As of 2020, three brands of autoinjectors are available in Canada: Allerject, Emerade, and EpiPen. [ 92 ]  One generic autoinjector has been approved by  Health Canada  but is not marketed. [ 93 ]  From 2015 to 2020 the only autoinjector marketed in Canada was EpiPen and production issues led to supply shortages during that period. [ 94 ] [ 95 ] [ 96 ]  During a 2018 shortage of EpiPens,  Health Canada  temporarily permitted the importation of Auvi-Q autoinjectors from the United States. [ 97 ]


As of 2005, epinephrine autoinjectors were not available in most of the developing world. [ 6 ]


As of May 2019 [update] , in Canada the wholesale cost of a single EpiPen is approximately  CA$95.00 . [ 93 ]


As of September 2016 [update] , two EpiPens cost around $100 in France and at maximum 10€ for members of the statutory health insurance in Germany. [ 43 ] [ 98 ]


As of September 2016 [update] , two Jext autoinjectors cost users about £8.50 (US$11.64) in Britain, and the National Health Service pays around £48 (US$65.75) in order to make them available; that price was about 17 percent less than 2013. [ 43 ]


Supplies of 150 microgram adrenaline auto-injectors were said to be “critical” in the United Kingdom in October 2018.  Community pharmacists were told to prioritise supplies for children weighing 25 kg or less.   Mylan  identified shortages because of manufacturing problems in May 2018. [ 99 ]


In October 2016 the CEO of  Mylan  testified to Congress that Pfizer/King charged Mylan about $34.50 for one EpiPen. [ 31 ]  The devices deliver about $1 worth of drug. [ 29 ] [ clarification needed ]  In September 2016, a Silicon Valley engineering consultancy performed a teardown analysis of the EpiPen and estimated the manufacturing and packaging costs at about $10 for a two-pack. [ 100 ]


The EpiPen, manufactured by Meridian Medical Technologies, and marketed by Mylan, has dominated the market. [ 57 ]  In 2007 when Mylan acquired the rights to market the product, annual sales of all epinephrine autoinjectors were about $200 million and EpiPen had around 90% of the market; in 2015 the market size was around $1.5 billion and Mylan still had about 90% of the market. [ 30 ] [ 57 ]  Mylan raised the price from around $100 for a package of two EpiPens in 2007 to around $600 in 2016. [ 78 ]  In the United Kingdom, an EpiPen costs £26.45 as of 2015. [ 101 ]  In Canada they are about 120 CAD each. [ 102 ]


Mylan acquired the right to market the EpiPen line of epinephrine autoinjector devices from  Merck KGaA  as part of their 2007 deal. [ 28 ]   Heather Bresch , Mylan's CEO, saw an opportunity to increase sales in the US through marketing and advocacy, and the company launched a marketing campaign to increase awareness of the dangers of  anaphylaxis  for people with severe allergies that made the  EpiPen  brand as identified with epinephrine autoinjectors as  Kleenex  is for facial tissue; the company also successfully lobbied the FDA to broaden the label to include risk of anaphylaxis and in parallel, successfully lobbied Congress to generate legislation making EpiPens available in public places like  defibrillators  are, and hired the same people that  Medtronic  had worked with on defibrillator legislation to do so. [ 29 ]


Mylan's efforts to maintain its market dominance were aided when  Sanofi 's competing product was recalled in November 2015 and further when  Teva 's generic competitor was rejected by the FDA in March 2016. [ 103 ]  By the first half of 2015, sales of EpiPen accounted for 40% of Mylan's profit. [ 29 ]  Those profits were also due in part to Mylan's continually raising the price of EpiPens starting in 2009: in 2007, the wholesale price of two EpiPens was about $100; the price was about the same in 2009; by July 2013, the price was about $265; in May 2015, it was around $461; and in May 2016, the price rose again to around $609, [ 28 ]  around a 500% jump from the price in 2009. [ 78 ]  The last price increase sparked widespread outrage in the late summer as parents prepared to send their children back to school and went to pharmacies to get new EpiPens. [ 79 ] [ 80 ]   Some Americans responded to the high price by buying EpiPens online from pharmacies outside the US, [ 104 ] [ 105 ]  forgoing new EpiPens and relying on their expired EpiPen, [ 104 ]  or forgoing an autoinjector altogether and having their children carry pre-loaded syringes. [ 106 ] [ 107 ]  Former Mylan CEO, Heather Bresch testified before the U.S. Senate Special Committee on Aging to argue that the price change was "fair". [ 108 ]


In response to criticism, Mylan increased financial assistance available for some patients to purchase EpiPens, [ 109 ]  a gesture that was called a "classic public relations move" by Harvard Medical School professor Aaron Kesselheim. [ 110 ]  The up to $300 saving cards can be used only by a small number of people who need the drug, and no one on  Medicaid . They do nothing about the high price which is still being paid by insurers, who ultimately pass the cost on to consumers. [ 110 ]   In October 2016, Mylan announced a settlement with the  US Department of Justice  over rebates paid by Mylan to states under the  Medicaid Drug Rebate Program . [ 83 ]   Questions had been raised by Congress and others about why EpiPen had been classified as a generic rather a proprietary product in the program since 1997; generic drugs have lower rebates (13%) than proprietary drugs (23%), and price hikes for generic drugs cannot be passed onto states, and a common form of  pharmaceutical fraud  involves misclassifying proprietary drugs as generic under the program. [ 111 ]   Under the agreement, Mylan agreed to pay a $465 million payment and to a sign a  corporate integrity agreement  requiring it to perform better in the future; [ 83 ]  the settlement also resolved cases brought by states related to the rebates. [ 112 ]


As of August 2016 [update] , the  authorized generic  of Adrenaclick cost $142 at retail stores. [ 107 ] [ 113 ]


In September 2016, a group of  hackers  called the  Four Thieves Vinegar  published a video and documents describing what they call an EpiPencil, an autoinjector which can be built using off-the-shelf parts, for a claimed price tag of about $30. [ 114 ]  At its core is a repurposed insulin autoinjector. [ 115 ]  This device has not been subject to any validation by regulatory agencies. [ 114 ]


Ethosomes  are  phospholipid   nanovesicles  used for dermal and  transdermal delivery  of molecules. Ethosomes were developed by Touitou et al.,1997, as additional novel lipid carriers composed of ethanol, phospholipids, and water. They are reported to improve the skin delivery of various drugs. Ethanol is an efficient permeation enhancer that is believed to act by affecting the intercellular region of the stratum corneum. Ethosomes are soft malleable vesicles composed mainly of phospholipids, ethanol (relatively high concentration), and water. These soft vesicles represent novel vesicles carriers for enhanced delivery through the skin. The size of the ethosomes vesicles can be modulated from tens of nanometers to microns. [ 1 ]


Ethosomes are mainly composed of multiple, concentric layers of flexible  phospholipid bilayers , with a relative high concentration of  ethanol  (20-45%),  glycols  and water. [ 2 ] [ 3 ]  Their overall structure has been confirmed by  31 P-NMR ,  EM  and  DSC . [ citation needed ]  They have high penetration of the  horny layer of the skin , which enhances the permeation of encapsulated drugs. The mechanism of permeation enhancement is attributed to the overall properties of the system. [ 4 ] [ 5 ]


Because of their unique structure, ethosomes are able to efficiently encapsulate and deliver into the skin highly  lipophilic  molecules such as  testosterone ,  cannabinoids  and  ibuprofen , as well as  hydrophilic  drugs such as  clindamycin phosphate ,  buspirone hydrochloride . They have been studied for the transdermal and intradermal delivery of  peptides ,  steroids ,  antibiotics ,  prostaglandins ,  antivirals  and  anti-pyretics . [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ] [ 14 ] [ 15 ] [ 16 ]  The components used to make ethosomes are already approved for pharmaceutical and  cosmetic  use and the formulated vesicles are stable when stored. [ citation needed ]  They can be incorporated in various pharmaceutical formulations such as  gels ,  creams ,  emulsions  and sprays. [ citation needed ]  They're consequently being developed for  pharmaceutical  and  cosmeceutical  products. [ 17 ] [ 18 ] [ 19 ] [ 20 ] [ 21 ] [ 22 ] [ 23 ]  Ethosomal systems compare favourably to alternative carriers for quantity and depth of molecule delivery. [ 24 ] [ 25 ] [ 26 ] [ 27 ] [ 28 ] [ 29 ] [ 30 ]


Exhalation delivery systems  ( EDS ) deliver medications to the  internal nose . Developed in 2006, [ 1 ]  EDS devices use the patient's exhaled breath to propel medication, such as steroids, [ 1 ]  into the nasal cavities. The method can deliver medication deeper into the nasal passages than intranasal sprays, [ 1 ]  and at a lower pressure than nasal irrigation methods. [ 1 ]


Using EDS to deliver  fluticasone  (EDS-FLU) to patients with  nasal polyps  has been shown to reduce the need for surgery. [ 1 ]


This  pulmonology  article is a  stub . You can help Wikipedia by  expanding it .


Extra-amniotic administration  is a  route of administration  to the space between the  fetal membranes  and  endometrium  inside the  uterus  of a  pregnant  woman.


It can be used to administer drugs affecting  uterus  motility, such as  oxytocin  and  prostaglandins , e.g. in  labor induction  or  medical abortion . [ 1 ]


Eye drops  or  eyedrops  are  liquid drops  applied directly to the surface of the  eye  usually in small amounts such as a single drop or a few drops. Eye drops usually contain  saline  to match the  salinity  of the eye. Drops containing only saline and sometimes  a lubricant are often used as artificial  tears  to treat  dry eyes  or simple  eye irritation  such as itching or  redness . Eye drops may also contain one or more medications to treat a wide variety of  eye diseases . Depending on the condition being treated, they may contain  steroids ,  antihistamines ,  sympathomimetics ,  beta receptor blockers ,  parasympathomimetics ,  parasympatholytics ,  prostaglandins ,  nonsteroidal anti-inflammatory drugs  (NSAIDs),  antibiotics ,  antifungals , or  topical anesthetics .


Eye drops have less of a risk of side effects than do oral medicines, and such risk can be minimized by occluding the  lacrimal punctum  (i.e. pressing on the inner corner of the eye) for a short while after instilling drops.


Prior to the development of single-use pre-loaded sterile plastic applicators, eye drops were administered using an  eye dropper , a glass pipette with a rubber bulb.


Although most bottles of eye drops contain preservatives to inhibit contamination once opened, these will not prevent contamination indefinitely. Ophthalmologists recommend keeping bottles for no longer than three months after opening. [ 1 ]  Eye drops that contain no preservatives are usually packaged in single-use tubes.  Dispensers typically oversize the drops; the human eye can only handle about 25 microlitres. [ 2 ]


Different pharmacological classes of eye drops can be recognized by patients by their different colored tops. For instance, the tops to dilating drops are a different color than anti-allergy drops.


Eyes drops sometimes do not have medications in them and are only lubricating and tear-replacing solutions. There is a wide variety of  artificial tear  eye drops that provide different surface healing strategies. One can find bicarbonate ions,  hypotonicity , high  viscosity  gels and ointments, and non-preserved types. They all act differently and therefore, one may have to try different artificial tears to find the one that works the best. [ 3 ]


Steroid and antibiotic eye drops are used to treat eye  infections . They also have  prophylactic  properties and are used to prevent infections after eye surgeries. They should be used for the entire time prescribed without interruptions. The infection may relapse if the use of the medication is stopped. [ 4 ]


Antibiotic eye drops are prescribed when infection  conjunctivitis  is caused by bacteria but not when it is caused by a virus. In the case of allergic conjunctivitis, artificial tears can help dilute irritating allergens present in the tear film. [ 5 ]


Some eye drops may contain  histamine antagonists  or  nonsteroidal anti-inflammatory drug  (NSAIDs), which suppress the optical mast cell responses to allergens including (but not limited to) aerosolized dust particles.


Eye drops used in managing  glaucoma  help the eye's  fluid  to drain better and decrease the amount of fluid made by the eye which decreases eye pressure. They are classified by their active ingredient and they include:  prostaglandin analogs ,  beta blockers , alpha agonists, and  carbonic anhydrase inhibitors . There are also combination drugs available for those patients who require more than one type of medication. [ 6 ]


These make the eye's  pupil  widen to maximum, to let an  optometrist  have the best view inside the  eyeball  behind the iris. Afterwards in sunny weather they can cause dazzling and  photophobia  until the effect of the  mydriatic  has worn off.


In some countries including  Russia  and  Italy , Tropicamide, a mydriatic eye drop, is used to some degree as an inexpensive recreational drug. [ 7 ]  Like other anticholinergics, when taken recreationally, tropicamide acts as a deliriant. When injected intravenously, as is most often the case, the tropicamide may cause problems such as slurred speech, unconsciousness, unresponsiveness, hallucinations, kidney pain, dysphoria, hyperthermia, tremors, suicidal tendency, convulsions, psychomotor agitation, tachycardia and headache. [ 7 ]


Syringe designed saline drops (e.g. Wallace Cameron Ultra Saline Minipod) are distributed in modern  needle-exchange programmes  as they can be used efficiently either by injection or ophthalmic (if the drug is potent in small doses) route of administer which is compared to intravenous use; by demonstration, the elimination of latanoprost acid from plasma is rapid (half-life 17 minutes) after either ophthalmic or intravenous administration. [ 8 ]


Steroid and antibiotic eye drops may cause stinging for one or two minutes when first used and if stinging continues, medical advice should be sought. Also, one should tell their doctor if vision changes occur or if they experience persistent  sore throat ,  fever , easy  bleeding  or  bruising  when using drops with  chloramphenicol . Also, one should be aware of symptoms of an allergic reaction, such as:  rash ,  itching ,  swelling ,  dizziness , and trouble breathing. [ 4 ]  Long term steroid use can cause many adverse effects including steroid-induced  glaucoma  and  cataract . [ 9 ]


Prostaglandin analogs may cause changes in  iris  color and  eyelid  skin, growth of  eyelashes , stinging,  blurred vision , eye redness, itching, and burning. Beta blockers' side effects include  low blood pressure , reduced  pulse rate ,  fatigue , shortness of breath, and in rare occasions, reduced  libido  and  depression . Alpha agonists can cause burning or stinging, fatigue,  headache ,  drowsiness ,  dry mouth  and  nose , and also they have a higher likelihood of allergic reaction. Carbonic anhydrase inhibitors may cause stinging, burning, and eye discomfort. [ 10 ]


Lubricant eye drops may cause some side effects and one should consult a doctor if pain in the eye or changes in vision occur.  Furthermore, when redness occurs but lasts more than 3 days, one should immediately consult a doctor. [ citation needed ]


EyePoint Pharmaceuticals Inc.  (formerly  pSivida Corporation ) is a  Watertown, Massachusetts  company specialising in the application of  microelectromechanical systems  (MEMS) and  nanotechnology  to drug delivery.


pSivida obtained  porous silicon  technology from the British government  Defence Evaluation and Research Agency  (DERA, now  QinetiQ ). [ citation needed ]  QinetiQ continues to be a strategic partner. [ 1 ] [ 2 ]


In June 2004, pSivida acquired full ownership of pSiMedica. [ 1 ]  In April 2018, pSivida purchased eye products firm Icon Bioscience. [ 3 ] [ 4 ]  Afterwards, it rebranded to its current name of EyepOint Pharmaceuticals, Inc. [ 5 ]


This United States manufacturing company–related article is a  stub . You can help Wikipedia by  expanding it .


Fumigatory boxes  were described in the 19th century as prophylactic or curative medical devices designed to use smoke or vapor to restore health or help prevent the spread of infectious or contagious diseases.


Fumigatory boxes were sometimes used to combat the spread of infectious diseases such as the  plague . One version used in 1837 in Turkey was described as a wooden box approximately 8 feet tall by 3 feet wide (about 2.4 m by 1 m).  At the bottom was a one-foot (30 cm) tall chamber in which the ingredients of the prophylactic were burned in a dish. Before entering a residence or public building, the clothed subject was to stand inside the box with his or her face protruding through an opening to avoid suffocation, while the rest of his or her body and clothing were engulfed in the smoke produced by the burning disinfectant.  Its purpose was to inhibit the spread of the virulent epidemic then decimating  Constantinople  and its environs.  Although the government ordered such devices installed outside all government buildings, they were often ignored by the populace. [ 1 ]


Another version was designed by Dr. Gales, an  apothecary  at the  Hospital St. Louis  in Paris, in 1812 or shortly thereafter. It had the naked subject seated on a chair in a wooden box, with the patient's entire head exposed through an opening at the box's top. The opening around the patient's neck was sealed so fumes could not escape. There were three chambers at the bottom of this box, the top one containing  sulfur  which was heated by a fire in a chamber below. A bottom chamber caught the ashes.  The sulfurous fumes rose through many small holes drilled through the floor of the patient compartment. If necessary, fumes could be applied directly to the head or face by means of a flexible hose attached to the main compartment. The purpose of this type of fumigatory box was curative or palliative rather than prophylactic, used as a treatment for ailments including  rheumatism  and  psoriasis , not to prevent the spread of disease. [ 2 ] [ 3 ]


A third type of fumigatory box was described at the turn of the 20th century as being used to fumigate imported plants on their arrival in Jamaica, to prevent the importation of plant diseases or pests. Plants were placed in the box for one hour and one vial of  cyanide  was released per 300 cubic feet (8.5 cubic meters) of space inside the fumigatory box. For delicate plants, one half the dose for one half-hour was recommended. [ 4 ]  Similar devices, often called fumigation chambers, are still sometimes used. [ citation needed ]


A  gel  is a  semi-solid  that can have properties ranging from soft and weak to hard and tough. [ 1 ] [ 2 ]  Gels are defined as a substantially dilute  cross-linked  system, which exhibits no flow when in the steady state, although the liquid phase may still diffuse through this system. [ 3 ]


Gels are mostly liquid  by mass , yet they behave like solids because of a three-dimensional cross-linked network within the liquid. It is the cross-linking within the fluid that gives a gel its structure (hardness) and contributes to the adhesive stick ( tack ). In this way, gels are a dispersion of molecules of a liquid within a solid medium. The word  gel  was coined by 19th-century Scottish chemist  Thomas Graham  by  clipping  from  gelatine . [ 4 ]


The process of forming a gel is called  gelation .


Gels consist of a solid three-dimensional network that spans the volume of a liquid medium and ensnares it through  surface tension  effects. This internal network structure may result from physical bonds such as polymer chain entanglements (see  polymers )  (physical gels) or  chemical bonds  such as  disulfide  bonds (see  thiomers ) (chemical gels), as well as  crystallites  or other junctions that remain intact within the extending fluid. Virtually any fluid can be used as an extender including water ( hydrogels ), oil, and air ( aerogel ). Both by weight and volume, gels are mostly fluid in composition and thus exhibit densities similar to those of their constituent liquids. Edible jelly is a common example of a hydrogel and has approximately the density of water.


Polyionic polymers are polymers with an ionic functional group. The ionic charges prevent the formation of tightly coiled polymer chains. This allows them to contribute more to  viscosity  in their stretched state, because the stretched-out polymer takes up more space. This is also the reason gel hardens. See  polyelectrolyte  for more information.


A  colloidal  gel consists of a  percolated  network of particles in a fluid medium, [ 5 ]  providing  mechanical properties , [ 6 ]  in particular the emergence of elastic behaviour. [ 7 ]  The particles can show attractive interactions through  osmotic depletion  or through polymeric links. [ 8 ]


Colloidal gels have three phases in their lifespan: gelation, aging and collapse. [ 9 ] [ 10 ]  The gel is initially formed by the assembly of particles into a space-spanning network, leading to a phase arrest. In the aging phase, the particles slowly rearrange to form thicker strands, increasing the elasticity of the material. Gels can also be collapsed and separated by external fields such as gravity. [ 11 ]  Colloidal gels show linear response rheology at low amplitudes. [ 12 ]  These materials have been explored as candidates for a drug release matrix. [ 13 ]


A  hydrogel  is a network of polymer chains that are hydrophilic, sometimes found as a  colloidal  gel in which water is the dispersion medium. A three-dimensional solid results from the hydrophilic polymer chains being held together by cross-links. [ clarification needed ]  Because of the inherent cross-links, the structural integrity of the hydrogel network does not dissolve from the high concentration of water. [ 14 ]  Hydrogels are highly  absorbent  (they can contain over 90% water) natural or synthetic polymeric networks.
Hydrogels also possess a degree of flexibility very similar to natural tissue, due to their significant water content. As responsive " smart materials ," hydrogels can encapsulate chemical systems which upon stimulation by external factors such as a change of pH may cause specific compounds such as glucose to be liberated to the environment, in most cases by a  gel-sol transition  to the liquid state. [ 15 ]  Chemomechanical polymers are mostly also hydrogels, which upon stimulation change their volume and can serve as  actuators  or  sensors . The first appearance of the term 'hydrogel' in the literature was in 1894. [ 16 ]


An  organogel  is a  non-crystalline ,  non-glassy  thermoreversible ( thermoplastic ) solid material composed of a  liquid   organic  phase entrapped in a three-dimensionally cross-linked network. The liquid can be, for example, an  organic solvent ,  mineral oil , or  vegetable oil . The  solubility  and  particle  dimensions of the structurant are important characteristics for the  elastic  properties and firmness of the organogel. Often, these systems are based on  self-assembly  of the structurant molecules. [ 17 ] [ 18 ]  (An example of formation of an undesired thermoreversible network is the occurrence of wax crystallization in  petroleum . [ 19 ] )


Organogels have potential for use in a number of applications, such as in  pharmaceuticals , [ 20 ]  cosmetics, art conservation, [ 21 ]  and food. [ 22 ]


A  xerogel   / ˈ z ɪər oʊ ˌ dʒ ɛ l /  is a solid formed from a gel by drying with unhindered shrinkage. Xerogels usually retain high porosity (15–50%) and enormous surface area (150–900 m 2 /g), along with very small  pore  size (1–10 nm). When  solvent  removal occurs under  supercritical  conditions, the network does not shrink and a highly porous, low-density material known as an  aerogel  is produced. Heat treatment of a xerogel at elevated temperature produces viscous  sintering  (shrinkage of the xerogel due to a small amount of viscous flow) which results in a denser and more robust solid, the density and porosity achieved depend on the sintering conditions.


Nanocomposite hydrogels [ 23 ] [ 24 ]  or hybrid hydrogels, are highly hydrated polymeric networks, either physically or covalently crosslinked with each other and/or with nanoparticles or nanostructures. [ 25 ]  Nanocomposite hydrogels can mimic native tissue properties, structure and microenvironment due to their hydrated and interconnected porous structure. A wide range of nanoparticles, such as carbon-based, polymeric, ceramic, and metallic  nanomaterials  can be incorporated within the hydrogel structure to obtain nanocomposites with tailored functionality. Nanocomposite hydrogels can be engineered to possess superior physical, chemical, electrical, thermal, and biological properties. [ 23 ] [ 26 ]


Many gels display  thixotropy  – they become fluid when agitated, but resolidify when resting.
In general, gels are apparently solid, jelly-like materials. It is a type of  non-Newtonian fluid .
By replacing the liquid with gas it is possible to prepare  aerogels , materials with exceptional properties including very low density,  high specific surface areas , and excellent thermal insulation properties.


A gel is in essence the mixture of a polymer network and a  solvent  phase. Upon stretching, the network  crosslinks  are moved further apart from each other. Due to the polymer strands between crosslinks acting as  entropic springs , gels demonstrate elasticity like  rubber  (which is just a polymer network, without solvent). This is so because the  free energy  penalty to stretch an  ideal polymer  segment

 N

 {\displaystyle N}

  monomers of size

 b

 {\displaystyle b}

  between crosslinks to an  end-to-end distance

 R

 {\displaystyle R}

  is approximately given by [ 27 ]


This is the origin of both gel and  rubber elasticity . But one key difference is that gel contains an additional solvent phase and hence is capable of having significant volume changes under  deformation  by taking in and out solvent. For example, a gel could swell to several times its initial volume after being immersed in a solvent after equilibrium is reached. This is the phenomenon of gel swelling. On the contrary, if we take the swollen gel out and allow the solvent to evaporate, the gel would shrink to roughly its original size. This gel volume change can alternatively be introduced by applying external forces. If a uniaxial compressive  stress  is applied to a gel, some solvent contained in the gel would be squeezed out and the gel shrinks in the applied-stress direction.


To study the gel mechanical state in equilibrium, a good starting point is to consider a cubic gel of volume

 V

 0

 {\displaystyle V_{0}}

  that is stretched by factors

 λ

 1

 {\displaystyle \lambda _{1}}

 ,

 λ

 2

 {\displaystyle \lambda _{2}}

  and

 λ

 3

 {\displaystyle \lambda _{3}}

  in the three orthogonal directions during swelling after being immersed in a solvent phase of initial volume

 V

 s
 0

 {\displaystyle V_{s0}}

 . The final deformed volume of gel is then

 λ

 1

 λ

 2

 λ

 3

 V

 0

 {\displaystyle \lambda _{1}\lambda _{2}\lambda _{3}V_{0}}

  and the total volume of the system is

 V

 0

 +

 V

 s
 0

 {\displaystyle V_{0}+V_{s0}}

 , that is assumed constant during the swelling process for simplicity of treatment. The swollen state of the gel is now completely characterized by stretch factors

 λ

 1

 {\displaystyle \lambda _{1}}

 ,

 λ

 2

 {\displaystyle \lambda _{2}}

  and

 λ

 3

 {\displaystyle \lambda _{3}}

  and hence it is of interest to derive the  deformation free energy  as a function of them, denoted as

 f

 gel

 (

 λ

 1

 ,

 λ

 2

 ,

 λ

 3

 )

 {\displaystyle f_{\text{gel}}(\lambda _{1},\lambda _{2},\lambda _{3})}

 . For analogy to the historical treatment of  rubber elasticity  and mixing free energy,

 f

 gel

 (

 λ

 1

 ,

 λ

 2

 ,

 λ

 3

 )

 {\displaystyle f_{\text{gel}}(\lambda _{1},\lambda _{2},\lambda _{3})}

  is most often defined as the free energy difference after and before the swelling normalized by the initial gel volume

 V

 0

 {\displaystyle V_{0}}

 , that is, a free energy difference density. The form of

 f

 gel

 (

 λ

 1

 ,

 λ

 2

 ,

 λ

 3

 )

 {\displaystyle f_{\text{gel}}(\lambda _{1},\lambda _{2},\lambda _{3})}

  naturally assumes two contributions of radically different physical origins, one associated with the  elastic deformation  of the polymer network, and the other with the  mixing  of the network with the solvent. Hence, we write [ 28 ]


We now consider the two contributions separately. The polymer elastic deformation term is independent of the solvent phase and has the same expression as a rubber, as derived in the Kuhn's theory of  rubber elasticity :


where

 G

 0

 {\displaystyle G_{0}}

  denotes the  shear modulus  of the initial state. On the other hand, the mixing term

 f

 mix

 (

 λ

 1

 ,

 λ

 2

 ,

 λ

 3

 )

 {\displaystyle f_{\text{mix}}(\lambda _{1},\lambda _{2},\lambda _{3})}

  is usually treated by the  Flory-Huggins free energy  of  concentrated polymer solutions

 f
 (
 ϕ
 )

 {\displaystyle f(\phi )}

 , where

 ϕ

 {\displaystyle \phi }

  is polymer volume fraction. Suppose the initial gel has a polymer volume fraction of

 ϕ

 0

 {\displaystyle \phi _{0}}

 , the polymer volume fraction after swelling would be

 ϕ
 =

 ϕ

 0

 /

 λ

 1

 λ

 2

 λ

 3

 {\displaystyle \phi =\phi _{0}/\lambda _{1}\lambda _{2}\lambda _{3}}

  since the number of monomers remains the same while the gel volume has increased by a factor of

 λ

 1

 λ

 2

 λ

 3

 {\displaystyle \lambda _{1}\lambda _{2}\lambda _{3}}

 . As the polymer volume fraction decreases from

 ϕ

 0

 {\displaystyle \phi _{0}}

  to

 ϕ

 {\displaystyle \phi }

 ,  a polymer solution of concentration

 ϕ

 0

 {\displaystyle \phi _{0}}

  and volume

 V

 0

 {\displaystyle V_{0}}

  is mixed with a pure solvent of volume

 (

 λ

 1

 λ

 2

 λ

 3

 −
 1
 )

 V

 0

 {\displaystyle (\lambda _{1}\lambda _{2}\lambda _{3}-1)V_{0}}

  to become a solution with polymer concentration

 ϕ

 {\displaystyle \phi }

  and volume

 λ

 1

 λ

 2

 λ

 3

 V

 0

 {\displaystyle \lambda _{1}\lambda _{2}\lambda _{3}V_{0}}

 . The free energy density change in this mixing step is given as


where on the right-hand side, the first term is the  Flory–Huggins  energy density of the final swollen gel, the second is associated with the initial gel and the third is of the pure solvent prior to mixing. Substitution of

 ϕ
 =

 ϕ

 0

 /

 λ

 1

 λ

 2

 λ

 3

 {\displaystyle \phi =\phi _{0}/\lambda _{1}\lambda _{2}\lambda _{3}}

  leads to


Note that the second term is independent of the stretching factors

 λ

 1

 {\displaystyle \lambda _{1}}

 ,

 λ

 2

 {\displaystyle \lambda _{2}}

  and

 λ

 3

 {\displaystyle \lambda _{3}}

  and hence can be dropped in subsequent analysis. Now we make use of the  Flory-Huggins  free energy for a polymer-solvent solution that reads [ 29 ]


where

 v

 c

 {\displaystyle v_{c}}

  is monomer volume,

 N

 {\displaystyle N}

  is polymer strand length and

 χ

 {\displaystyle \chi }

  is the  Flory-Huggins  energy parameter. Because in a network, the polymer length is effectively infinite, we can take the limit

 N
 →
 ∞

 {\displaystyle N\to \infty }

  and

 f
 (
 ϕ
 )

 {\displaystyle f(\phi )}

  reduces to


Substitution of this expression into

 f

 mix

 (

 λ

 1

 ,

 λ

 2

 ,

 λ

 3

 )

 {\displaystyle f_{\text{mix}}(\lambda _{1},\lambda _{2},\lambda _{3})}

  and addition of the network contribution leads to [ 28 ]


This provides the starting point to examining the swelling equilibrium of a gel network immersed in solvent. It can be shown that gel swelling is the competition between two forces, one is the  osmotic pressure  of the polymer solution that favors the take in of solvent and expansion, the other is the restoring force of the polymer network  elasticity  that favors shrinkage. At equilibrium, the two effects exactly cancel each other in principle and the associated

 λ

 1

 {\displaystyle \lambda _{1}}

 ,

 λ

 2

 {\displaystyle \lambda _{2}}

  and

 λ

 3

 {\displaystyle \lambda _{3}}

  define the equilibrium gel volume. In solving the force balance equation, graphical solutions are often preferred.


In an alternative, scaling approach, suppose an  isotropic  gel is stretch by a factor of

 λ

 {\displaystyle \lambda }

  in all three directions. Under the  affine network  approximation, the mean-square  end-to-end distance  in the gel increases from initial

 R

 0

 2

 {\displaystyle R_{0}^{2}}

  to

 (
 λ

 R

 0

 )

 2

 {\displaystyle (\lambda R_{0})^{2}}

  and the elastic energy of one stand can be written as


where

 R

 ref

 {\displaystyle R_{\text{ref}}}

  is the mean-square fluctuation in end-to-end distance of one strand. The modulus of the gel is then this single-strand elastic energy multiplied by strand number density

 ν
 =
 ϕ

 /

 N

 b

 3

 {\displaystyle \nu =\phi /Nb^{3}}

  to give [ 27 ]


This modulus can then be equated to  osmotic pressure  (through differentiation of the free energy) to give the same equation as we found above.


Consider a  hydrogel  made of  polyelectrolytes  decorated with  weak acid  groups that can ionize according to the reaction


is immersed in a salt solution of physiological concentration. The degree of  ionization  of the  polyelectrolytes  is then controlled by the

 pH

 {\displaystyle {\text{pH}}}

  and due to the charged nature of

 H

 +

 {\displaystyle {\text{H}}^{+}}

  and

 A

 −

 {\displaystyle {\text{A}}^{-}}

 ,  electrostatic interactions  with other ions in the systems. This is effectively a reacting system governed by  acid-base equilibrium  modulated by electrostatic effects, and is relevant in  drug delivery , sea water  desalination  and  dialysis  technologies. Due to the elastic nature of the gel, the dispersion of

 A

 −

 {\displaystyle {\text{A}}^{-}}

  in the system is constrained and hence, there will be a partitioning of salts ions and

 H

 +

 {\displaystyle {\text{H}}^{+}}

  inside and outside the gel, which is intimately coupled to the  polyelectrolyte  degree of ionization. This ion partitioning inside and outside the gel is analogous to the partitioning of ions across a semipemerable membrane in classical  Donnan  theory, but a membrane is not needed here because the gel volume constraint imposed by network elasticity effectively acts its role, in preventing the macroions to pass through the fictitious membrane while allowing ions to pass. [ 30 ]


The coupling between the ion partitioning and polyelectrolyte ionization degree is only partially by the classical  Donnan  theory. As a starting point we can neglect the electrostatic interactions among ions. Then at equilibrium, some of the weak acid sites in the gel would dissociate to form

 A

 −

 {\displaystyle {\text{A}}^{-}}

 that electrostatically attracts positive charged

 H

 +

 {\displaystyle {\text{H}}^{+}}

  and salt cations leading to a relatively high concentration of

 H

 +

 {\displaystyle {\text{H}}^{+}}

  and salt cations inside the gel. But because the concentration of

 H

 +

 {\displaystyle {\text{H}}^{+}}

  is locally higher, it suppresses the further ionization of the acid sites. This phenomenon is the prediction of the classical Donnan theory. [ 31 ]  However, with electrostatic interactions, there are further complications to the picture. Consider the case of two adjacent, initially uncharged acid sites

 HA

 {\displaystyle {\text{HA}}}

  are both dissociated to form

 A

 −

 {\displaystyle {\text{A}}^{-}}

 . Since the two sites are both negatively charged, there will be a charge-charge repulsion along the backbone of the polymer than tends to stretch the chain. This energy cost is high both elastically and electrostatically and hence suppress ionization. Even though this ionization suppression is qualitatively similar to that of Donnan prediction, it is absent without electrostatic consideration and present irrespective of ion partitioning. The combination of both effects as well as gel elasticity determines the volume of the gel at equilibrium. [ 30 ]  Due to the complexity of the coupled acid-base equilibrium, electrostatics and network elasticity, only recently has such system been correctly recreated in  computer simulations . [ 30 ] [ 32 ]


Some species secrete gels that are effective in parasite control. For example, the  long-finned pilot whale  secretes an enzymatic gel that rests on the outer surface of this animal and helps prevent other organisms from establishing colonies on the surface of these whales' bodies. [ 33 ]


Hydrogels  existing naturally in the body include  mucus , the  vitreous humor  of the eye,  cartilage ,  tendons  and  blood clots . Their viscoelastic nature results in the soft tissue component of the body, disparate from the mineral-based hard tissue of the skeletal system. Researchers are actively developing synthetically derived tissue replacement technologies derived from hydrogels, for both temporary  implants  (degradable) and permanent implants (non-degradable). A review article on the subject discusses the use of hydrogels for  nucleus pulposus  replacement, cartilage replacement, and  synthetic tissue  models. [ 34 ]


Many substances can form gels when a suitable  thickener or gelling agent  is added to their formula. This approach is common in the manufacture of a wide range of products, from foods to paints and adhesives.


In fiber optic communications, a soft gel resembling  hair gel  in viscosity is used to fill the plastic tubes containing the fibers. The main purpose of the gel is to prevent water intrusion if the buffer tube is breached, but the gel also buffers the fibers against mechanical damage when the tube is bent around corners during installation, or flexed. Additionally, the gel acts as a processing aid when the cable is being constructed, keeping the fibers central whilst the tube material is extruded around it.


In  polymer chemistry ,  gelation  ( gel transition ) is the formation of a  gel  from a system with  polymers . [ 1 ] [ 2 ]   Branched polymers  can form  links  between the chains, which lead to progressively larger polymers. As the linking continues, larger branched polymers are obtained and at a certain extent of the reaction, links between the polymer result in the formation of a single  macroscopic molecule . At that point in the reaction, which is defined as  gel point , the system loses fluidity and  viscosity  becomes very large. The onset of gelation, or gel point, is accompanied by a sudden increase in viscosity. [ 3 ]  This "infinite" sized polymer is called the gel or network, which does not dissolve in the solvent, but can swell in it. [ 4 ]


Gelation is promoted by  gelling agents .
Gelation can occur either by physical linking or by chemical  crosslinking . While the physical gels involve physical bonds, chemical gelation involves covalent bonds. The first quantitative theories of chemical gelation were formulated in the 1940s by  Flory and Stockmayer . Critical percolation theory was successfully applied to gelation in 1970s. A number of growth models (diffusion limited aggregation, cluster-cluster aggregation, kinetic gelation) were developed in the 1980s to describe the kinetic aspects of aggregation and gelation. [ 5 ]


It is important to be able to predict the onset of gelation, since it is an irreversible process that dramatically changes the properties of the system.


According to the  Carothers equation  number-average degree of polymerization

 D

 P

 n

 {\displaystyle DP_{n}}

  is given by


D

 P

 n

 =

 2

 2
 −
 p
 .

 f

 a
 v

 {\displaystyle DP_{n}={\frac {2}{2-p.f_{av}}}}


where

 p

 {\displaystyle p}

  is the extent of the reaction and

 f

 a
 v

 {\displaystyle f_{av}}

  is the average functionality of reaction mixture. For the gel

 D

 P

 n

 {\displaystyle DP_{n}}

  can be considered to be infinite, thus the critical extent of the reaction at the gel point is found as


p

 c

 =

 2

 f

 a
 v

 {\displaystyle p_{c}={\frac {2}{f_{av}}}}


If

 p

 {\displaystyle p}

  is greater or equal to

 p

 c

 {\displaystyle p_{c}}

 , gelation occurs.


Flory and Stockmayer used a statistical approach to derive an expression to predict the gel point by calculating when

 D

 P

 n

 {\displaystyle DP_{n}}

  approaches infinite size. The statistical approach assumes that (1) the reactivity of the functional groups of the same type is the same and independent of the molecular size and (2) there are no intramolecular reactions between the functional groups on the same molecule. [ 6 ] [ 7 ]


Consider the polymerization of bifunctional molecules

 A
 −
 A

 {\displaystyle A-A}

 ,

 B
 −
 B

 {\displaystyle B-B}

  and multifunctional

 A

 f

 {\displaystyle A_{f}}

 , where

 f

 {\displaystyle f}

  is the functionality. The extends of the functional groups are

 p

 A

 {\displaystyle p_{A}}

 and

 p

 B

 {\displaystyle p_{B}}

 , respectively. The ratio of all A groups, both reacted and unreacted, that are part of branched units, to the total number of A groups in the mixture is defined as

 ρ

 {\displaystyle \rho }

 . This will lead to the following reaction


A
 −
 A
 +
 B
 −
 B
 +

 A

 f

 →

 A

 f
 −
 1

 −
 (
 B
 −
 B
 A
 −
 A

 )

 n

 B
 −
 B
 A
 −

 A

 f
 −
 1

 {\displaystyle A-A+B-B+A_{f}\rightarrow A_{f-1}-(B-BA-A)_{n}B-BA-A_{f-1}}


The probability of obtaining the product of the reaction above is given by

 p

 A

 [

 p

 B

 (
 1
 −
 ρ
 )

 p

 A

 ]

 n

 p

 B

 ρ

 {\displaystyle p_{A}[p_{B}(1-\rho )p_{A}]^{n}p_{B}\rho }

 , since the probability that a B group reach with a branched unit is

 p

 B

 ρ

 {\displaystyle p_{B}\rho }

  and the probability that a B group react with non-branched A is

 p

 B

 (
 1
 −
 ρ
 )

 {\displaystyle p_{B}(1-\rho )}

 .


This relation yields to an expression for the extent of reaction of A functional groups at the gel point


p

 c

 =

 1

 {
 r
 [
 1
 +
 ρ
 (
 f
 −
 2
 )
 ]

 }

 1

 /

 2

 {\displaystyle p_{c}={\frac {1}{\{r[1+\rho (f-2)]\}^{1/2}}}}


where r is the ratio of all A groups to all B groups. If more than one type of multifunctional branch unit is present and average

 f

 {\displaystyle f}

  value is used for all monomer molecules with functionality greater than 2.


Note that the relation does not apply for reaction systems containing monofunctional reactants and/or both A and B type of branch units.


Gelation of polymers can be described in the framework of the  Erdős–Rényi model  or the  Lushnikov model , which answers the question when a  giant component  arises. [ 8 ]


The structure of a gel network can be conceptualised as a random graph. This analogy is exploited to calculate the gel point and gel fraction for monomer precursors with arbitrary types of functional groups. Random graphs can be used to derive analytical expressions for simple polymerisation mechanisms, such as step-growth polymerisation, or alternatively, they can be combined with a system of rate equations that are integrated numerically.


Hindustan Syringes & Medical Devices  is one of the major world firms manufacturing  medical syringes  and one of the few producing a special type of syringe suitable for making efficient use of the  Pfizer–BioNTech COVID-19 vaccine . [ 1 ]


The  New Delhi  factories have been producing 2.5 billion syringes a year, increasing their capacity because of the  coronavirus pandemic . Two thirds of the capacity is for the market in India but there is global demand, increased by stockpiling, from the US and Europe where investment focused on the vaccine development rather than syringe manufacture. The  United Nations  is also being supplied for the  COVAX  programme. [ 2 ] [ 1 ]  Before the pandemic, global production was about 16 billion syringes per annum but only 5 to 10 percent were used for vaccination and immunisation. Now 8 to 10 billion vaccination syringes are required. [ 1 ]


To make best use of the Pfizer–BioNTech vaccine a dose no larger than 0.3  millilitres  is required which allows six or even seven doses to be extracted from each  vial . The device must also be a  low dead space syringe  so scarcely anything is left in the syringe after injection and the syringe itself must break after use so that there is no possibility of repeated use spreading infection. [ 1 ]  For this reason Japan ordered 15 million syringes at the beginning of 2021 and deliveries started within a month. [ 3 ]


Hindustan Syringes & Medical Devices was established in 1957 [ 4 ]  and is a family run business. In 1995 new machines were required for an increase in production and so private capital was needed. The latest ramping up could be achieved very quickly because no further investment was required. [ 1 ]


A  hypodermic needle  (from  Greek  ὑπο- ( hypo-  = under), and δέρμα ( derma  = skin)) is a very thin, hollow tube with one sharp tip. It is one of a category of medical tools which enter the skin, called  sharps . [ 1 ]  It is commonly used with a  syringe , a hand-operated device with a plunger, to  inject  substances into the body (e.g.,  saline solution , solutions containing various drugs or liquid medicines) or extract fluids from the body (e.g., blood). Large-bore hypodermic intervention is especially useful in catastrophic blood loss or treating  shock .


A hypodermic needle is used for rapid delivery of liquids, or when the injected substance cannot be ingested, either because it would not be  absorbed  (as with  insulin ), or because it would harm the  liver . It is also useful to deliver certain medications that cannot be delivered orally due to vomiting. There are many possible  routes  for an injection, with  intramuscular  (into a  muscle ) and  intravenous  (into a  vein ) being the most common. A hypodermic syringe has the ability to retain liquid and blood in it up to years after the last use and a great deal of caution should be taken to use a new syringe every time.


The hypodermic needle also serves an important role in research environments where sterile conditions are required.  The hypodermic needle significantly reduces contamination during  inoculation  of a sterile  substrate . The hypodermic needle reduces contamination for two reasons: First, its surface is extremely smooth, which prevents airborne  pathogens  from becoming trapped between irregularities on the needle's surface, which would subsequently be transferred into the media (e.g.  agar ) as contaminants; second, the needle's surface is extremely sharp, which significantly reduces the diameter of the hole remaining after puncturing the membrane and consequently prevents microbes larger than this hole from contaminating the substrate. [ 2 ] [ 3 ] [ 4 ] [ 5 ]


The ancient  Greeks  and  Romans  knew injection as a method of medicinal delivery from observations of snakebites and poisoned weapons. [ 6 ]  There are also references to "anointing" and "inunction" in the  Old Testament  as well as the works of  Homer , but injection as a legitimate medical tool was not truly explored until the 17th century. [ 7 ]


Christopher Wren  performed the earliest confirmed experiments with crude hypodermic needles, performing intravenous injection into dogs in 1656. [ 7 ]  These experiments consisted of using animal bladders (as the syringe) and goose quills (as the needle) to administer drugs such as  opium  intravenously to dogs. Wren and others' main interest was to learn if medicines traditionally administered orally would be effective intravenously. In the 1660s,  Johann Daniel Major  of  Kiel  and  Johann Sigismund Elsholtz  of  Berlin  were the first to experiment with injections in humans. [ 6 ] [ 8 ]


The 19th century saw the development of medicines that were effective in small doses, such as opiates and strychnine. This spurred a renewed interest in direct, controlled application of medicine. "Some controversy surrounds the question of priority in hypodermic medication." [ 9 ]  Irish physician  Francis Rynd  is generally credited with the first successful injection in 1844, in the  Meath Hospital  in  Dublin ,  Ireland . [ 10 ] [ 11 ]


Alexander Wood 's main contribution was the all-glass syringe in 1851, which allowed the user to estimate dosage based on the levels of liquid observed through the glass. [ 12 ]  Wood used hypodermic needles and syringes primarily for the application of localized, subcutaneous injection (localized anesthesia) and therefore was not as interested in precise dosages. [ 8 ]


Simultaneous to Wood's work in Edinburgh,  Charles Pravaz  of Lyon also experimented with sub-dermal injections in sheep using a syringe of his own design. Pravaz designed a hypodermic needle measuring 3 cm (1.18 in) long and 5 mm (0.2 in) in diameter; it was made entirely of silver. [ citation needed ]


Charles Hunter , a London surgeon, is credited with the coining of the term "hypodermic" to describe subcutaneous injection in 1858. The name originates from two Greek words:  hypo , "under", and  derma , "skin". Furthermore, Hunter is credited with acknowledging the systemic effects of injection after noticing that a patient's pain was alleviated regardless of the injection's proximity to the pained area. [ 7 ] [ 8 ]  Hunter and Wood were involved in a lengthy dispute over not only the origin of the modern hypodermic needle, but also because of their disagreement as to the medicine's effect once administered. [ 13 ]


Dr. Francis Rynd  used the first "Hollow Needle" as a hypodermic syringe on Ms. Margaret Cox in Ireland on June 3rd, 1844. Dr. Wood can be largely credited with the popularization and acceptance of injection as a medical technique, as well as the widespread use and acceptance of the hypodermic needle. The basic technology of the hypodermic needle has stayed largely unchanged since the 19th century, but as the years progressed and medical and chemical knowledge improved, small refinements have been made to increase safety and efficacy, with needles being designed and tailored for very particular uses. Hypodermic needles remain essential to large volume administration or exchange in settings of trauma or dialysis. The trend of needle specification for use began in the 1920s, particularly for the administration of insulin to diabetics. [ 14 ]


The onset of World War II spurred the early development of partially disposable syringes for the administration of  morphine  and  penicillin  on the battlefield. Development of the  fully disposable  hypodermic needle was spurred on in the 1950s for several reasons. The  Korean War  created blood shortages and in response disposable, sterile syringes were developed for collecting blood. The widespread  immunization against polio  during the period required the development of a fully disposable syringe system. [ 14 ]


The 1950s also saw the rise and recognition of cross-contamination from used needles. This led to the development of the first fully disposable plastic syringe by New Zealand pharmacist Colin Murdoch in 1956. [ 15 ]  This period also marked a shift in interest from needle specifications to general sterility and safety. [ 14 ]


The 1980s saw the  rise of the HIV epidemic  and with it renewed concern over the safety of cross-contamination from used needles. New safety controls were designed on disposable needles to ensure the safety of medical workers in particular. These controls were implemented on the needles themselves, such as retractable needles, but also in the handling of used needles, particularly in the use of  hard-surface disposal receptacles  found in every medical office today. [ 14 ]


By 2008, all-plastic needles were in production and in limited use. One version was made of  Vectra (plastic)   aromatic   liquid crystal polymer  tapered from 1.2 mm at the hub to 0.72 mm at the tip (equivalent to 22 gauge metal needle), with an ID/OD ratio of 70%. [ 16 ]


Hypodermic needles are normally made from a  stainless-steel  or  Niobium  tube [ 17 ]  through a process known as  tube drawing  where the tube is drawn through progressively smaller  dies  to make the needle. The end of the needle is  bevelled  to create a sharp pointed tip, letting the needle easily penetrate the skin. [ 18 ]


The main system for measuring the diameter of a hypodermic needle is the  Birmingham gauge  (also known as the Stubs Iron Wire Gauge); the  French gauge  is used mainly for catheters. Various needle lengths are available for any given gauge. Needles in common medical use range from 7 gauge (the largest) to 34 (the smallest). 21-gauge needles are most commonly used for drawing blood for testing purposes, and 16- or 17-gauge needles are most commonly used for blood donation, as the larger luminal cross-sectional area results in lower fluid shear, reducing harm to red blood cells while also allowing more blood to be collected in a shorter time. [ 19 ]


Although reusable needles remain useful for some scientific applications, disposable needles are far more common in medicine. Disposable needles are embedded in a plastic or aluminium hub that attaches to the syringe barrel by means of a press-fit or twist-on fitting. These are sometimes referred to as "Luer Lock" connections, referring to the trademark  Luer-Lok . The male and female luer lock and hub—produced by pharmaceutical equipment manufacturers—are two of the most critical parts of disposable hypodermic needles. [ 20 ]


Hypodermic needles are usually used by medical professionals ( dentists ,  phlebotomists ,  physicians ,  pharmacists ,  nurses ,  paramedics ), but they are sometimes used by patients themselves. This is most common with  type one diabetics , who may require several  insulin  injections a day. [ 21 ]  It also occurs with patients who have  asthma  or other severe  allergies . Such patients may need to take  desensitization  injections or they may need to carry injectable medicines to use for first aid in case of a severe allergic reaction. In the latter case, such patients often carry a syringe loaded with  epinephrine  (e.g.  EpiPen ), [ 22 ]   diphenhydramine  (e.g.  Benadryl ), or  dexamethasone . Rapid injection of one of these drugs may stop a severe allergic reaction.


Multiple sclerosis  patients may also treat themselves by injection; several MS therapies, including various  interferon  preparations, are designed to be self-administered by subcutaneous or intramuscular injection. [ 23 ]


Transgender  people may also inject their own  hormone replacement therapy , using either  intramuscular injection  or  subcutaneous injection  methods.


Hypodermic needles are also used for  erotic piercing . [ 24 ]


It is estimated that anywhere from nearly 3.5 to 10% of the world's population may have a  phobia  of needles (trypanophobia), [ 25 ]  and it is much more common in children, ages 5–17. Topical anesthetics can be used to desensitize the area where the injection will take place to reduce pain and discomfort. [ 26 ]  For children, various techniques may be effective at reducing distress or pain related to needles. [ 27 ]  Techniques include: distraction,  hypnosis , combined  cognitive behavioral therapy , and breathing techniques. [ 27 ]


Immunoliposome therapy  is a targeted drug delivery method that involves the use of  liposomes  (artificial lipid bilayer vesicles) coupled with monoclonal  antibodies  to deliver therapeutic agents to specific sites or tissues in the body. [ 1 ]  The antibody modified liposomes target tissue through cell-specific antibodies with the release of drugs contained within the assimilated liposomes. [ 1 ]  Immunoliposome aims to improve drug stability, personalize treatments, and increased drug efficacy. [ 1 ]  This form of therapy has been used to target specific cells, protecting the encapsulated drugs from degradation in order to enhance their stability, to facilitate sustained drug release and hence to advance current traditional  cancer  treatment. [ 1 ]


Alec D. Bangham  discovered liposomes in the 1960s as spherical vesicles made of a phospholipid bilayer that houses hydrophilic cores. [ 2 ]  The liposomes were then studied to uncover the properties of biological membranes and a hydration method was discovered to prepare artificial liposomes from 1968 to 1975. [ 2 ]  Since then, multiple methods of preparing liposomes have been utilized and their characteristics (physical and chemical) have been studied. [ 2 ]


Monoclonal antibodies  are proteins that stick to specific  antigens  that tag specific cells and can be synthesized in the lab. [ 3 ]  They were first generated in 1975 and have since advanced to being used for immunotherapy. [ 3 ]


Immunolipsomes were developed utilizing both of these components. [ 1 ]  The first anticancer drug made with this method was  doxorubicin  (DOX) in the 1990s. [ 4 ]


The core structure of immunoliposomes is a  lipid bilayer . This lipid bilayer forms a hydrophilic core, which provides stable encapsulation for a therapeutic payload. [ 5 ]  Common lipids used are  phosphatidylcholine  (PC),  phosphatidylethanolamine  (PE), and  cholesterol . [ 5 ]  The lipid bilayer is surface modified through conjugation using monoclonal antibodies for specific recognition of the target cells or tissues of interest. [ 5 ]  The core of the immunoliposome contains the therapeutic payload, which can be anything from small drugs, nucleic acids, peptides, or imaging agents. [ 5 ]


There are often stabilizers and excipients present for formulation, stability, and functionality. [ 5 ]  Some include  polyethylene glycol  (PEG), antioxidants to prevent degradation of lipids, and buffering agents for optimal pH. [ 5 ]


Immunoliposomes are created when antibodies are conjugated to liposomes. [ 6 ]  One way to do this is through covalent bonds between the antibody (or its fragment) and the lipid. [ 6 ]  Another way is through chemical modification of antibodies so they have a higher affinity for the liposome. [ 6 ]  “In general, the conjugation methodology is based on three main reactions; a reaction between activated carboxyl groups and amino groups which yields an amide bond, a reaction between pyridyl dithiols and thiols which yields disulfide bonds, and a reaction between  maleimide  derivatives and thiols, which yields  thioether  bonds.”  [ 6 ]


Amine groups are found throughout an antibody and are used as a target due to their easy steric accessibility and modification. An overview of this reaction is found in  Figure 2 . Most often amine groups found on lysine are covalently bonded to  carboxyl groups  of  glutamic  and  aspartic acid  on formed liposomes using certain agents. A two step process is utilized where the first step uses 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide to create an amine reactive product from the carboxyl group. [ 6 ]  This product is a target for a nucleophilic attack by the amine but it hydrolyzes quickly, so EDC is added to stabilize it. As seen in the  Figure 2 , the intermediate can lead to the desired stable amide bond by chance or the recreation of a carboxyl group. [ 6 ]  To create more of the desired carboxyl-amine bond, N-hydroxysulfosuccinimide (sulfo-NHS) is added to form another intermediate that is an NHS ester. [ 6 ]  The second step to this reaction is for the antibodies to use the N-terminus of the lipid to covalently conjugate by creating an amide bond via displacement of sulfo-NHS groups. [ 6 ]  This leads to the final product of an antibody conjugated to a liposome to create an immunoliposome. This process is highly efficient and effective while maintaining the biological activity of the antibody. [ 6 ]


Another process of creating immunoliposomes is by using a thiol group and creating a thioether bond. [ 6 ]  The sulfhydryl group is a key player can is found in cysteine bridges on proteins and reagents like  Traut’s reagents , SATA, and Sulfo-LC-SPDP. [ 6 ]  The reduction or hydrolysis of these groups generates thiol groups that create antibody conjugation to lipids. [ 6 ]  There are multiple methods of this process, and one uses the crosslinking agent SATA as shown in  Figure 3 . [ 6 ]  The ester end of SATA reacts with amino groups in proteins to form an amide link and a molecule with a protected sulfhydryl group. [ 6 ]  In order to continue the reaction, this group must be freed which is done by adding hydroxylamine. The following step is to add a chemical that can be an anchor between the lipid and the thiol group. Some examples of molecules that are capable of being this anchor are maleimide, iodoacetyl groups or 2-pyridyldithiol groups. [ 6 ]  Ultimately, these steps create an antibody-enzyme conjugate that has been formulated using a thiol group. [ 6 ]


Immunoliposomes use similar functionality as liposomes with the added measure of conjugating monoclonal antibodies and their fragments to the liposomes. [ 6 ]  The use of antibodies allow for easy targeting as they can recognize many different types of antigens. [ 6 ]  Diseased cells typically contain more antigens than healthy cells, which is how antibodies are able to appropriately target certain extracellular domains (depending on antigen overexpression) and kill diseased cells. [ 6 ]  Liposomal drug delivery combined with antibodies as a targeting ligand are what help immunoliposomes function as an effective drug carrier. [ 6 ]


Once the immunoliposomes deliver the appropriate drugs to the targeted cells, they can enter the cell using either selective uptake of liposomes by endocytosis or liposome release near the targeted cell. [ 6 ]  Because of antibody conjunction, the cellular uptake amount is increased for immunoliposomes allowing greater drug entry into diseased cells. [ 6 ]  To control when a drug is released, immunoliposomes are being developed that can sense stimuli. This stimuli can come from the microenvironment of a tumor using factors such as reduced pH, temperature, and enzyme levels. [ 6 ]  External stimuli like light, heat, magnetic fields, or ultrasound can also act as a trigger for drug release. [ 6 ]


Immunoliposomes can target a wide variety of cell options. This can be split into two main types commonly known as intravascular and extravascular space as seen in  Figure 4 . [ 7 ]  Intravascular cells are more accessible during circulation and include  erythrocytes ,  myeloid cells ,  lymphocytes ,  neutrophils , etc. [ 7 ]  Extravascular cells are located on tissue  parenchymal  or  stromal  cells. [ 7 ]  Because immunoliposomes have many antibody copies, they contain a higher avidity than just one antibody alone allowing for effective targeting against cancer cells and some drug resistant cells. [ 7 ]


Immunoliposome applications use its ability to act as a drug delivery system and release specific drug components to target cells. This mechanism can be specifically highlighted in cancer cell targeting and through nutrient delivery systems.


The most common use of immunoliposomes is to target cancer cells using different antibodies.  Folate receptors  and  transferrin receptors  are typically overexpressed on cancer cells, so immunoliposomes will target these corresponding ligands. [ 8 ]  Folate receptors dictate tumor cell specificity and have been seen to be expressed in multiple inflammatory diseases including  psoriasis ,  Crohn’s disease ,  atherosclerosis , and  rheumatoid arthritis  making folate-targeted immunoliposomes an efficient drug carrier to deliver antiinflammatory drugs. [ 8 ]  Transferrin receptors help with the iron demand in proliferating cancer cells and allow for formation of transferrin receptor-targeted anticancer therapies. [ 8 ]   EGFR  (epidermal growth factor) is a tyrosine kinase receptor overexpressed in solid tumors such as colorectal, non small-cell lung cancer, squamous cell carcinoma, and breast cancer making it another target receptor for immunoliposomes. [ 8 ]  Some cancers create tumors that have multiple different receptors being overexpressed or utilize cancer stem cells, which allow for differentiation of numerous cancer types, so to combat this, dual-targeting immunoliposomes are being created to target multiple ligands and increase therapeutic efficacy. [ 9 ]  A study provides a promising preclinical demonstration of the effectiveness and ease of preparation of Valrubicin-loaded immunoliposomes (Val-ILs) as a novel nanoparticle technology. In the context of hematological cancers, Val-ILs have the potential to be used as a precise and effective therapy based on targeted vesicle-mediated cell death. [ 10 ]


Immunoliposomes can also be used as nutrient delivery systems to help stimulate brain activity. The effective transport of certain nutrients to the  hypothalamus  in order to regulate brain activity is currently a huge problem. [ 11 ]  The  leptin  gene is used to regulate feedback loops and send signals from the adipose tissue to the hypothalamus. [ 11 ]  Using this physiological function of leptin, immunoliposome nutrient delivery systems can be integrated into the body to help with nutrition transport to the brain as seen in  Figure 5 . [ 11 ]  Transferrin receptors have high expression at the BBB ( blood brain barrier ) and can be used as targets for immunoliposomes to transport p-glycoprotein substances. [ 11 ]


Immunoliposomes have many possible applications as described above and have certain advantages in new research and ideas. [ 6 ]  Some advantages being researched include immunoliposomes targeting specific molecules in the body. [ 6 ]  In preclinical testing, they can be environmentally responsive to specific conditions of temperature, pH, enzymes, redox reactions, magnetic energy, and light to release drugs. [ 6 ]  This conditional ability allows immunoliposomes to focus on specific target areas which can be beneficial for drug delivery. [ 6 ]  Increased targeting allows the possibility for decreased systemic toxicity while increasing drug concentration at a certain site. [ 6 ]  Even with this advantage of immunoliposomes, there are some challenges in their application.


The success of immunoliposomes during in vivo testing has been shown by multiple groups including Meeroekyai et al 2023 [ 12 ]  and animal testing has been successful in groups such as Refaat et al 2022. [ 13 ]  However, they struggle to thrive in higher level and clinical testing. [ 6 ]  This challenge stems from the variability and lack of understanding of tumors, pharmacokinetics, and large scale production of immunoliposomes. For example, tumors vary but typically have increased vascular permeability and decreased lymphatic drainage which lead to the EPR effect. EFR is the enhanced permeability and retention effect in which drug carriers depend on but the effect and environment can vary in solid tumors. [ 14 ]  This varying environment makes it hard to predict how the immunoliposome acts and quantify its pharmacokinetics. [ 6 ]  Additionally, it has been a concern that the animal models used in preclinical testing will not reflect the same effect in humans. [ 6 ]  Because of this idea, despite any preclinical success, there is a concern to test in humans due to unknown risks. For environmentally responsive immunoliposomes, more modification and purification steps are required to produce the final product. This increase in complexity for immunoliposomes and their behavior also increases costs. [ 6 ]  Another challenge to marketability and clinical research is the difficulty of scaling up the production of immunoliposomes. The procedure and use of small quantities in the laboratory make upscaling the production a challenge that has not been focused upon. [ 6 ]


Liposomal medicine research for cancer therapy has increased over the years as an alternative to conventional cancer treatment. [ 15 ]  There is an interest in liposomal medicine because it features targeted drug delivery while mitigating the damage to healthy cells and tissues. [ 15 ]  One of the combination products under liposome therapy that is being researched for cancer therapy applications is immunoliposome therapy. [ 15 ]  Other research areas in liposome combination therapy include  photodynamic therapy , photothermal agents,  radiotherapy , and gas therapy agents. [ 15 ]


A immunoliposome therapy clinical study that was completed was conducted by the  Swiss Group for Clinical Cancer Research from 2006 to 2009 . [ 16 ]  The study was a phase II clinical trial that looked at the combination of commercially sold  Doxorubicin  with  bevacizumab , a monoclonal antibody that blocks tumor growth. [ 16 ]  The therapy was used to treat patients with locally recurrent or  metastatic breast cancer . [ 16 ]  Out of the 43 patients, 16 had grade 3 palmar-plantar erythrodysesthesia, one had grade 3 mucositis, and one severe cardiotoxicity, according to the study. [ 16 ]  As a result, the combination therapy demonstrated higher than anticipated toxicity while only having modest therapeutic effect. [ 16 ]  These results concluded that, although immunoliposome therapy has promise, there is still more research needed before translating into commercial products. [ 16 ]


There are several liposome medicines currently available commercially, which helps set the regulatory pathway for immunoliposome therapies. [ 15 ]


As immunoliposome therapy has progressed in research, big market players in pharmaceutical research and manufacturing have invested in the development of these therapies. [ 15 ]  A relevant example of this is a  phase I/II trial  that examined the effectiveness of PDS0101 in combination with  pembrolizumab , an immune checkpoint inhibitor (sold under the brand name  Keytruda ). [ 17 ]  The study is funded by PDS Biotechnology and in partnership with  Merck . [ 18 ]  The purpose of the study is to determine the effectiveness of PDS0101 + pembrolizumab in shrinking tumors in patients with virus-related  oropharyngeal cancer  tumors in humans. [ 15 ]  PDS0101 is a peptide-based vaccine that aids in the immune response to kill tumor cells. [ 15 ]  The study also relies on pembrolizumab monoclonal antibodies to help the body's immune system attack the cancer and interfere with the spread of tumor cells. [ 15 ]
Although immunoliposome therapy exhibits clinical and commercial promise, there are several known challenges in the translation from laboratory studies to clinical studies and ultimately to commercialization. [ 15 ]  One obstacle is that immunoliposome therapy is limited by having a short half-life and retention time once it reaches the tumor microenvironment. [ 15 ]  Additionally, immunoliposome therapies are often individualized which requires close clinical monitoring and comprehensive evaluation methods. [ 15 ]  From a biochemical perspective, other challenges that immunoliposome therapies face are drug instability due to the phospholipid bilayer and the known possibility for  hepatotoxicity . [ 15 ]  From a manufacturing perspective, designing liposome drug delivery systems at an industrial scale can present a challenge due to the complexity of these drug release mechanisms and their related biosafety. [ 15 ]


Though immunoliposomes serve as a possible advancement, there are other therapies similar to it that trail on the role of targeted drug delivery systems. [ 19 ]  One example of such therapy is Immune Polymeric  nanoparticles , which are similar to liposomes but consist of small particles composed of biodegradable polymers. [ 19 ]  These nanoparticles similarly encapsulate drugs and can function to enhance specificity towards targeted diseased cells with peptide ligands. [ 19 ]  Another type is Targeting  Antibody Drug Conjugates , which combine monoclonal antibodies with the cytotoxicity of chemotherapy drugs. [ 20 ]  This specific type is catered towards cancer cells expressing a specific target antigen. [ 20 ]  They are well-tolerated by the body as they are biodegradable, eliminating many potential toxicity factors, and proving to be a possible new model for therapeutics. [ 20 ]


An  infusion pump   infuses  fluids,  medication  or  nutrients  into a  patient's   circulatory system . It is generally used  intravenously , although  subcutaneous ,  arterial  and  epidural  infusions are occasionally used.


Infusion pumps can administer fluids in ways that would be impractically expensive or unreliable if performed manually by nursing staff.  For example, they can administer as little as 0.1 mL per hour injections (too small for a drip), injections every minute, injections with repeated  boluses  requested by the patient, up to maximum number per hour (e.g. in  patient-controlled analgesia ), or fluids whose volumes vary by the time of day.


Because they can also produce quite high but controlled  pressures , they can inject controlled amounts of fluids subcutaneously (beneath the skin), or epidurally (just within the surface of the  central nervous system  – a very popular local spinal  anesthesia  for  childbirth ).


The  user interface  of pumps usually requests details on the type of infusion from the technician or nurse that sets them up:


To get the entire dose of antibiotics into the patient, the "volume to be infused" or VTBI must be programmed for at least 30 CCs more than is in the medication bag; failure to do so can potentially result in up to half of the antibiotic being left in the IV tubing.


Some pumps offer modes in which the amounts can be scaled or controlled based on the time of day.  This allows for  circadian cycles  which may be required for certain types of medication.


There are two basic classes of pumps.  Large volume pumps can pump   fluid replacement  such as  saline solution , medications such as  antibiotics  or nutrient solutions large enough to feed a patient.  Small-volume pumps infuse  hormones , such as  insulin , or other medicines, such as  opiates .


Within these classes, some pumps are designed to be portable, others are designed to be used in a hospital, and there are special systems for charity and battlefield use.


Large-volume pumps usually use some form of  peristaltic pump .  Classically, they use computer-controlled rollers compressing a silicone-rubber tube through which the medicine flows.  Another common form is a set of fingers that press on the tube in sequence.


Small-volume pumps usually use a  computer -controlled motor turning a screw that pushes the plunger on a syringe.


The classic medical improvisation for an infusion pump is to place a  blood pressure  cuff around a bag of fluid.  The battlefield equivalent is to place the bag under the patient.  The pressure on the bag sets the infusion pressure.  The pressure can actually be read-out at the cuff's indicator.  The problem is that the flow varies dramatically with the cuff's pressure (or patient's weight), and the needed pressure varies with the administration route, potentially causing risk when attempted by an individual not trained in this method.


Places that must provide the least-expensive care often use pressurized infusion systems.  One common system has a purpose-designed plastic "pressure bottle" pressurized with a large disposable plastic syringe.  A combined  flow restrictor , air filter and drip chamber helps a nurse set the flow.  The parts are reusable, mass-produced  sterile  plastic, and can be produced by the same  machines that make plastic soft-drink bottles and caps.  A pressure bottle, restrictor and chamber requires more nursing attention than electronically controlled pumps.  In the areas where these are used, nurses are often volunteers, or very inexpensive.


The restrictor and high pressure helps control the flow better than the improvised schemes because the high pressure through the small restrictor orifice reduces the variation of flow caused by patients' blood pressures.


An air filter is an essential safety device in a pressure infusor, to keep air out of the patients' veins.  Small bubbles could cause harm in arteries, but in the veins they pass through the heart and leave in the patients' lungs. The air filter is just a membrane that passes gas but not fluid or  pathogens . When a large air bubble reaches it, it bleeds off.


Some of the smallest infusion pumps use  osmotic  power.  Basically, a bag of salt solution absorbs water through a membrane, swelling its volume.  The bag presses medicine out.  The rate is precisely controlled by the salt concentrations and pump volume.  Osmotic pumps are usually recharged with a syringe.


Spring-powered clockwork infusion pumps have been developed, and are sometimes still used in veterinary work and for ambulatory small-volume pumps.  They generally have one spring to power the infusion, and another for the alarm bell when the infusion completes.


Battlefields often have a need to perfuse large amounts of fluid quickly, with dramatically changing blood pressures and patient condition.  Specialized infusion pumps have been designed for this purpose, although they have not been deployed.


Many infusion pumps are controlled by a small  embedded system .  They are carefully designed so that no single cause of failure can harm the patient.  For example, most have batteries in case the wall-socket power fails.  Additional hazards are uncontrolled flow causing an  overdose , uncontrolled lack of flow, causing an underdose, reverse flow, which can siphon blood from a patient, and air in the line, which can cause an  air embolism .


Elastomeric pumps , also known as balloon pumps or ball pumps, rely on the gradual contraction of an internal elastomeric reservoir to deliver medication at a pre-determined flow rate over several hours or days. These pumps do not require electricity and offer simplicity and portability, making them suitable for administering various medications, including antibiotics, in situations where continuous, low-rate infusion is required. These features make them useful for infusions in outpatient settings, such as  outpatient parenteral antibiotic therapy  (OPAT). However, due to their limited features and programmability, they are not suitable for all medications or flow rates. [ 1 ] [ 2 ]


The range of safety features varies widely with the age and make of the pump.  A state of the art pump in 2003 [update]  might have had the following safety features:


By 2019  intravenous smart pumps were being introduced. They could include wireless connectivity, drug libraries, profiles of care areas, and soft and hard limits. [ 3 ]


Infusion pumps have been a source of multiple patient safety concerns, and problems with such pumps have been linked to more than 56,000 adverse event reports from 2005 to 2009, including at least 500 deaths. [ 4 ]  As a result, the U.S.  Food and Drug Administration  (FDA) has launched a comprehensive initiative to improve their safety, called the Infusion Pump Improvement Initiative. [ 5 ]   The initiative proposed stricter regulation of infusion pumps.  It cited software defects, user interface issues, and mechanical or electrical failures as the main causes of adverse events.


An  inhaler  ( puffer ,  asthma pump  or  allergy spray ) is a medical device used for delivering medicines into the  lungs  through the work of a person's breathing. This allows medicines to be delivered to and absorbed in the lungs, which provides the ability for targeted medical treatment to this specific region of the body, as well as a reduction in the side effects of oral medications. There are a wide variety of inhalers, and they are commonly used to treat numerous medical conditions with  asthma  and  chronic obstructive pulmonary disease  (COPD) being among the most notable. [ 1 ]


Some of the common types of inhalers include  metered-dose inhalers ,  dry powder inhalers , soft mist inhalers, and  nebulizers . Each device has advantages and disadvantages and can be selected based on individually specific patient needs, as well as age, pathological conditions, coordination, and lung function. [ 2 ]  Proper education on inhaler use is important to ensure that inhaled medication creates its proper effects in the lungs. [ 3 ]  Using a spacer can ensure that more medicine reaches the lungs, [ 4 ] [ 5 ]  thus providing the most optimal treatment.


Inhalers are designed to deliver medication directly to the lungs through a person's own breathing. This may benefit a patient by providing medicines directly to areas of disease, allowing medication to take a greater effect on its intended target, and limit side effects of medications when administered locally. [ 1 ]  Inhalers are used in a variety of different medical conditions with  diseases of the lungs  and  respiratory system  being among the most common. Individuals with these diseases/conditions need medications designed to decrease airway inflammation and obstruction to allow for easier and comfortable breathing. [ 6 ]  Antibiotic medications have even been developed for inhalers to allow for direct delivery to areas of infection within the lungs. [ 7 ]  Two of the most common conditions that warrant inhaler therapy are  asthma  and  chronic obstructive pulmonary disease . [ 6 ] [ 8 ]


Asthma  is a condition of intermittent  airway obstruction  due to  inflammatory  processes in the lungs. Inhaled medications are used to calm down the inflammation present in the lungs and allow for relief of the airway obstruction. Common inhaled medications used for treatment of asthma include long term inhalational steroidal  anti-inflammatory drugs  (most commonly  inhaled corticosteroids , also called ICS) and fast-relieving bronchodilators such as  salbutamol  (known commonly as "Ventolin") and  salmeterol . These medications allow for patients to have relief of airway obstruction symptoms and reduced inflammation. [ 6 ]  If some people are unable to use inhalers,  non-steroidal anti-inflammatory drugs  (NSAIDs) may be used, but with caution since they may cause immunological  hypersensitivity  to NSAIDs, resulting in respiratory-related symptoms such as  bronchospasms , acute  asthma exacerbation , and severe asthma morbidity. [ 9 ] [ 10 ]


COPD is an obstructive lung disease due to long-term damage to the airways of the lungs. The long-term damage leads to the inability of the airways to open properly, causing  airway obstruction . Inhaled medications allow patients to see improvement in symptoms and better function of daily living. Some commonly used inhaled medications in patient's with COPD are  ipratroprium ,  salmeterol , and  corticosteroids . [ 8 ]  Inhalers that combine two or three different medications including inhaled corticosteroids, long-active muscarinic medications (LAMA) and long acting beta2 agonists (LABA) for treating COPD may be associated with improvements in some quality of life variables and small improvements in lung function and respiratory symptoms, however, may also be associated with an increase in the risk of pneumonia. [ 11 ]


The most common type of inhaler is the pressurized  metered-dose inhaler  (MDI) which is made up of 3 standard components- a metal canister, plastic actuator, and a metering valve. The medication is typically stored in solution in a pressurized canister that contains a propellant or suspension. The MDI canister is attached to a plastic, hand-operated actuator. On activation, the metered-dose inhaler releases a fixed dose of medication in  aerosol  form through the actuator and into a patient's lungs. [ 12 ]   These devices require significant coordination as a person must discharge the medication at or near the same time that they inhale in order for the medication to be effective. [ 13 ]


Dry powder inhalers  release a metered or device-measured dose of powdered medication that is inhaled through a DPI device. This device usually contains a chamber in which the powdered medication is deposited prior to each dosage. [ 3 ]  The powder can then be inhaled with a quick breath. [ 1 ]   This allows for medication to be delivered to the lungs without the need for use of propellant/suspension. [ 13 ]


Soft mist inhalers release a light mist containing medication without the need for a propellant/suspension. Upon pressing a button, the inhaler creates a mist of medication, allowing for inhalation into the lungs. SMIs suspend inhaled medications for roughly 1.2 seconds, which is longer than the average MDI inhaler suspension time period.  This requires less coordination when using and may be helpful for young patients or patients that find the MDI inhalers difficult to use. [ 13 ]


Nebulizers  are designed to deliver medications over an extended period of time over multiple breaths through a mouthpiece or face mask.  They generate a continuous mist with aerosolized medication, allowing a patient to breathe normally and receive medications. [ 13 ]   They are commonly used in infants and toddlers requiring inhaled medications or in patients in the hospital who require inhaled medications. [ 2 ]


The smart-inhaler is an inhaler that will automatically update an app with information that includes the time of day, air quality, and how many times it has been used through sensor technology on the device. [ 14 ]  The first smart-inhaler was approved in 2019 by the FDA, its purpose is to track patient use of the device and some other circumstantial factors that could affect the effectiveness of the dosage. [ 14 ]  This information is sent via Bluetooth to a mobile device app, and is later shared with their physician to determine what kind of things can trigger issues with asthma and other problems. [ 14 ]  This technology presents a great way to cut down on medical costs associated with asthma and also help patients better manage their condition with fewer emergencies.


The Teva ProAir Digihaler was the first FDA approved smart inhaler. [ 15 ]  It shows how effective the device is at aiding patients in using the proper dose amount for their asthma. In a study published by the European Respiratory Journal, the ProAir Digihaler accurately identified when patients were using their inhalers and whether they were effectively administering the dose in a 370 patient trial with the device. [ 15 ]  This study further gives an overview on the technology regarding applications and devices that help aid in the tracking and medication management for asthma and other lung conditions. Another study showed that smart inhalers accurately recorded all doses administered by patients with their technology, which signifies their importance in providing accurate dosage information to patients and their physicians. [ 16 ]


In 2009, the FDA banned the use of inhalers that use  chlorofluorocarbons  (CFC) as  propellants . In their place, inhalers now use  hydrofluoroalkane  (HFA). HFA is not environmentally inert as it is a  greenhouse gas  but it does not affect the  ozone layer . [ 17 ]  While some people with asthma and advocacy groups contend that HFA inhalers are not as effective, [ 18 ]  published clinical studies indicate CFC and HFA inhalers are equally effective in controlling asthma. [ 19 ]


While the impact of CFCs from inhalers on the ozone layer had been minuscule (dwarfed by industrial processes using CFCs), the FDA in its interpretation of the  Montreal Protocol  mandated the switch in propellants. [ 17 ]  Patients expressed concern about the high price of the HFA inhalers as there were initially no generic versions, whereas generic CFC inhalers had been available. [ 18 ]


It is important to use proper techniques when administering medications through inhalers.


Proper use of inhalers often involves initial  deep breathing  (which involves mostly the  diaphragm 's movements), and then rapid breathing [ 20 ]  (which involves most of the muscles of respiration, such as external and internal  intercostal muscles [ 21 ] ) during intake of one or more puffs from the inhalers.


Improper use of inhalers is very common, can lead to distribution of the medicine into the mouth or throat where it cannot create its desired effect and may cause harm. [ 1 ] [ 22 ] [ 23 ]  Education on the correct use of inhalers for delivery of medications is a commonly cited topic in medical studies and a great deal of thought has been put into how best to help people learn to use their inhalers effectively. [ 24 ] [ 3 ]  Below is a description of proper inhaler technique for each different type of inhaler as well as a helpful video explaining what the text states.


Spacer is placed at the mouthpiece of a meter-dosed inhaler while keeping mouth at the end of the spacer. After pressing the canister of the inhaler, the medicine will linger inside the spacer, allowing for the user of the inhaler to directly absorb medicine into their lungs. [ 25 ]  Deep breathing is done to be ready for the delivery of the medicine to the lungs; this minimizes need for coordination of breathing with inhaler activation. [ 1 ]  Cleanage of the spacer regularly with warm soapy water is recommended. [ 25 ] [ 5 ]


If inhaler is used everyday, the inhaler usually has to be primed the first time using a new cartridge, but it may need to be primed again if it has not been used in multiple days. [ 1 ]


If using inhaled corticosteroids, one should wash the mouth out directly after use of an inhaler. This helps to prevent  mouth infections  that can occur due to  immunosuppressant  effects of corticosteroids. [ 1 ]


In the United States, pharmaceutical manufacturers use legal and regulatory strategies to keep inhaler prices artificially high. There has been little innovation in inhaler technology for decades — the most recent drug to be approved by the FDA for treating asthma or COPD via a novel  target of action  was  Ipratropium bromide  in 1986. Since then, manufacturers have used small changes to drug delivery mechanisms, or have switched active ingredients from one inhaler device to another (a strategy known as a " device hop ") to keep patents active. This has the effect of limiting competition, keeping inhalers expensive. [ 26 ]  Because of high prices, patients sometimes skip doses or give up using their inhalers.


The idea of directly delivering medication into the lungs was based on ancient traditional cures that involved the use of aromatic and medicinal vapors. These did not involve any special devices beyond the apparatus used for burning or heating to produce fumes. Early inhalation devices included one devised by John Mudge in 1778. It had a pewter mug with a hole allowing attachment of a flexible tube. Mudge used it for the treatment of coughs using opium. These devices evolved with modifications by Wolfe, Mackenzie (1872) and better mouth attachments such as by Beigel in 1866. Many of these early inhalers needed heat to vaporize the active chemical ingredient. The benefits of forced expiration and inspiration to treat asthma were noted by J. S. Monell in 1865. Chemicals used in inhalers included ammonia, chlorine, iodine, tar, balsams, turpentine camphor and numerous others in combinations. [ 27 ]   Julius Mount Bleyer  used a variation in 1890 in New York. [ 28 ]


In 1968, Robert Wexler of  Abbott Laboratories  developed the Analgizer, a disposable inhaler that allowed the self-administration of  methoxyflurane   vapor  in air for  analgesia . [ 29 ]  The Analgizer consisted of a  polyethylene  cylinder 5 inches long and 1 inch in diameter with a 1 inch long mouthpiece. The device contained a rolled  wick  of  polypropylene   felt  which held 15  milliliters  of methoxyflurane.


Because of the simplicity of the Analgizer and the  pharmacological  characteristics of methoxyflurane, it was easy for patients to self-administer the drug and rapidly achieve a level of  conscious analgesia  which could be maintained and adjusted as necessary over a period of time lasting from a few minutes to several hours. The 15 milliliter supply of methoxyflurane would typically last for two to three hours, during which time the user would often be partly  amnesic  to the sense of pain; the device could be refilled if necessary. [ 30 ]


The Analgizer was found to be safe, effective, and simple to administer in  obstetric  patients during childbirth, as well as for patients with  bone fractures  and  joint dislocations , [ 30 ]  and for dressing changes on  burn  patients. [ 31 ]  When used for labor analgesia, the Analgizer allows labor to progress normally and with no apparent  adverse effect  on  Apgar scores . [ 30 ]  All  vital signs  remain normal in obstetric patients, newborns, and injured patients. [ 30 ]  The Analgizer was widely utilized for analgesia and  sedation  until the early 1970s, in a manner that foreshadowed the  patient-controlled analgesia   infusion pumps  of today. [ 32 ] [ 33 ] [ 34 ] [ 35 ]  The Analgizer inhaler was withdrawn in 1974, but use of methoxyflurane as a sedative and analgesic continues in Australia and New Zealand in the form of the  Penthrox inhaler . [ 36 ] [ 37 ] [ 38 ] [ 39 ] [ 40 ] [ 41 ]


An  injector pen  (also called a  medication pen ) is a device used for injecting medication  under the skin . First introduced in the 1980s, injector pens are designed to make injectable medication easier and more convenient to use, thus increasing  patient adherence . The primary difference between injector pens and traditional vial and syringe administration is the easier use of an injector pen by people with low dexterity, poor vision, or who need portability to administer medicine on time. Injector pens also decrease the fear or adversity towards self-injection of medications, which increases the likelihood that a person takes the medication.


Injector pens are commonly used for medications that are injected repeatedly by a person over a relatively short period of time, especially  insulin and insulin analogs  used in the treatment of diabetes (called  insulin pens ). Many other medications are also available as injector pens, including other injectable medicines for diabetes, high cholesterol, migraine prevention, and other  monoclonal antibodies . Studies have shown injector pens to be at least as effective as vial and syringe administration, and surveys have shown that a vast majority of people would prefer an injector pen over vial and syringe administration if one was available. After a slow uptake in the United States, injector pens have surpassed vial and syringe administration of insulin in  type 2 diabetes .


The primary goal of injector pens is to increase  patient adherence  by making it easier and more convenient for people to use injectable therapy. This is especially problematic with injectable medications given the extra work associated with an injection, as well as the potential aversion to self-injecting medication. [ 1 ] [ 2 ]


Injector pens increase patient adherence by increasing the ease of self-administering injectable medication, as well as the portability of injection medication. [ 2 ]  Furthermore, injector pens are easier to handle and use than vials and syringes, making them useful in people with low dexterity, cognitive or visual impairment, or those who worry about being able to properly use a vial and syringe. [ 2 ]  For medications which do not follow standard dosage in all people, injector pens may be designed to enable easier and more accurate administration of an exact dose, whereas a vial and syringe requires the person to prepare the correct dose themselves. [ 2 ]  Injector pens may also remove stigma or fear around the use of injection medication in public environments, such as insulin before a meal at a restaurant. [ 2 ]


Combination injector pens which include multiple medications used to treat a disease are designed to reduce the number of injections a person must use to administer their medications. [ 3 ]  The reduction in number of injections required may decrease the risk of non-adherence due to forgetfulness or unwillingness to self-inject medication. [ 3 ]


An injector pen consists of a chamber or cartridge of medication, a tip to attach a needle, and a piston or plunger to inject the dose. [ 4 ]  Some pens, including most insulin pens, include dials to adjust the dose of the injection before each administration. [ 2 ]  Dials enable more accurate dose measuring than traditional vial and syringe administration, especially for low doses of insulin. [ 2 ]  Injector pens which have dials to adjust dosages may also include a clicking sound or other method to confirm the dose adjustment. [ 2 ]


Some pens may include a cartridge filled with medication which can be replaced when empty to enable reuse of the pen itself, whereas other pens are designed to be disposed of after their prefilled chamber is depleted. [ 2 ]  Injector pens designed for single use may also be  autoinjectors , which do not require the user to press a plunger to inject the dose. [ 4 ]


All injector pens other than those designed for single use require the use of single-use replaceable pen needles for each injection. These pen needles come in various lengths to accommodate varying depths of subcutaneous tissue under the top of the skin. [ 5 ]  Pen needles are designed for single use  subcutaneous injection  of medication and are not designed to be reused for more than one administration. [ 6 ]  The needles are generally manufactured with an outer protective plastic shell, which is used by a person to attach the needle to the pen, and an inner plastic shell protecting the needle itself. Instruction on how to properly attach and use needles is the responsibility of the doctor or  pharmacist  to ensure proper use. [ 2 ] [ 7 ]


Today, pen needles are manufactured at shorter needle lengths than required for typical vial and syringe administration, which decreases the pain associated with injection. [ 2 ]  They are available in multiple lengths and  gauge of needle , including 3.5mm, 4mm, 5mm, and 8mm lengths, and 31 through 34 gauge. [ 8 ]  Over time, needles have also had bevels designed which decrease the force required to penetrate the skin, which decreases the pain associated with injection and may increase the acceptability of self-injection. [ 8 ]  Furthermore, pen needles are designed for insertion at a 90-degree angle to the skin, as opposed to normal syringes which are designed to be injected at an angle. Pen needles generally do not require pinching of the skin for proper administration, unlike historically used syringes. [ 9 ]  Pen needles should be disposed of properly after each use, preferably in a purpose-made sharps container, to prevent injury from accidental contact after use. [ 9 ]