects of LADD before this technique could be employed as a standard of treatment. Besides its application in drug delivery, the prospect of using LADD to improve the transdermal delivery of vaccines, promote wound healing, correct genetic sequence, and as a complement to inflammatory dermatoses and cosmetic indications is being investigated [ 58 ]


Liniment  (from  Latin :  linere , meaning "to  anoint "), also called  embrocation  and  heat rub , is a medicated topical preparation for application to the skin. Some liniments have a viscosity similar to that of water; others are  lotion  or balm; still, others are in  transdermal patches , soft solid sticks, and sprays. Liniment usually is rubbed into the skin, which the active ingredients penetrate.


Liniments are typically sold to relieve pain and stiffness, such as from  muscular   aches  and  strains , and  arthritis . These are typically formulated from  alcohol ,  acetone , or similar quickly evaporating  solvents  and contain  counterirritant  aromatic chemical compounds, such as  methyl salicylate ,  benzoin resin ,  menthol , and  capsaicin . They produce a feeling of warmth within the  muscle  of the area they are applied to, typically acting as  rubefacients  via a counterirritant effect.


Methyl salicylate , which is the  analgesic  ingredient in some heat rubs, can be toxic if used in excess. [ 1 ]   Heating pads  are also not recommended for use with heat rubs, because the added warmth may cause overabsorption of the active ingredients.


Liniments are commonly used on horses following exercise, applied either by rubbing on full-strength, especially on the legs; or applied in a diluted form, usually added to a bucket of water and sponged on the body. They are used in hot weather to help cool down a horse after working, the alcohol cooling through rapid evaporation, and counterirritant oils dilating capillaries in the skin, increasing the amount of blood releasing heat from the body. [ 16 ]


Many horse liniment formulas in diluted form have been used on humans, though products for horses which contain  DMSO  are not suitable for human use, as DMSO carries the topical product into the bloodstream. [ 17 ]  Horse liniment ingredients such as menthol,  chloroxylenol , or iodine are also used in different formulas in products used by humans. [ 18 ]


Absorbine , a horse liniment product manufactured by  W.F. Young, Inc. , was reformulated for humans and marketed as Absorbine Jr. [ 19 ]   The company also acquired other liniment brands including Bigeloil and RefreshMint. [ 20 ]   The equine version of Absorbine is sometimes used by humans, [ 21 ]  though, anecdotally, its benefits in humans may be because the smell of menthol releases  serotonin , or due to a  placebo effect . [ 19 ]


Earl Sloan  was a US entrepreneur who made his initial fortune selling his father's horse liniment formula beginning in the period following the Civil War. Sloan's liniment with capsicum as a key ingredient was also marketed for human use. He later sold his company to the predecessor of  Warner–Lambert , which was purchased in 2000 by  Pfizer . [ 22 ] [ 23 ]


Lip balm  or  lip salve  is a  wax -like substance applied to the lips to moisturize and relieve  chapped  or dry lips,  angular cheilitis ,  stomatitis , or  cold sores . Lip balm often contains   beeswax  or  carnauba wax ,  camphor ,  cetyl alcohol ,  lanolin ,  paraffin , and  petrolatum , among other ingredients. Some varieties contain dyes, flavor, fragrance,  phenol ,  salicylic acid , and  sunscreen .


The primary purpose of lip balm is to provide an occlusive layer on the lip surface to seal moisture in lips and protect them from external exposure. Dry air, cold temperatures, and wind all have a drying effect on skin by drawing moisture away from the body. Lips are particularly vulnerable because the skin is so thin, and thus they are often the first to present signs of dryness. Occlusive materials like waxes and  petroleum jelly  prevent moisture loss and maintain lip comfort while flavorings, colorants, sunscreens, and various medicaments can provide additional, specific benefits. Lip balms are produced from bee wax and natural candelilla and carnauba waxes. [ 1 ]


Lip balm can be applied by a finger to the lips, or in a  lipstick -style tube from which it can be applied directly.


In 2022, the global lip balm market was valued at US$732.76 mln. The market is predicted to grow at a rate of 9.28% within the next five years and is likely to reach US$1247.74 mln by 2027. [ 2 ]


Production for lip balms includes the following stages: [ 3 ]


Since 40 BC, the Egyptians made treatment for lip care, which was made with a mixture of beeswax, olive oil, and animal fat. [ 4 ]


In the 1800s,  Lydia Maria Child  recommended earwax as a treatment for cracked lips in her highly-popular book,  The American Frugal Housewife .  Child observed that, "Those who are troubled with cracked lips have found this earwax remedy successful when others have failed. It is one of those sorts of cures, which are very likely to be laughed at; but I know of its having produced very beneficial results." [ 5 ]  The invention of the lip balm was first formally invented in the 1880s by physician  Charles Brown Fleet [ 6 ]  though its origins may be traced to  earwax . [ 7 ]  Fleet later named his lip balm product " ChapStick ". [ 8 ]


In 1872, chemist  Robert Chesebrough  discovered and sampled a new petroleum jelly, initially describing it as a "natural, waxy ingredient, rich in minerals from deep within the earth" which could be used as a solution for skin repair. He then distributed his product under the name "Wonder Jelly" before shortly changing it to "Vaseline". [ 9 ]


In the early 1880s, Charles Brown Fleet created ChapStick. [ 8 ]  However, due to the lack of sales, Fleet sold his formula and rights to ChapStick to John Morton in 1912 for $5, who saw the marketing potential in the brand. [ 4 ]  After making the purchase, Morton commissioned Frank Wright, Jr. to create a design for the logo of ChapStick for $15 in 1936. [ 4 ]  In 1972, ChapStick tubes concealing hidden microphones were used during the  Watergate scandal . [ 10 ]


In 1937, Alfred Woelbing created  Carmex  to treat cold sores in Milwaukee, though the occurrence of  World War 2  would slow the production and sales due to the lack of  lanolin . In 1980, Carmex underwent a product change by converting its packaging into squeezable tubes. [ 11 ]


In 1973,  Bonne Bell  created the first flavored lip balm and marketed the company as Lip Smackers. The company would later collaborate on various different-flavored lip balms including  Dr. Pepper  in 1975,  The Wrigley Company  in 2004, and  The Coca-Cola Company  in 2006. Bonne Bell also collaborated with  Disney  to produce lip balms with various princess characters in 2010. [ 12 ]


In 1991, Burt Shavitz and Roxanne Quimby created their first beeswax based lip balm solution through their company,  Burt's Bees . [ 13 ]  In 2020, it was reported that Burt's Bees had used 50 percent of recycled material to package various products and that 100 percent of the products were recyclable. [ 14 ]


In 2011,  Evolution of Smooth  (or commonly known as EOS) created a spherical-shaped lip balm as well as describing its 95% organic ingredients. [ 4 ]


With the gradual legalization of cannabis in the United States, some companies have produced lip balms containing doses of  THC  or  CBD  oil. The lip balms were infused with a low dosage of THC in order to prevent the occurrence of any psychoactive or related effect.  [ citation needed ]


According to a report, professor Brad Rohu states that it is natural for the lips to feel dry. [ 15 ]  The exposure to environments with cold, dry, or windy weather can directly cause the chapping of the lips as well as behaviors such as lip licking or  mouth breathing . [ 16 ]  These factors may directly contribute to an increased amount of lip balm usage. According to dermatologist Amy Derick, those who have expressed dependencies on lip balm have developed a desire of how the lips feel after application. She also mentions that the variety of lip balm flavor may also directly cause lip balm dependency as a person may want to lick their lips to taste the flavor, which may consequentially remove the lip balm coating from the lips. This may also leave saliva on the lips which can dry up and make the lips feel even more dry than they initially were. [ 17 ]


Some physicians have suggested that certain types of lip balm can be addictive or contain ingredients that actually cause drying, [ 18 ]  though, it has been debated by many professionals. Lip balm manufacturers sometimes state in their FAQs that there is nothing addictive in their products or that all ingredients are listed and approved by the  FDA .  Snopes  found the claim that there are substances in  Carmex  that are irritants necessitating reapplication, such as ground glass, to be false. [ 19 ]  However, some experts such as dermatologist Dr. Cynthia Bailey state that some ingredients in lip balm directly causes sensitive lip skin which may lead to addiction. [ 20 ]  Dermatology professor Marcia Driscoll also adds onto this argument by stating that aroma ingredients found in flavored or scented lip balms have the potential to irritate skin. [ 21 ]


The human lips have an inadequate capability of holding moisture as well as an imperfect lip barrier function. [ 22 ]  The  Journal of the American Academy of Dermatology  performed a study in order to determine whether consistent use of lip balm would enhance the overall quality of the lips. The study used 32 female participants within the ages of 20 to 40 years and the participants had mild to moderate dried lips without any history of health-related complications. The participants underwent a procedure in which no lip treatment was provided on the first 3 days, then 2 weeks of consistent lip balm usage, and then a period of no treatment for 3 days. The study determined the quality of the lips based on the physical details and appearance throughout the study. The study showed a direct improvement of the physical details of the lips except for lip cracking during the second week of treatment and after the period of no treatment. The study also showed that hydration of the lips lasted for approximately 8 hours after usage and the lip balm improved the lip barrier function despite discontinued usage. The study concluded that lip balms assist the hydration of the lips which consequentially improves the lip barrier function and the quality. [ 23 ]  This study was completely funded by  Burt's Bees , a lip balm company.


In 2015, German consumer watchdog  Stiftung Warentest  analyzed cosmetics containing mineral oils. After developing a new detection method they found high concentrations of Mineral Oil Aromatic Hydrocarbons (MOAH) and even polyaromatics in products containing mineral oils with Vaseline products containing the most MOAH of all tested cosmetics (up to 9%). [ 24 ]  The  European Food Safety Authority  sees MOAH and polyaromatics as possibly carcinogenic. [ 24 ]  Based on the results, Stiftung Warentest warns not to use Vaseline or any product that is based on mineral oils for lip care.


In 2019, a research report conducted by the  Statista Research Department  concluded that ChapStick was the leading lip balm brand in the United States with an approximate unit sale of 55.8 million. Carmex was the second leading brand with approximately 35.2 million units sold and Burt's Bees being the third leading brand with approximately 32.3 million units sold. [ 25 ]


Beezin' is a trend dating back to 2013 in which a person applies  Burt's Bees  brand lip balm onto the eyelids. [ 26 ]  The practice is done in order to feel a sensation of being high or drunk, and even to increase the desired effects of alcohol and other substances. [ 27 ]  In 2022, Beezin' became a viral trend on the social media platform  TikTok . [ 28 ]  Some ingredients, including peppermint oil, are known to be eye irritants which can cause an unintentional inflammatory response which may require treatment and may also cause dermatitis on the eyelids. [ 29 ]


A  liposome  is a small artificial  vesicle , spherical in shape, having at least one  lipid bilayer . [ 2 ]  Due to their hydrophobicity and/or hydrophilicity, biocompatibility, particle size and many other properties, [ 2 ]  liposomes can be used as  drug delivery  vehicles for  administration  of  pharmaceutical drugs  and  nutrients , [ 3 ]  such as  lipid nanoparticles  in  mRNA vaccines , and  DNA vaccines .  Liposomes can be prepared by disrupting biological membranes (such as by  sonication ).


Liposomes are most often composed of  phospholipids , [ 4 ]  especially  phosphatidylcholine , and  cholesterol , [ 2 ]  but may also include other lipids, such as those found in  egg  and  phosphatidylethanolamine , as long as they are compatible with  lipid bilayer  structure. [ 5 ]  A liposome design may employ surface  ligands  for attaching to desired cells or tissues. [ 1 ]


Based on vesicle structure, there are seven main categories for liposomes: multilamellar large (MLV), oligolamellar (OLV), small unilamellar (SUV), medium-sized unilamellar (MUV), large unilamellar (LUV), giant unilamellar (GUV) and multivesicular vesicles (MVV). [ 6 ]  The major types of liposomes are the multilamellar vesicle (MLV, with several  lamellar phase   lipid bilayers ), the small  unilamellar liposome  vesicle (SUV, with one  lipid bilayer ), the large unilamellar vesicle (LUV), and the cochleate vesicle. A less desirable form is multivesicular liposomes in which one vesicle contains one or more smaller vesicles.


Liposomes should not be confused with  lysosomes , or with  micelles  and  reverse micelles . [ 8 ]  In contrast to liposomes, micelles typically contain a monolayer of fatty acids or surfactants. [ 9 ]


The word  liposome  derives from two Greek words:  lipo  ("fat") and  soma  ("body"); it is so named because its composition is primarily of phospholipid.


Liposomes were first described by British hematologist  Alec Douglas Bangham [ 10 ] [ 11 ] [ 12 ]  in 1961 at the Babraham Institute, in Cambridge—findings that were published 1964. The discovery came about when Bangham and R. W. Horne were testing the institute's new  electron microscope  by adding  negative stain  to dry phospholipids. The resemblance to the  plasmalemma  was obvious, and the microscopic pictures provided the first evidence that the cell membrane is a bilayer lipid structure. The following year, Bangham, his colleague Malcolm Standish, and  Gerald Weissmann , an American physician, established the integrity of this closed, bilayer structure and its ability to release its contents following detergent treatment (structure-linked latency). [ 13 ]  During a Cambridge pub discussion with Bangham, Weissmann first named the structures "liposomes" after something which laboratory had been studying, the lysosome: a simple organelle whose structure-linked latency  could be disrupted by detergents and streptolysins. [ 14 ]  Liposomes are readily distinguishable from micelles and hexagonal lipid phases through negative staining transmission electron microscopy. [ 15 ]