DESs have emerged as the primary therapeutic approach for managing symptomatic peripheral arterial disease (PAD). These specialized stents are now widely utilized in the treatment of peripheral arterial occlusive disease (PAOD), a condition that shares similarities with coronary artery disease but affects the peripheral arteries. By deploying DESs, healthcare professionals can effectively address and alleviate the complications associated with PAOD, enhancing patient outcomes and quality of life. [ 68 ] [ 69 ] [ 51 ]  The use of DESs in peripheral arterial interventions has shown encouraging results in terms of primary patency (PP) and target lesion  revascularization  (TLR) compared with bare-metal stents (BMSs). [ 70 ] [ 71 ] [ 52 ] [ 53 ]


Different types of DESs are available on the market, each with different concentrations of drugs and showing varying efficacy. [ 52 ] [ 53 ]  Among the different DESs,  sirolimus -eluting stents and  everolimus -eluting stents were found to be more effective than  paclitaxel -eluting stents. [ 52 ] [ 53 ]


PCI and stent placement are considered when someone shows signs of reduced blood flow in the arteries that supply the heart or when tests, such as different types of coronary artery imaging, show a blockage in those arteries. [ 72 ] [ 73 ]


Symptoms can include:


In a medical setting, it's not very useful for doctors to rely solely on what people say about where their pain comes from or how it feels, because the way people describe chest pain caused by reduced blood flow to the heart can vary greatly and may not match what is typically taught in medical education or described in books and articles. [ 75 ] [ 76 ]


DES is not recommended in some cases as it may do more harm than good. DES is not suitable:


Bleeding disorders make DES unsuitable because of the need for anticoagulation drugs (blood thinners) during the procedure and in post-stenting aftercare. Other factors that could rule out the use of stents include a history of in-stent blockage, bleeding problems, complex or unsuitable coronary anatomy, or a short life expectancy due to other serious medical conditions. [ 80 ]


Stent placement risks include bleeding, allergic reactions to the contrast agents used to visualize the coronary arteries, and myocardial infarction. With  percutaneous coronary intervention  (PCI), the requirement for emergency  coronary artery bypass graft (CABG) surgery  has decreased as better practices have been introduced. [ 81 ]   In some situations, coronary stenting is permitted in hospitals without cardiac surgery facilities, [ 82 ]  but such permission remains controversial because of the rare but unpredictable risk of coronary artery perforation. [ 83 ]


A complication of coronary stenting is stent thrombosis (blood clots). This occurs when a new clot forms within the stent and occludes blood flow, causing a heart attack. [ 84 ] [ 85 ] [ 86 ]


DES were designed to specifically combat issues of restenosis that occurred with older bare-metal stents (BMS). [ 70 ] [ 87 ]  Though less frequent with drug-eluting stents, restenosis can still occur. [ 88 ]


Since the advent of DES technology, the incidence of ISR has significantly decreased. [ 89 ] [ 90 ]


DES have been shown to be superior to BMS in reducing short-term complications of stenting in  saphenous vein  grafts. [ 91 ]  However, the use of DESs in  bypass grafts  was not their originally intended use nor within the scope of originally regulatory approval ( US FDA ,  European Medicines Agency , etc.). The practice of using a medical device or drug in a way not specified in the original or current approved labeling is often referred to as " off-label " use. [ 92 ]


In regions were cardiac stenting has become commonplace, think tanks and advocacy groups express concern about the overzealous use of stents, [ 93 ]  because patients who received stents for unapproved reasons [ 94 ] [ 95 ]  often have worse outcomes compared to patients who received stents for approved uses. [ 96 ] [ 97 ] [ 98 ]


People who receive a coronary stent have different needs depending on their medical condition. Some patients are actually having a heart attack and need immediate life-saving emergency care. Other patients are at high risk of having a heart attack in the very near future. For people from each of these groups, PCI procedures may vary slightly, with particular modifications as to how they are sedated, pain management, and broader  intensive care  issues such as breathing support. [ 99 ]


Many people who are not in critical care situations are usually fully awake during the PCI procedure and DES placement, but they receive local anesthetic at the site of catheter entry, to ensure there is no pain. Different sedation and pain management practices are used by different medical institutions and practitioners, but patient comfort is always a primary consideration. [ 100 ]


The catheter/stent system is inserted into the body by piercing a peripheral artery (an artery in the arm or leg) and moved through the arterial system to deliver the DES into the blocked coronary artery. The stent is then expanded to widen (open) blocked or narrowed coronary arteries (narrowed by plaque buildup), caused by a condition called atherosclerosis. Peripheral arterial access is usually through the femoral (upper leg) or the radial artery (arm/wrist) and less often done through the brachial or ulnar artery (wrist/arm). [ 101 ] [ 102 ]  In the past, controlling bleeding at the point of arterial access after the procedure was a problem.  Modern arterial pressure bands and arterial closure systems now exist, which have helped control bleeding after the procedure, but it is still a concern. [ 103 ] [ 104 ] [ 105 ]


Modern catheter/stent systems are integrated medical devices, made of a guidewire, catheter, balloon, and stent. The stent tube mesh is initially collapsed onto the balloon of the device, and it is small enough to be passed through relatively narrow peripheral arteries. When in position, the balloon is inflated by introducing physiological saline, and this pushes the overlaying stent firmly into the diseased artery wall, inflation time and pressure are recorded during this placement procedure. After placement, the balloon is deflated, and the device is removed from the body, leaving the expanded stent in place and opening up the artery. [ 67 ] [ 106 ]


The interventional cardiologist decides how to treat the blockage in the best way during the PCI/DES placement, based on real-time data. The cardiologist uses imaging data provided by both  intravascular ultrasound  (IVUS), and  fluoroscopic  imaging (combined with a  radiopaque  dye). During the procedure, the information obtained from these two sources enables the cardiologist to track the path of the catheter-DES device as it moves through the arterial blood vessels. This information also helps determine both the location and characteristics of any plaque causing narrowing in the arteries. Data from these two techniques is used to correctly position the stent and to obtain detailed information relating to the coronary arterial anatomy. Given that this anatomy varies greatly among individuals, having this information becomes a prerequisite for effective treatment. The obtained data is recorded on video and may be used in cases when further treatment is needed. [ 107 ] [ 108 ] [ 109 ]


For many people the stenting procedure does not require staying in the hospital for any extended time period, most people leave the hospital the same day. Much of the time immediately after the stenting is spent in a recovery area to make sure the access site is not bleeding and to ensure vital signs are stable. [ 110 ]


In most hospital settings, the interventional cardiologist who performed the procedure will speak directly with the patient/family and give them information about how things went, and follow-up instructions. The nursing staff will keep an eye on the person's condition and use tools like ECG to monitor their heart. To prevent a blood clot from forming in the stent, medications are given right after the procedure. One common medication is  plavix , which is a potent blood thinner that comes as a pill. Other medicines that thin the blood are also used, and it's typical to combine  aspirin  with  plavix . [ 111 ]  For people who have had a heart attack, the length of hospitalization is dependent on the degree of heart muscle damage caused by the event. [ 112 ]


A catheter with DES is a medical device, so people who receive it are given a medical device card. This card has information on the implanted DES and a medical device serial number. This information is important for future medical procedures, because it helps the doctors to know what type of device is in the person's body. Some arterial closure systems, which are devices that help to seal the access site after the procedure, are also medical devices and have their own informational cards. [ 113 ]


The access site is the place where the catheter enters the artery in the arm or leg. There is usually soreness and bruising at this site. This bruising and soreness usually get better after a week or so. People are advised to rest for a week or two and not to lift heavy things. This is mainly to make sure the access site heals well. It is normal to have follow-up appointments with a cardiologist or a primary care provider/general practitioner within a week or two of the procedure. [ 114 ] [ 115 ]


People who get a coronary stent usually have more check-ups every three to six months for the first year, but this can vary. They usually do not need to have another  coronary angiography , which is a test that uses a special dye and X-rays to see the arteries of the heart. If the doctors suspect that the heart disease is getting worse, they can prescribe a stress test, which is a test that measures how the heart works during physical activity. People who have symptoms or show signs of reduced blood flow to the heart in a stress test may need to have a diagnostic cardiac re-catheterization. [ 116 ]


After PCI-stenting procedures, physical examinations are important. People who have a high risk of complications or more complex coronary problems may need to have angiography. This may be the case even if the results of non-invasive stress tests, which are tests that measure how the heart works during physical activity, appear normal. [ 117 ]


Cardiac rehabilitation activities depend on many factors, but mainly on how much the heart muscle was damaged before the PCI/DES procedure. Many people who have this procedure have not had a heart attack, and their hearts may be fine. Others may have had a heart attack and their hearts may have trouble pumping oxygen-rich blood to the body. Rehabilitation activities are tailored to each person's needs. [ 118 ]


DES are an improvement over older BMS devices as they reduce the chances of in-stent blockages. This reduces the incidence of serious post-stenting events such as, angina occurrence or recurrence, heart attacks, and death. They also reduce the likelihood of requiring another PCI procedure to open a blockage caused by the actual stent. [ 70 ]


The major benefit of drug-eluting stents (DES) when compared to bare-metal stents (BMS) is the prevention of in-stent restenosis (ISR). [ 70 ]  Restenosis is a gradual re-narrowing of the stented segment that occurs most commonly between 3–12 months after stent placement. [ 119 ]  High rates of restenosis associated with BMS prompted the development of DES, which resulted in a reduction of ISR incidence to around 5-10%. [ 120 ]  Continued development of newer generation DES have resulted in the near-elimination of BMS from clinical practice. [ 121 ]


A key benefit of DES usage compared to BMS is a lower incidence of repeat revascularization procedures (re-stenting, invasive bypass surgeries etc.). Revascularization procedures are treatments that restore blood flow to parts of the heart that are not getting enough blood, a problem called ischemia. This can happen because of plaque buildup in the arteries of the heart, which can narrow or block them. [ 122 ]  Rates of repeat revascularizations and stent thrombosis (blood clots) are significantly lower in those who received DES compared to BMS. [ 120 ]


Newer generations of DES devices have substantially improved safety outcomes, specifically regarding stent thrombosis, recurrent  myocardial infarctions , and death. [ 122 ]


There are a number of very detailed medical device design considerations for DES products, these considerations are included in submissions for approval to regulatory authorities such as the US FDA: [ 18 ]


The drug choice is a critical design element and determining its true effectiveness in inhibiting  neointimal  growth due to the proliferation of smooth muscle cells that would cause restenosis can be a design challenge. Much of the  neointimal hyperplasia  seems to be caused by inflammation. [ 123 ]


Vascular stents are classified by the US as class III medical devices, [ 124 ]  meaning that they pose the highest risk to patients and are subject to both general and  premarket approval , which requires clinical trials and scientific evidence of safety and effectiveness, as well as rigorous mechanical testing. [ 125 ]  During the mechanical testing process, universal testing machines induce bending, stretching, twisting, and putting pressure on vascular stents from various angles. [ 124 ]


The specific properties of each type of stent and its intended use depend on the results of testing, and vice versa: different types of stents may need different or additional tests based on where they will be placed in the body and what they will be used for. Some of these additional tests might include checking how well the stent can withstand being crushed or bent out of shape, its resistance to getting kinks in it, whether it resists corrosion or damage over time, as well as making sure any coatings on the device remain intact. [ 124 ]


Pharmacological therapy  for coronary artery disease may be indicated instead of or in addition to invasive treatment. For those requiring  percutaneous coronary intervention  or surgery, medical therapy should be viewed as complementary to revascularization procedures, rather than an opposing strategy.  Coronary artery bypass graft  (CABG) surgery is an alternative to percutaneous coronary intervention (PCI) with drug-eluting stents (DES) for patients with ischemic left ventricular systolic dysfunction (LVSD). CABG is associated with lower risks of all-cause mortality, repeat revascularization, and myocardial infarction compared to PCI. However, there is no significant difference between the two procedures in terms of cardiovascular mortality, stroke, major adverse cardiovascular and cerebrovascular events, and ventricular tachycardia. [ 126 ]


The first procedure to treat blocked  coronary arteries  was  coronary artery bypass graft  surgery (CABG), wherein a section of vein or artery from elsewhere in the body is used to bypass the diseased segment of the coronary artery. In 1977,  Andreas Grüntzig  introduced  percutaneous transluminal coronary angioplasty  (PTCA), also called balloon angioplasty, in which a catheter was introduced through a peripheral artery and a balloon expanded to dilate the narrowed segment of the artery. [ 127 ]


As equipment and techniques improved, the use of PTCA rapidly increased, and by the mid-1980s, PTCA and CABG were being performed at equivalent rates. [ 128 ]  Balloon angioplasty was generally effective and safe, but restenosis was frequent, occurring in about 30–40% of cases, usually within the first year after dilation. In about 3% of balloon angioplasty cases, failure of the dilation and acute or threatened closure of the coronary artery (often because of dissection) prompted emergency CABGs. [ 128 ]


Charles Theodore Dotter  and  Melvin Judkins  had proposed using prosthetic devices inside arteries in the leg to maintain blood flow after dilation as early as 1964. [ 129 ]   In 1986, Puel and Sigwart implanted the first coronary stent in a human patient. [ 130 ]  Several trials in the 1990s showed the superiority of stent placement over balloon angioplasty.  Restenosis was reduced because the stent acted as a scaffold to hold open the dilated segment of the artery. Acute closure of the coronary artery (and the requirement for emergency CABG) was reduced, because the stent repaired dissections of the arterial wall. By 1999, stents were used in 84% of  percutaneous  coronary interventions (i.e., those done via a catheter, and not by open-chest surgery). [ 130 ]


Early difficulties with coronary stents included a risk of early  thrombosis  (clotting) resulting in occlusion of the stent. [ 128 ]  Coating stainless steel stents with other substances such as platinum or gold did not eliminate this problem. [ 130 ]  High-pressure balloon expansion of the stent to ensure its full apposition to the arterial wall, combined with drug therapy using aspirin and another inhibitor of  platelet  aggregation (usually  ticlopidine  or clopidogrel) nearly eliminated this risk of early stent thrombosis. [ 128 ] [ 130 ]


Though it occurred less frequently than with balloon angioplasty or other techniques, stents nonetheless remained vulnerable to restenosis, caused almost exclusively by neointimal tissue growth (tissue formation in the inner 'tube'  structure of the artery). To address this issue, developers of drug-eluting stents used the devices themselves as a tool for delivering medication directly to the arterial wall.  While initial efforts were unsuccessful, the release (elution) of drugs with certain specific physicochemical properties from the stent was shown in 2001 to achieve high concentrations of the drug locally, directly at the target lesion, with minimal systemic side effects. [ 131 ]   As currently used in clinical practice, "drug-eluting" stents refers to metal stents that elute a drug designed to limit the growth of neointimal scar tissue, thus reducing the likelihood of stent  restenosis . [ 132 ]


The first type of DES to be approved by the  European Medicines Agency  (EMA) and the  US Food and Drug Administration  (FDA) were sirolimus-eluting stents (SES), which release a natural product called  sirolimus , [ 133 ]  an immunosuppressant drug. [ 134 ]  SES were shown to reduce the need for repeat procedures and improve the outcomes of patients with coronary artery disease. [ 135 ] [ 136 ] [ 137 ]  The sirolimus-eluting Cypher stent received CE mark approval in Europe in 2002, and then underwent a larger trial to demonstrate its safety and effectiveness for the US market. [ 138 ] [ 139 ] [ 140 ]  The trial, published in 2003, enrolled 1058 patients with more complex lesions and confirmed the superiority of SES over bare metal stents in terms of angiographic and clinical outcomes. [ 141 ] [ 142 ] [ 143 ] [ 144 ]  Based on these results, the Cypher stent received FDA approval and was released in the US in 2003. [ 130 ]  The FDA approval process for DES involves submitting an investigational device exemption (IDE) application to conduct clinical trials under 21 CFR Part 812, and then a premarket approval (PMA) application to obtain marketing authorization under 21 CFR Part 8144. The FDA assigns the primary review responsibility to the Center for Devices and Radiological Health (CDRH), but also consults with the Center for Drug Evaluation and Research (CDER) for the drug component of the combination product.


The second type of DES to be approved by the EMA and the FDA were paclitaxel-eluting stents (PES), which release another natural product called  paclitaxel . PES also reduced the need for repeat procedures and improved the outcomes of patients with different types of lesions and risk factors. The paclitaxel-eluting Taxus stent received FDA approval and was launched in the US in 2004, [ 145 ]  after a series of trials that compared it with a bare metal stent in various settings. The trials showed a significant reduction in target lesion revascularization and major adverse cardiac events with the Taxus stent at 9 and 12 months. Both SES and PES use natural products as the active agents to prevent the recurrence of blockages in the arteries. [ 146 ]  These DES have changed the practice of interventional cardiology and have become the preferred treatment for many patients with coronary artery disease. [ 146 ] [ 147 ] [ 148 ]


The initial rapid acceptance of DES led to their peak usage in 2005, accounting for 90% of all stent implantations, but concerns about late stent thrombosis led to a decrease in DES usage in late 2006. Subsequent studies reassured the medical community about their safety, showing that while DES may have a slightly higher risk for very late stent thrombosis, they significantly reduce target vessel revascularization without increasing the incidence of death or myocardial infarction; these reassurances led to a resurgence in DES utilization, although it did not reach the peak usage rates seen in early 2006. [ 149 ] [ 150 ]


The concept of using absorbable (also called biodegradable, bioabsorbable or bioresorbable) [ 151 ]  materials in stents was first reported in 1878 by Huse who used magnesium wires as ligatures to halt the bleeding in vessels of three patients. Despite extensive search, the full name of this pioneer in the field remains elusive. [ 151 ] [ 152 ]  In 20th century, a resorbable stent tested in humans was developed by the Igaki Medical Planning Company in Japan and was constructed from poly-L-lactic acid (a form of  polylactic acid ); they published their initial results in 2000. [ 153 ]  The German company  Biotronik  developed a  magnesium  absorbable (bioresorbable) stent and published clinical results in 2007. [ 153 ]


The first company to bring a bioresorbable stent to market was  Abbott Vascular  which received European marketing approval in September 2012; the second was Elixir which received its CE mark in May 2013. [ 154 ] [ 155 ] [ 156 ]


Despite the initial promise, the first-generation bioresorbable stents, such as the Absorb bioresorbable stent by Abbott, faced significant challenges in their performance. In comparison to current-generation drug-eluting stents, numerous trials revealed that these first-generation bioresorbsble stents exhibited poor outcomes. Specifically, they showed high rates of stent thrombosis (cases where an implanted coronary stent caused a thrombotic occlusion), target-lesion myocardial infarction (heart attack occurring at the site of the treated lesion), and target vessel revascularization (the need for further procedures to restore blood flow in the treated artery). In 2017, Abbott pulled its bioabsorbable stent, Absorb, from the European market after negative press regarding the device. [ 157 ]   Boston Scientific  also announced termination of its Renuvia bioresorbable coronary stent program as studies showed higher risk of serious adverse events. [ 158 ]


Currently, fully bioresorbable stents do not play a significant role in coronary interventions. [ 159 ] [ 160 ] [ 161 ]  While various manufacturers are proposing new stents and continuing their development, [ 162 ]  it remains uncertain whether they will have a substantial impact, unless there will be more data from their clinical trials. As of now, these stents are not widely utilized in practice. [ 163 ] [ 164 ] [ 159 ]


Due to challenges in developing resorbable stents, many manufacturers have focused efforts on targeting or reducing drug release through bioabsorbable-polymer coatings. Boston Scientific's Synergy bioabsorbable polymer stent has been shown potential to reduce the length of dual antiplatelet therapy post-implantation. [ 165 ]   MicroPort's  Firehawk target eluting stent has been shown to be non-inferior to traditional drug-eluting stents while using one-third of the amount of equivalent drug. [ 166 ]


As for the materials used to make a DES, the first DES products available for treating patients were stainless steel alloys composed of iron, nickel, and chromium and were based on existing bare metal stents. [ 123 ]  These stents were hard to visualize with medical imaging, posed a risk of causing allergic responses, and were difficult to deliver. Subsequent new alloys were used, namely  cobalt-chrome  and platinum chrome, with improved performance.  Bioresorbable stents  have been developed in which the stent itself dissolves over time. [ 58 ]  Materials explored for use include  magnesium ,  polylactic acid ,  polycarbonate  polymers, and  salicylic acid  polymers. [ 153 ]   Resorbable stents have held the promise of providing an acute treatment that would eventually allow the vessel to function normally, without leaving a permanent device behind. [ 167 ]


For the coating of DES, one to three or more layers of  polymer  can be used: a base layer for adhesion, a main layer that holds and elutes (releases) the drug into the arterial wall by contact transfer, and sometimes a top coat to slow down the release of the drug and extend its effect. The first few drug-eluting stents to be licensed used durable coatings. The first generation of coatings appears to have caused immunological reactions at times, and some possibly led to thrombosis. This has driven experimentation and the development of new coating approaches. [ 154 ]


A research direction for a DES is to improve the material from which a device is made. The first-generation DES were made of stainless steel, while contemporary DES mainly consist of different kinds of alloys such as cobalt chromium and platinum chromium. In the current generation DES, thinner struts are employed than in the first-generation DES with preserved radial strength and radio-opacity. The lower strut thickness is believed to be associated with better stent-related outcomes including target lesion revascularization, myocardial infarction, and stent thrombosis. [ 168 ]


Another area of research for DES focuses on polymers. The current generation DES includes both durable polymer-coated stents and biodegradable polymer-coated stents. It has been reported that the presence of a durable polymer in the body over a long period can lead to chronic inflammation and neoatherosclerosis. To address this potential limitation, researchers have developed biodegradable polymer DES as an alternative solution. [ 168 ] [ 169 ] [ 170 ]


Scientists are also studying different drugs that could be used in DES to prevent restenosis. These drugs, which have immunosuppressive [ 134 ]  and anti-cancer properties, aim to inhibit the growth of smooth muscle cells. Additionally, there is a specific type of stent that features an extra layer of anti-CD4 antibodies on its struts. This additional layer is positioned on top of the polymer coating and aims to capture circulating endothelial progenitor cells. The goal behind this design is to promote improved healing of the blood vessel lining, known as the  endothelium . [ 168 ] [ 61 ]


A potential research focus for DES is the application of a polymer-free DES in clinical practice: moving away from polymer-based DES and instead using either a polymer-free DES or a drug-coated coronary stent. In the case of the polymer-free DES, it utilizes an abluminal coating of probucol to control the release of sirolimus. On the other hand, the drug-coated coronary stent has a micro-structured abluminal surface that allows for direct application of an anti-restenotic drug. [ 168 ] [ 61 ]


As of 2023 [update]  there are over 20 different types of drug-eluting stents available, with differences in features and characteristics. [ 171 ]


The economic evaluation of DES has been a topic of extensive research. [ 172 ]  In 2007, the overall incremental cost-effectiveness ratio in Europe was €98,827 per quality-adjusted life-years gained. Avoiding one revascularization with DES would cost €4,794, when revascularization with BMS costs €3,2606. [ 173 ]


There were controversies related to the use of DES. In 2012, a  meta-analysis  of clinical trial data [ 174 ]  showed no benefit of the use of DES for people with stable coronary artery compared to treatment with drugs, yet,  The New York Times  interviewed David Brown, an author of the analysis, who said that more than half of patients with stable  coronary artery disease  were implanted with stents without even trying drug treatment and that he believed this happened because hospitals and doctors wanted to make more money. [ 175 ]


The interview sparked a debate among cardiologists, researchers, and patients about the appropriateness and effectiveness of DES for stable coronary artery disease: some agreed with the study's findings and questioned the overuse of stents, [ 176 ] [ 177 ] [ 178 ]  while others criticized the study's methods and limitations and defended the benefits of stents, arguing that the interviewee's statement was "outrageous and defamatory" and that he was "insulting the integrity of the entire profession. [ 179 ] [ 180 ] [ 181 ]


In 2013 the Times of India reported that DES were widely overused and that Indian distributors used profits from high  markups  on DES to bribe doctors to use them. [ 182 ] [ 183 ]


In 2014 an investigation by the  Maharashtra  Food and Drug Administration found that high markups and bribery related to DES was still widespread. [ 184 ]


There have been several patent disputes related to drug-eluting stents. In one of them, Boston Scientific Corporation (BSC) has been found guilty of infringing upon a patent awarded to the University of Texas at Arlington in 2003 and licensed to TissueGen. [ 185 ] [ 186 ] [ 187 ]  This patent involves technology developed by TissueGen founder Kevin Nelson, during his time as a faculty member at the University. The technology is designed to deliver drugs through an extruded fiber within an implanted vascular stent. As a result, BSC has been ordered to pay $42 million in lost royalties to both TissueGen and the University [ 185 ] [ 186 ]


Drug-eluting stents have been associated with legal and ethical controversies, and there have been related class action lawsuits. In 2014, the former owners of St. Joseph Medical Center in Maryland settled a class action lawsuit for $37 million with hundreds of patients who received unnecessary DES implantation. The lawsuit alleged that Dr. Mark Midei, a cardiologist at the center, falsified the degree of coronary artery stenosis to justify the use of DES, exposing the patients to increased risks of thrombosis, bleeding, and infection. Another DES manufacturer, Cordis Corporation, a subsidiary of Johnson & Johnson, was involved in lawsuits from people who suffered adverse events from the Cypher Stent, a stainless-steel DES coated with sirolimus, [ 188 ] [ 189 ]  an immunosuppressant drug. [ 134 ]  The Cypher Stent was approved by the FDA in 2003, but soon after, the FDA issued a Safety Warning following 290 reports of subacute thrombosis and at least 60 deaths related to the device. [ 188 ] [ 189 ]


Dry shampoo  otherwise known as hybrid shampoo is a type of  shampoo  which reduces  hair greasiness  without the need for water. It is in powder form and is typically administered from an  aerosol  can. Dry shampoo is often based on  corn starch  or rice starch. [ citation needed ]  In addition to cleansing hair, it can also be used as a tool for hair-styling as it can create volume, help tease hair, keep  bobby pins  in place, and be used in place of  mousse  in wet hair. [ 1 ]  Dry shampoo proponents attest that daily wash-and-rinse with detergent shampoo can strip away natural oils from hair. [ 2 ]  However, others attest that spraying dry shampoo every day will lead to a build-up of product that can dull hair color and irritate the scalp, arguing that the scalp needs regular cleansing and  exfoliating  to get rid of  bacteria , remove dead skin cells, and stay healthy. [ 3 ]


The powders within dry shampoo are meant to absorb the  sebum  in hair, which is excreted from  sebaceous glands  and can give hair a greasy appearance when the oil is overproduced. By absorbing the oils, the greasy appearance of the hair is improved; however, the absorbed oils and powders remain in the scalp, so the hair may appear clean but feel unclean to the user. [ 4 ]  The user may need to wash their hair with traditional  shampoos  to actually remove the oils and dry shampoo powder in order for the scalp and hair to feel and appear clean.


Throughout history, people have used powder-based products similar to dry shampoo to cleanse and improve the appearance of hair. Evidence suggests that people in Asia used clay powder to clean their hair as early as the late 15th century. [ 5 ]  During the  Elizabethan era , a lack of regular bathing made clay powders popular among women to cleanse their hair of excess dirt and oil. Some powders were even colored for decorative purposes. [ 6 ]  Powders were also used by 18th-century British and American elites to absorb the oils in hair and wigs at a time when long hair was a marker of masculine privilege. [ 7 ]  The first written reference of dry shampoo in the United States is from the late 1700s, when starches were used to deodorize and alter the color of wigs. [ 8 ]  Other early mentions of dry shampoo include foam substances used by barbers to clean hair in the late 1800s. [ 9 ]


The first commercially produced dry shampoo was sold in the 1940s, but the product existed before that. By the early 1940s, the Stephanie Brooke Company of Jersey City, New Jersey had developed Minipoo, the first brand of commercially produced dry shampoo powder. Minipoo was marketed to women and children for use in scenarios such as "surprise dates" or when they were sick in bed, according to the  Smithsonian 's  National Museum of American History . [ 10 ]  Since 1790, 71 patents have been filed for dry shampoo products in the United States. [ 11 ]


Dry shampoo is generally composed of a carrier agent containing an active powder. [ 12 ]  Normally,  starch  is used as the active powder. When the powder is sprayed onto hair, the carrier agent evaporates while the starch remains attached. While the active powder can be replaced with other substances such as  activated carbon  and  alumina , these substances are generally not used due to their inability to biodegrade. In particular, activated carbon and alumina leave behind a residue that is difficult to remove. [ 13 ]  Presently,  oryza sativa  starch and  cetrimonium chloride  are the most common starches used in dry shampoos. Dry shampoo in the form of aerosol also often contains a propellant ingredient. [ 14 ]  The propellant used in dry shampoo usually consists of  butane ,  isobutane , and  propane , which makes up 70–90% of the total composition. [ 14 ]


Dry shampoos often contain  anionic surfactants  that do not dissolve in water. The surfactant molecules have a hydrophilic portion as well as a hydrophobic portion to bind with water and oils. Surfactants such as detergents rely heavily on micelle formations.  Amphiphile  molecules organize into small clusters of micelles with the hydrocarbon non-polar ends facing inwards. [ 15 ]  When dry shampoo is applied, amphiphile molecules surround suspended oil drops which then can be removed. The anionic substances often leave a form of calcium salts, which are not soluble, in the hair strands that causes hair to be dry and tangled. The alkaline residue may also cause hair and skin irritations. [ 16 ]


Dry shampoo can be administered as a powder, where all the ingredients of dry shampoo are combined together and applied to the scalp with the hand, or through the aerosol form where the dry shampoo is sprayed directly onto the head. In the aerosol form, the powders comprising the dry shampoo are dispersed throughout pressurized gas inside a can; when the release is pressed, the pressurized gas and powders inside are released, forming the aerosol that lands on the head or scalp. [ 17 ]


This product has also been made at home, in addition to being purchased in stores.  DIY  dry shampoos usually have some sort of starch base, which is one of the key products in commercially produced dry shampoos, and often contains  essential oils  for scent. [ 18 ]


Herbal powder shampoos are another form of dry shampoo. As a natural hair-care product, they tend to have fewer negative side effects than traditional mass-market shampoos, and contain a dry powder mixture of  aloe vera  and other plant byproducts to reduce skin, eye, and scalp irritation from  surfactants . [ 19 ]


Clay  has been used throughout history as a form of dry shampoo. The  Rhassoul  clay, also known as red clay, originating from Morocco is traditionally used as a leave-in shampoo and conditioner. Due to its high absorbance of sebum, clay is often used as a remedy for  dandruff  and  seborrhea . Such properties of clay stem from its colloidal particle size and crystalline structure. Even though clay is generally considered to be a natural non-toxic material, it should not be stored in metal containers due to its retention of heavy metals. [ 20 ]


In addition to the liquid shampoos, there are dry shampoos available for pets with fur. The waterless-foaming shampoo is applied directly into the fur of the pet without the need to pre-wet or rinse the pet after application. These shampoos often contain a combination of detergents, antimicrobial agents, and surfactants. Certain conditioners may also contain additional agents such as  Melaleuca  oil for the treatment of fleas. [ 21 ]  The foaming component of the shampoo comes from a pressurized gas such as carbon dioxide mixing with a foaming liquid. Once the foam is applied to the fur, the foam needs to be worked in vigorously before being wiped off.


The product is applied to the scalp or roots of the hair, either through aerosol form or directly applying the powder, the powder within the product is allowed to sit on the hair for an extended period of time, and then the powder is massaged or brushed through the scalp. [ 22 ]  Allowing the product to sit in the hair before brushing it out allows more time for the product to absorb the sebum oils in the hair and brushing out the product would reduce the powder's potentially noticeable appearance.


A  dry-powder inhaler  ( DPI ) is a device that delivers medication to the lungs in the form of a dry powder.  DPIs are commonly used to treat  respiratory diseases  such as  asthma ,  bronchitis ,  emphysema  and  COPD  although DPIs (such as  inhalable insulin ) have also been used in the treatment of  diabetes mellitus . [ 1 ]


DPIs are an alternative to the aerosol-based inhalers commonly called  metered-dose inhaler  (or MDI). The DPIs may require some procedure to allow a measured dose of powder to be ready for the patient to take. The medication is commonly held either in a capsule for manual loading or in a proprietary form inside the inhaler. Once loaded or actuated, the operator puts the mouthpiece of the inhaler into their mouth and takes a sharp, deep inhalation (ensuring that the medication reaches the lower parts of the lungs), holding their breath for 5–10 seconds.


There are a variety of such devices. The dose that can be delivered is typically less than a few tens of milligrams in a single breath since larger powder doses may lead to provocation of  cough .


Most DPIs rely on the force of patient inhalation to entrain powder from the device and subsequently break-up the powder into particles that are small enough to reach the lungs. [ 2 ]  For this reason, insufficient patient inhalation flow rates may lead to reduced dose delivery and incomplete deaggregation of the powder, leading to unsatisfactory device performance. Thus, most DPIs have a minimum inspiratory effort that is needed for proper use and it is for this reason that such DPIs are normally used only in older children and adults.


While DPIs are commonly used in the treatment of lung-based disorders, their use requires dexterity to complete the required sequential steps to achieve application of these devices. Incorrect completion of one or more steps in the use of a DPI can substantially reduce the delivery of the administrated medication and consequently its effectiveness and safety. Numerous studies have demonstrated that between 50 and 100% of patients do not use their inhaler devices correctly, with patients often unaware that they are using their inhaled medication incorrectly. [ 3 ] [ 4 ]  Incorrect inhaler technique has been associated with poorer outcomes. [ 4 ] [ 5 ]


Some powder inhalers use  lactose  to:


It has been suggested that such  lactose  may be harmful to  lactose intolerant  people, [ 6 ]   and some doctors advise patients not to use lactose containing DPIs [ 7 ]  to minimize the risk of hypersensitivity reactions. [ 8 ]


DPI medication must be stored in a dry place in a temperature of not more than 25 °C (77 °F) and humidity between 40 and 50% in a sealed packaging, since exposure of the powder to moisture degrades the ability of the device to disperse its medication as a fine powder upon inhalation. Some medication also needs photo protection.


A  dual therapy stent  is a  coronary artery stent  that combines the technology of an  antibody -coated  stent  and a  drug-eluting stent . [ 1 ]  Currently, second-generation  drug-eluting stents  require long-term use of  dual-antiplatelet therapy , which increases the risk of major bleeding occurrences in patients. [ 2 ]  Compared to  drug-eluting stents , dual therapy stents have improved vessel regeneration and cell proliferation capabilities. [ 1 ] [ 2 ]  As a result, dual therapy stents were developed to reduce the long-term need for  dual-antiplatelet therapy . [ 3 ]


The COMBO stent is the first and only dual therapy stent that addresses the challenges of vessel healing in  drug-eluting stents . [ 4 ]  This stent is an  anti-CD34 antibody -coated and  sirolimus -eluting bioresorbable stent. [ 2 ]  The COMBO stent combines the  Genous  stent's  endothelial cell  capture technology with an antiproliferative, biodegradable  sirolimus  drug elution. [ 5 ]  The COMBO stent has received  CE Mark approval . [ 6 ]


The field of  interventional cardiology  began in the 20th century with the development of the  plain old balloon angioplasty . [ 4 ]  However, this procedure carried risks of promoting  platelet aggregation , tearing, arterial recoil, and  restenosis . [ 4 ]  Thus, coronary artery stents were created to prevent  restenosis  after  balloon dilation . [ 4 ]  There are three types of stents:  bare-metal stents  (BMS),  drug-eluting stents  (DES), and bioresorbable vascular scaffolds (BRS). [ 4 ]


The first stents created were bare-metal stents where they were made from stainless steel and had poor flexibility. Despite its reduced rates of  restenosis  compared to  plain old balloon angioplasty , it still had high rates of  stent thrombosis  and required a high dosage of  blood thinners . [ 4 ]  This led to the development of  drug-eluting stents  to act as local drug delivery and vascular scaffold platform to reduce  in-stent restenosis . [ 4 ]


Antiproliferative drugs  like  sirolimus  and  paclitaxel  were used in the first-generation  drug-eluting stents  to inhibit the migration of  vascular smooth muscle cells  and  restenosis . [ 4 ] [ 1 ]  The first implanted  drug-eluting stent  occurred in 1999, which revolutionized the course of  interventional cardiology . [ 1 ]  However, despite the  drug-eluting stents  superiority over the  bare-metal stents , drug-eluting stent implantation had possible concerns over  platelet aggregation  and significant  blood clotting  in a localized area. [ 1 ]


As a result, improvements in the stent material, strut thickness, polymer, and drug choice led to the development of  second-generation drug-eluting stents  that showcased overall clinical enhancements to its predecessor. [ 4 ] [ 1 ]  The new stent used more biocompatible molecules like  zotarolimus  and  everolimus  with quicker drug elution. [ 4 ]  However, despite these improvements, concerns persisted on the risk of  stent thrombosis .


The development of dual therapy stents resulted from the health risks of long-term use of  dual antiplatelet therapy  from  drug-eluting stents . [ 2 ]   Drug-eluting stents  inhibit the growth of  endothelial cells  and  vascular smooth muscle cells , which are essential for in-stent endothelialization. [ 1 ]  Due to inhibition of vital vascular system cells, this causes risk of stent thrombosis, and, thus, patients with  drug-eluting stents  are required to use  dual antiplatelet therapy  for approximately 12 months. [ 2 ]  Although long term use of  dual antiplatelet therapy  research showcases reduced risk of cardiovascular deaths, it has increased occurrences of major bleeding events, which has challenges for patients with  bleeding disorders . [ 2 ]


The COMBO dual therapy stent is the first and only dual therapy stent presently developed. [ 1 ]  The COMBO dual therapy stent combines the  anti-CD34 antibody  coating of the  Genous Stent  with antiproliferative  sirolimus  elution. [ 1 ]  The  sirolimus  drug reduces the risk of  stent restenosis  through inhibiting the formation of  neointima  while the  anti-CD34 antibody  coating reverses the inhibition of local  endothelial cells  from the  sirolimus  elution. [ 1 ]


The predecessor of the biotechnology used to create a dual therapy stent was the development of the  Genous stent . [ 1 ]  The  Genous stent  is a coronary artery stent coated with  anti-CD3 monoclonal antibodies  that bind with circulating endothelial cells to the stent. [ 7 ]  The coated stent promotes the formation of an  endothelial layer , which protects against  thrombosis  and reduces  restenosis . [ 7 ]   Furthermore, the Genous stent promotes coronary vascular repair response and reduces  neointimal hyperplasia  after stent implantation. [ 8 ]   Although the Genous stent promotes rapid vessel healing, it did not decrease the rate of target lesion failure compared to  drug-eluting stents , which increases the risk of  restenosis  and  stent  failure. [ 8 ] [ 9 ]


The COMBO stent is a pro-healing stent with  sirolimus  drug elution and anti-CD3 monoclonal antibodies that has enhanced degree of endothelization. [ 10 ]  The stent has an abluminal, facing vessel wall, bioabsorbable coating that continuously releases  sirolimus  and a luminal  anti-CD34 antibody  cell capture coating. [ 10 ]


The COMBO stent's enhanced endothelization is due to the  sirolimus  drug that reduces the risk of stent  restenosis  and the  Genous stent 's  anti-CD3 antibodies  capture biotechnology. [ 8 ]  The COMBO stent reduces not only the rate of  stent restenosis  but also the need for  dual antiplatelet therapy , which enables high-risk patient groups like patients who are under long-term  anticoagulation regimens  or patients with  bleeding disorders  to use this type of stent. [ 1 ]


Ear drops  are a form of  topical medication  for the ears used to treat  infection, inflammation ,  impacted ear wax   and  local anesthesia . They are commonly used for short-term treatment and can be purchased with or without a prescription. Before using ear drops, refer to the package insert or consult a health professional for the amount of drops to use and the duration of treatment.


Prior to using the medication, refer to package label for specific instructions or ask a local pharmacist. Check to make sure a  tamper-evident  seal is intact and the medication is not expired. Let a health care provider know of any drug allergies to any medications or other ingredients in the medication. Let a healthcare provider know what was prescribed and what over the counter medications, vitamins, supplements, and herbal supplements are being taken with this medication. If pregnant, planning to become pregnant, or breastfeeding, make sure to inform a healthcare before using any medications. [ 1 ]


Always wash hands with soap and water for 30 seconds prior to administering ear drops and after administering.


For adults and teenagers: [ 2 ]


For children under 3: [ 3 ]


For children 3 and over: [ 3 ]


Eye drops can generally be used safely in the ears, but ear drops should never be used in the eyes. [ 4 ]  Prescribers must specifically indicate the use of eye drops for ear drops on the prescription; do not make this substitution without consulting a medical provider.


Side effects from using ear drops used to remove ear wax are uncommon, but may result in discomfort, irritation, or pain. [ 5 ]  Antibiotic ear drops may cause ear discomfort, pain, or itching. [ 1 ]  When cold ear drops are used, it may cause brief but severe dizziness and/or vertigo. [ 6 ]


If a dose is missed, do not double up at the next administration to catch up and the dose can be administered when recalled. Additionally if it is close to the next dose, skip that missed dose and resume as normal. [ 9 ]


Although ear drops typically contain preservatives that slow the growth of bacteria and other microorganisms, this does not offer long term protection from contamination. The shelf life of ear drops varies with products generally needing to be discarded within 4 weeks after opening. [ 10 ] [ 11 ]  With proper use and storage, ear drops should remain effective and safe until the expiration date printed in the medication package insert.


Ear wax, also known as  cerumen , protects the ear from dust, bacteria, and small objects from entering and damaging the ear. It also provides a coating to protect the skin inside the ear canal from irritation from water during showers and water activities. [ 6 ]


However, some individuals have more active glands which can produce more ear wax. That can lead to a build up and block the ear canal causing hearing loss, noises in the ear, sensation of ear is plugged and full, and earache. [ 6 ]  The excess ear wax may also harden causing an impaction and discomfort. Healthcare providers recommend against reaching into the ears to clean it because the ear wax may be pushed even deeper into the ear canal. [ 6 ]


Drops to safely break up earwax are available over-the-counter and are labeled 'otic' drops. [ 12 ]  Products in this category contain carbamide peroxide, which dissolves some of the  earwax . Some common brands include Auro and Debrox. When carbamide peroxide ear drops are applied to the ear canal, there may hear some fizzing as a result of the reaction with the earwax. Drops should be used according to the package instructions (typically recommended maximum of 4 days) or as directed by a healthcare provider. If the blockage has worsened or not improved, consult a doctor. [ 13 ]


Another method to break up earwax is by using body temperature water. While having the head upright, straighten the ear canal by gently pulling the upper outer ear back and up. Then use a syringe (do not use jet irrigator that is designed for teeth cleaning) [ 6 ]  to aim a small gentle stream of water at the ear canal wall next to the ear wax to be removed. Next, tilt the head to allow water to drain and repeat if necessary.  After removing the ear wax, allow the ear to dry thoroughly. Adding a few drops of alcohol in the ear may help to dry the ear. [ 6 ]


Do not use irrigation or ear drops if there is a hole in the ear drum or had recent ear surgery to prevent damage or infection in the ears. [ 6 ]


Otitis externa, also known as  swimmer's ear , is an inflammation (infectious or non-infectious) of the external auditory canal. [ 14 ]  Risk factors include retained water in the outer ear, particularly due to swimming, humidity, trauma or external devices, dermatologic conditions, or scratching the ear canal that may lead to bacterial growth. [ 14 ] [ 15 ]


Otitis externa can generally be prevented by keeping the ear canal dry and/or applying ear drops labeled for swimmer's ear (typically a dilution of isopropyl and glycerin) after exposure to water to assist with keeping the ear canal dry. [ 16 ]


Treatment of otitis externa is centered around antibiotic ear drops and pain control (e.g.  acetaminophen ,  non-steroidal anti-inflammatory drugs , and opioids including  oxycodone  or  hydrocodone ). Antibiotic ear drops are generally safe and well-tolerated. Some studies have demonstrated that the addition of topical steroids to antibiotic ear drops provides quicker pain relief, but these results are conflicting. [ 17 ]  Symptoms of uncomplicated otitis externa typically improve within 48 hours of initiating antibiotics. If pain does not improve within 48 to 72 hours of antibiotic therapy, individuals should consult their provider to confirm the diagnosis. [ 17 ]  Common antibiotic ear drops for treating otitis externa include: [ 14 ]


Bacterial ear infections are treated with antibiotics; local administration is preferred over systemic delivery due to increased antibiotic concentration and lack of systemic side effects. [ 18 ]  Antibiotic ear drops are much faster at killing the bacteria. [ 19 ]  Ear drops work faster since the medication directly goes to the site of infection whereas oral antibiotics enter the bloodstream first. [ 19 ]  Some commonly used antibiotics include:


Antibiotics for ear infections are prescribed for infections that are recurrent or difficult for the body to clear. Antibiotic ear drops should be used as prescribed. Do not stop the use of medication even if the infection appears cleared because remaining bacteria can cause the infection to return. [ 23 ]


Otic analgestic-anesthetic are drops that can help alleviate swelling, pain and congestion caused by middle ear inflammation. However, these ear drops do not treat the infections because they do not contain any antibiotic properties. [ 24 ]  A common over-the-counter product sold as  Auralgan  contained  antipyrine  (analgesic) and  benzocaine  (anesthetic). It was prescribed alone or with an antibiotic ear drop to help manage an ear infection. However, Auralgran was reformulated without meeting the FDA requirements to be reapproved and was removed from the market in July 2, 2015. [ 25 ]


There is some literature to suggest that anesthetic ear drops helped with acute pain. This study was conducted in Australia in 2008 in a hospital emergency room. It included 63 children who were between the ages of 3 and 17 who presented to the emergency department reporting of ear pain. Children were randomized such that 32 received placebo and 31 children received topical  lignocaine  prior to being offered an oral pain medication. The study showed that a topical pain medication was helpful while waiting for an oral pain medication to be effective. [ 26 ]  There is another small study conducted in England and  Wales  that reported that an analgestic-anesthetics could reduce the amount of antibiotics being used in children. While the study did show evidence of less antibiotic use, it did not meet the sample size goal of  96 participants. Additionally did not evaluate if pain relief was linked to reduced antibiotic use. [ 27 ]


An   elixir  is a sweet liquid used for medical purposes, to be taken orally and intended to cure one's illness. [ 1 ]  When used as a  pharmaceutical preparation , an elixir contains at least one  active ingredient  designed to be taken orally.


The word was introduced in late  Middle English , through  Latin  from the  Arabic   الإكسير  ( al-ʾiksīr ), which in turn is the  Arabization  of the  Ancient Greek   ξήριον  ( xērion )  ' powder for drying wounds '  (from  ξηρός  ( xēros )  ' dry ' ). [ 1 ]  For centuries,  elixir  primarily meant an ingredient used in  alchemy , either referring to a liquid which purportedly converts lead to gold, or a substance or liquid which is believed to cure all ills and  give eternal life .


These are used as  solvents  or vehicles for the preparation of medicated elixirs. Active ingredients are dissolved in a 15–50% by volume solution of  ethyl alcohol :


These include:


Daily non-alcoholic non-caffeinated 'vitamin drinks' have been popular in East Asia since the 1950s, with  Oronamin  from  Otsuka Pharmaceutical  perhaps the market leader. Packaged in brown light-proof bottles, these drinks have the reputation of being enjoyed by old men and other health-conscious individuals. Counterparts exist in South Korea and China.


Western  energy drinks  typically have caffeine and are targeted at a younger demographic, with colorful labels and printed claims of increased athletic/daily performance.


See  Patent medicine .


An elixir is a  hydro - alcoholic  solution of at least one active ingredient. The alcohol is mainly used to:


The lowest alcoholic quantity that will dissolve completely the active ingredient(s) and give a clear solution is generally chosen. High concentrations of alcohol give burning taste to the final product.


An elixir may also contain the following  excipients :


Elixirs should only be stored in a tightly closed, light resistant container away from direct heat and sunlight.


An  emulsion  is a  mixture  of two or more  liquids  that are normally  immiscible  (unmixable or unblendable) owing to liquid-liquid  phase separation . Emulsions are part of a more general class of two-phase systems of  matter  called  colloids . Although the terms  colloid  and  emulsion  are sometimes used interchangeably,  emulsion  should be used when both phases, dispersed and continuous, are liquids. In an emulsion, one liquid (the dispersed  phase ) is  dispersed  in the other (the continuous phase). Examples of emulsions include  vinaigrettes , homogenized  milk , liquid  biomolecular condensates , and some  cutting fluids  for  metal working .


Two liquids can form different types of emulsions. As an example, oil and water can form, first, an oil-in-water emulsion, in which the oil is the dispersed phase, and water is the continuous phase. Second, they can form a water-in-oil emulsion, in which water is the dispersed phase and oil is the continuous phase. Multiple emulsions are also possible, including a "water-in-oil-in-water" emulsion and an "oil-in-water-in-oil" emulsion. [ 1 ]


Emulsions, being liquids, do not exhibit a static internal structure. The droplets dispersed in the continuous phase (sometimes referred to as the "dispersion medium") are usually assumed to be  statistically distributed  to produce roughly spherical droplets.


The term "emulsion" is also used to refer to the photo-sensitive side of  photographic film . Such a  photographic emulsion  consists of  silver halide  colloidal particles dispersed in a  gelatin  matrix.  Nuclear emulsions  are similar to photographic emulsions, except that they are used in particle physics to detect high-energy  elementary particles .


A fluid system in which liquid droplets are dispersed in a liquid.


Note 1 : The definition is based on the definition in ref. [ 2 ]


Note 2 : The droplets may be amorphous, liquid-crystalline, or any mixture thereof.


Note 3 : The diameters of the droplets constituting the  dispersed phase usually range from approximately 10 nm to 100 μm; i.e., the droplets may exceed the usual size limits for  colloidal  particles.


Note 4 : An emulsion is termed an oil/water (o/w) emulsion if the dispersed phase is an organic material and the  continuous phase  is water or an aqueous solution and is termed water/oil (w/o) if the dispersed phase is water or an aqueous solution and the continuous phase is an organic liquid (an "oil").


Note 5 : A w/o emulsion is sometimes called an inverse emulsion. The term "inverse emulsion" is misleading, suggesting incorrectly that the emulsion has properties that are the opposite of those of an emulsion. Its use is, therefore, not recommended. [ 3 ]


The word "emulsion" comes from the Latin  emulgere  "to milk out", from  ex  "out" +  mulgere  "to milk", as milk is an emulsion of fat and water, along with other components, including  colloidal   casein  micelles (a type of secreted  biomolecular condensate ). [ 4 ]


Emulsions contain both a dispersed and a continuous phase, with the boundary between the phases called the "interface". [ 5 ]  Emulsions tend to have a cloudy appearance because the many  phase interfaces   scatter  light as it passes through the emulsion. Emulsions appear  white  when all light is scattered equally. If the emulsion is dilute enough, higher-frequency (shorter-wavelength) light will be scattered more, and the emulsion will appear  bluer  – this is called the " Tyndall effect ". [ 6 ]  If the emulsion is concentrated enough, the color will be distorted toward comparatively longer wavelengths, and will appear more  yellow . This phenomenon is easily observable when comparing  skimmed milk , which contains little fat, to  cream , which contains a much higher concentration of milk fat. One example would be a mixture of water and oil. [ 7 ]


Two special classes of emulsions –  microemulsions  and nanoemulsions, with droplet sizes below 100 nm – appear translucent. [ 8 ]  This property is due to the fact that light waves are scattered by the droplets only if their sizes exceed about one-quarter of the wavelength of the incident light. Since the  visible spectrum  of light is composed of wavelengths between 390 and 750  nanometers  (nm), if the droplet sizes in the emulsion are below about 100 nm, the light can penetrate through the emulsion without being scattered. [ 9 ]  Due to their similarity in appearance, translucent nanoemulsions and microemulsions are frequently confused. Unlike translucent nanoemulsions, which require specialized equipment to be produced, microemulsions are spontaneously formed by "solubilizing" oil molecules with a mixture of  surfactants , co-surfactants, and co- solvents . [ 8 ]  The required surfactant concentration in a microemulsion is, however, several times higher than that in a translucent nanoemulsion, and significantly exceeds the concentration of the dispersed phase. Because of many undesirable side-effects caused by surfactants, their presence is disadvantageous or prohibitive in many applications. In addition, the stability of a microemulsion is often easily compromised by dilution, by heating, or by changing pH levels. [ citation needed ]


Common emulsions are inherently unstable and, thus, do not tend to form spontaneously. Energy input – through shaking, stirring,  homogenizing , or exposure to power  ultrasound [ 10 ]  – is needed to form an emulsion. Over time, emulsions tend to revert to the stable state of the phases comprising the emulsion. An example of this is seen in the separation of the oil and vinegar components of  vinaigrette , an unstable emulsion that will quickly separate unless shaken almost continuously. There are important exceptions to this rule – microemulsions are  thermodynamically  stable, while translucent nanoemulsions are  kinetically  stable. [ 8 ]


Whether an emulsion of oil and water turns into a "water-in-oil" emulsion or an "oil-in-water" emulsion depends on the volume fraction of both phases and the type of emulsifier (surfactant) (see  Emulsifier , below) present. [ 11 ]


Emulsion stability refers to the ability of an emulsion to resist change in its properties over time. [ 12 ] [ 13 ]  There are four types of instability in emulsions:  flocculation ,  coalescence ,  creaming / sedimentation , and  Ostwald ripening . Flocculation occurs when there is an attractive force between the droplets, so they form flocs, like bunches of grapes. This process can be desired, if controlled in its extent, to tune physical properties of emulsions such as their flow behaviour. [ 14 ]  Coalescence occurs when droplets bump into each other and combine to form a larger droplet, so the average droplet size increases over time. Emulsions can also undergo creaming, where the droplets rise to the top of the emulsion under the influence of  buoyancy , or under the influence of the  centripetal force  induced when a  centrifuge  is used. [ 12 ]  Creaming is a common phenomenon in dairy and non-dairy beverages (i.e. milk, coffee milk,  almond milk , soy milk) and usually does not change the droplet size. [ 15 ]  Sedimentation is the opposite phenomenon of creaming and normally observed in water-in-oil emulsions. [ 5 ]  Sedimentation happens when the dispersed phase is denser than the continuous phase and the gravitational forces pull the denser globules towards the bottom of the emulsion. Similar to creaming, sedimentation follows  Stokes' law .


An appropriate surface active agent (or surfactant) can increase the kinetic stability of an emulsion so that the size of the droplets does not change significantly with time. The stability of an emulsion, like a  suspension , can be studied in terms of  zeta potential , which indicates the repulsion between droplets or particles. If the size and dispersion of droplets does not change over time, it is said to be stable. [ 16 ]  For example, oil-in-water emulsions containing  mono- and diglycerides  and milk protein as surfactant showed that stable oil droplet size over 28 days storage at 25 °C. [ 15 ]


The stability of emulsions can be characterized using techniques such as light scattering, focused beam reflectance measurement, centrifugation, and  rheology . Each method has advantages and disadvantages. [ 17 ]


The kinetic process of destabilization can be rather long – up to several months, or even years for some products. [ 18 ]  Often the formulator must accelerate this process in order to test products in a reasonable time during product design. Thermal methods are the most commonly used – these consist of increasing the emulsion temperature to accelerate destabilization (if below critical temperatures for phase inversion or chemical degradation). [ 19 ]  Temperature affects not only the viscosity but also the interfacial tension in the case of non-ionic surfactants or, on a broader scope, interactions between droplets within the system. Storing an emulsion at high temperatures enables the simulation of realistic conditions for a product (e.g., a tube of sunscreen emulsion in a car in the summer heat), but also accelerates destabilization processes up to 200 times. [ citation needed ]


Mechanical methods of acceleration, including vibration, centrifugation, and agitation, can also be used. [ 20 ]


These methods are almost always empirical, without a sound scientific basis. [ citation needed ]


An  emulsifier  is a substance that stabilizes an emulsion by reducing the oil-water  interface tension . Emulsifiers are a part of a broader group of compounds known as  surfactants , or "surface-active agents". [ 21 ]  Surfactants are compounds that are typically  amphiphilic , meaning they have a polar or  hydrophilic  (i.e., water-soluble) part and a non-polar (i.e., hydrophobic or  lipophilic ) part. Emulsifiers that are more soluble in water (and, conversely, less soluble in oil) will generally form oil-in-water emulsions, while emulsifiers that are more soluble in oil will form water-in-oil emulsions. [ 22 ]


Examples of food emulsifiers are:


In food emulsions, the type of emulsifier greatly affects how emulsions are structured in the stomach and how accessible the oil is for gastric  lipases , thereby influencing how fast emulsions are digested and trigger a  satiety  inducing  hormone  response. [ 24 ]


Detergents  are another class of surfactant, and will interact physically with both  oil  and  water , thus stabilizing the interface between the oil and water droplets in suspension. This principle is exploited in  soap , to remove  grease  for the purpose of  cleaning . Many different emulsifiers are used in  pharmacy  to prepare emulsions such as  creams  and  lotions . Common examples include  emulsifying wax ,  polysorbate 20 , and  ceteareth 20 . [ 25 ]


Sometimes the inner phase itself can act as an emulsifier, and the result is a nanoemulsion, where the inner state disperses into " nano-size " droplets within the outer phase. A well-known example of this phenomenon, the " ouzo effect ", happens when water is poured into a strong alcoholic  anise -based beverage, such as  ouzo ,  pastis ,  absinthe ,  arak , or  raki . The anisolic compounds, which are soluble in  ethanol , then form nano-size droplets and emulsify within the water. The resulting color of the drink is opaque and milky white.


A number of different chemical and physical processes and mechanisms can be involved in the process of emulsification: [ 5 ]


Oil-in-water emulsions are common in food products:


Water-in-oil emulsions are less common in food, but still exist:


Other foods can be turned into products similar to emulsions, for example  meat emulsion  is a suspension of meat in liquid that is similar to true emulsions.


In  pharmaceutics ,  hairstyling ,  personal hygiene , and  cosmetics , emulsions are frequently used. These are usually oil and water emulsions but dispersed, and which is continuous depends in many cases on the  pharmaceutical formulation . These emulsions may be called  creams ,  ointments ,  liniments  (balms),  pastes ,  films , or  liquids , depending mostly on their oil-to-water ratios, other additives, and their intended  route of administration . [ 26 ] [ 27 ]  The first 5 are  topical   dosage forms , and may be used on the surface of the  skin ,  transdermally ,  ophthalmically ,  rectally , or  vaginally . A highly liquid emulsion may also be used  orally , or may be  injected  in some cases. [ 26 ]


Microemulsions are used to deliver  vaccines  and kill  microbes . [ 28 ]  Typical emulsions used in these techniques are nanoemulsions of  soybean oil , with particles that are 400–600 nm in diameter. [ 29 ]  The process is not chemical, as with other types of  antimicrobial  treatments, but mechanical. The smaller the droplet the greater the  surface tension  and thus the greater the force required to merge with other  lipids . The oil is emulsified with detergents using a  high-shear mixer  to stabilize the emulsion so, when they encounter the lipids in the  cell membrane  or envelope of  bacteria  or  viruses , they force the lipids to merge with themselves. On a mass scale, in effect this disintegrates the membrane and kills the pathogen. The soybean oil emulsion does not harm normal human cells, or the cells of most other  higher organisms , with the exceptions of  sperm cells  and  blood cells , which are vulnerable to nanoemulsions due to the peculiarities of their membrane structures. For this reason, these nanoemulsions are not currently used  intravenously  (IV). The most effective application of this type of nanoemulsion is for the  disinfection  of surfaces. Some types of nanoemulsions have been shown to effectively destroy  HIV-1  and  tuberculosis  pathogens on non- porous  surfaces.


Emulsifying agents are effective at extinguishing fires on small, thin-layer spills of flammable liquids ( class B fires ). Such agents encapsulate the fuel in a fuel-water emulsion, thereby trapping the flammable vapors in the water phase. This emulsion is achieved by applying an  aqueous  surfactant solution to the fuel through a high-pressure nozzle. Emulsifiers are not effective at extinguishing large fires involving bulk/deep liquid fuels, because the amount of emulsifier agent needed for extinguishment is a function of the volume of the fuel, whereas other agents such as  aqueous film-forming foam   need cover only the surface of the fuel to achieve vapor mitigation. [ 37 ]


Emulsions are used to manufacture polymer dispersions – polymer production in an emulsion 'phase' has a number of process advantages, including prevention of coagulation of product. Products produced by such polymerisations may be used as the emulsions – products including primary components for glues and paints. Synthetic  latexes  (rubbers) are also produced by this process.


Engineered chimeric antigen receptor (CAR)-T cell delivery  is the methodology by which clinicians introduce the cancer-targeting therapeutic system of the  CAR-T cell  to the human body. CAR-T cells, which utilizes genetic modification of human  T-cells  to contain antigen binding sequences in addition to the receptor systems  CD4  or  CD8 , are useful in direct targeting and elimination of cancer cells through  cytotoxicity .


CAR-T cell delivery involves many varying modalities for implementation, spurring innovative biomedical research to address these modalities. These delivery mechanisms serve to address the limitations of CAR-T cells in translational experimentation and clinical trials, including shelf-life, off-target effects, and  tumor infiltration . [ 1 ]  As of April 2023, six CAR-T cell therapies are clinically approved by the  FDA , all of which target  hematologic  (blood-based) cancers, including  multiple myeloma  and  B-cell leukemias . [ 2 ] [ 3 ]  Novel engineered compound-based delivery methods, some of which are in clinical trials, aim to address limitations related to CAR-T cell delivery with the focus to target non-blood based cancers. [ 4 ] [ 5 ]


The classic method of administration of CAR-T cells to cancers within the human body is through intravenous (IV)  central line  infusion. [ 6 ]  This infusion allows the CAR-T cells to enter the body’s  cardiovascular system , entering the circulation (systemically) amongst developing hematologic cancers. This facilitates the final step in generation and implementation of both autologous and allogeneic CAR-T cell therapy. While this delivery method is reliable for hematologic cancers, as demonstrated by successful clinical trials and FDA regulation, systemic delivery may result in an increase in autoimmune overload, leading to toxic disorders such as  cytokine release syndrome  (CRS). [ 1 ]  Discrimination between healthy and malignant cancer cells may additionally result in  aplasia , or extremely low or absent amounts of healthy blood cells. [ 7 ]  Thus, clinically recommended dosage amounts are in place for current CAR-T cell therapies. [ 8 ] [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ] [ 14 ]  Current methods exploring ways to improve such complications have been introduced recently by researchers, including “off-switches” to turn off CAR-T cells after initial therapies and further genetic modification to avoid immune rejection. [ 1 ] [ 7 ] [ 15 ] [ 16 ]  While systemic delivery is important for targeting hematologic cancers, it remains inefficient at targeting  solid, or non-circulatory, cancerous tumors . Therefore, regional, or localized targeting strategies utilizing CAR-T cells have arisen in pre-clinical research. [ 4 ] [ 5 ] [ 17 ] [ 18 ] [ 19 ]


Solid tumors, which typically take the form of neoplasms in  epithelial cells  or in bones, tissue, or  adipose  (fat), are different than hematologic cancers in that they form a mass of cells, thereby maintaining multiple layers of protection. [ 20 ]  Because CAR-T cells attack cancerous cells at a surface level, this leaves the CAR-T cells vulnerable to cancerous cell resistance, which renders the CAR-T cell inefficient. [ 21 ] [ 22 ]  In recent years, cellular and genetic engineering methods have been explored by researchers to overcome layered protection of solid tumors, in addition to other challenges that have been presented in the advent of CAR-T cell delivery such as  in-situ  editing and manufacturing, negative  immune responses , and  biocompatibility  of delivery structures. [ 4 ] [ 5 ] [ 17 ] [ 23 ] [ 24 ] [ 25 ] [ 26 ]  Some of the methodologies used to suspend and deliver CAR-T cells include  hydrogel  and polymeric gel-based delivery systems,  thin polymeric films , and  microneedle  patches. Most of these devices, currently still in the pre-clinical phase, are intended to be injected or surgically inserted directly into the solid tumor mass. While initial clinical trials have been unsuccessful due to relatively inefficient delivery as compared to direct injection and high  immunosuppression , recent research has shown promise in overcoming these barriers. [ 4 ]


Gel-based delivery of CAR-T cells involves implantation or injection of a hydrogel or polymer gel into the target solid tumor. These gels suspend CAR-T cells in various ways through manipulation of cell-specific chemistry or by fixing the cells in a polymeric matrix. One strength of gel-based delivery is that these systems are functionally  biodegradable , so once the CAR-T cells have been administered, the depot does not stay in the body, reducing immunosuppressive conditions or tumor resistance. [ 24 ] [ 27 ]


One of the earliest examples of this methodology developed by Luo et al. in 2020 consisted of a layered hydrogel microchip that facilitated CAR-T survival from immunosuppressive elements of the tumor system which could be injected into the tumor. [ 28 ]  In addition, this system was able to take advantage of the  hypoxic  (low oxygen) conditions of the tumor by additionally containing oxygen-releasing agents that when released with  interleukin-15  (IL-15)  cytokines  could cause tumor cell death. [ 28 ]


Two recent examples utilizing gel-based delivery towards specific cancers include targeted  fibrin  gel-based delivery to  glioblastoma  and modified CAR-T cell hydrogel complexes to  retinoblastoma . [ 29 ] [ 30 ]  In the glioblastoma-targeting system, Ogunnaike et al. used CAR-T cells loaded in a fibrin matrix, which undergoes in-situ  polymerization  upon mixture of  fibrinogen  and  thrombin  (as part of the coagulation cascade). In addition, the CAR-T cells were modified to target the  B7-H3  antigen, present on some forms of cancer including glioblastoma. [ 29 ] [ 31 ]  In the retinoblastoma-targeting system, Wang et al. fabricated CAR-T cells specific to the  GD2  ganglioside, specific to retinoblastoma, and suspended them into an IL-15/ chitosan - polyethylene glycol  (PEG) hydrogel suspension, effectively targeting the tumor via injection. [ 30 ]


Additionally, researchers have developed hydrogel-based systems that limit further growth and proliferation of tumors, such as the  hyaluronic acid  hydrogel system developed by Hu et al. [ 32 ]  This system, which targets  melanoma  through targeting the  CSPG4  antigen, was shown to slowly but efficiently release IL-15 and CAR-T cells from a cross-linked hyaluronic acid matrix and  poly(lactic-co-glycolic acid)  (PLGA) nanoparticle suspension intratumorally. [ 32 ]  In addition, the system utilized anti- PDL1  antibody delivery, increasing platelet release of programmed cell death molecules onto the tumors, killing them. [ 32 ]


Sustained delivery and long-term retention of CAR-T cells through hydrogel systems has also been developed, as shown by Grosskopf et al., to address controlled release of CAR-T cells onto tumors. [ 33 ]  In this system, the researchers crosslinked a combination of dodecyl-modified  hydroxypropyl methylcellulose  (HPMC-C12) and PEG- poly(lactic acid)  (PLA) nanoparticles to form the hydrogel, then mixed CAR-T cells and IL-15 into the matrix. [ 33 ]  The sustained release profiles showed promise in tumor suppression treatments due to the slow release duration profiles. [ 33 ]


Codelivery of CAR-T cells with other  agonists , such as  stimulator of interferon (IFN) genes  (STING), remain a popular new method of administration of CAR-T cells to solid tumors. [ 34 ]  Smith et al. developed a  silica  nanoparticle based coating conjugated with  lipid  film to suspend CAR-T cells and select antibodies onto an  alginate  polymer scaffold. This system was tested in mouse  pancreatic cancer  and melanoma models, and showed expansion of CAR-T cells at the tumor site, increasing the therapeutic efficiency.


There are still challenges with these delivery systems, however, as they have limitations on CAR-T cell suspension amounts, host-specific immunogenic responses, and have been performed primarily in mouse models. [ 24 ] [ 28 ] [ 33 ]  Regardless, hydrogel-based CAR-T delivery systems have shown promise in translational experimentations towards solid tumor targeting.


Thin-film targeting has emerged as an alternative method of CAR-T cell delivery to solid tumors, utilizing metal-based microfilms made of  nitinol , an alloy of nickel and titanium, a composite commonly used in  stents . [ 17 ] [ 35 ]  One such example using these nitinol scaffolds was developed by Coon et al., whereby the researchers suspended CAR-T cells into pores laden throughout the film, combined with fibrin. [ 35 ]


Upon implantation, the CAR-T cells would release from the film, but remain within the site of the tumor due to engineered antibody attraction of the film. [ 35 ]  This caused increased localization and duration of CAR-T therapy to the tumor site as compared to intravenous or local injection of CAR-T cells. [ 35 ]


Microneedle patches have been used previously as a minimally-invasive, distributive system to release drugs across certain body systems, most notably on the skin. [ 36 ]  Microneedles patches have been used recently as a method of CAR-T cell release to solid tumor cancers such as melanoma and pancreatic cancer. [ 23 ] [ 37 ]  Using a porous PLGA microneedle-shaped scaffold, Li et al. developed a system to suspend and release CAR-T cells. [ 37 ]  An advantage of this method is that the patch could be inserted on the surface of the tumor, allowing for surface-targeting of CAR-T cells upon release. Additionally, the needles would penetrate into the solid tumor, allowing for a distribution of CAR-T cells release along the interior axis of the tumor. [ 37 ]


Production of CAR-T cells involve removal of T cells via an extraction process known as  leukapheresis , followed by cell culture with  viral vectors  containing ingredients needed to construct the chimeric system. [ 2 ] [ 38 ] [ 39 ]  These methodologies, while important, have been shown to be expensive and time-consuming. [ 21 ] [ 40 ]  Recent advances in research have introduced “scaffold factories” to program, produce, and release autologous CAR-T cells into the body after implantation. [ 41 ] [ 42 ] [ 43 ] [ 44 ]  These “scaffold factories” have shown to function in targeting hematologic cancers and show promise in future research to target solid tumors.


One method of in-situ generation involves the injection of  lentiviral vectors , containing genetic information relating to targeting of CD4 antigens directly to  lymphocytes  in conjugation with the CAR gene, allowing for the construction of this system within the body, as shown by Agarwal et al. [ 41 ]  Another method of in-situ generation involves the manufacture polymeric  nanocarriers  to carry genes involved in the development of the CAR-T cell. [ 44 ]  Smith et al. used poly(β-amino ester) (PBAE) particles laden with  polyglutamic acid  (PGA),  nuclear localization signals , and T-cell targeting fragments to deliver CAR genes to T cells for translation into CAR-T cells. [ 44 ]


These advances have led to the investigation and development of a novel system for manufacturing CAR-T cells known as Multifunctional Alginate Scaffold for T Cell Engineering and Release (MASTER). [ 43 ]  These alginate scaffolds, which are highly porous, are embedded with  azide ,  cyclooctyne -conjugated targeting antibodies, CAR-based  retroviral  vectors, and  mononuclear  blood cells. The azide and cyclooctyne-conjugated particles undergo a rapid  click chemistry  reaction, whereby when implanted, alongside introduction of the blood cells, the scaffold will generate CAR-T cells. This system was shown to be long-lasting and biodegradable, factors that are important for long suppression of cancers. [ 44 ]


An  epinephrine autoinjector  (or  adrenaline autoinjector , also known by the  trademark   EpiPen ) is a medical device for injecting a measured dose or doses of  epinephrine  (adrenaline) by means of  autoinjector  technology. It is most often used for the treatment of  anaphylaxis . The first epinephrine autoinjector was brought to market in 1983.


Epinephrine autoinjectors are hand-held devices carried by those who have severe allergies; the  epinephrine  delivered by the device is an emergency treatment for  anaphylaxis . [ 1 ] [ 2 ]


When anaphylaxis is suspected, epinephrine solution should be given as soon as possible as an  intramuscular injection , in the middle of the outer side of the thigh, which corresponds to the location of the  vastus lateralis muscle . [ 3 ]  The injection may be repeated every 5 to 15 minutes if there is insufficient response. [ 4 ]  A second dose is needed in 16–35% of episodes with more than two doses rarely required; in around 80% of the cases where a second dose is administered, it is by a medical professional. [ 4 ]   It is not clear which are the  people who might need a second injection at the outset. [ 4 ]  The intramuscular route is preferred over  subcutaneous  administration because the latter may have delayed absorption. [ 4 ] [ 5 ]  Minor adverse effects from epinephrine include  tremors , anxiety, headaches, and  palpitations . [ 4 ]


The epinephrine in autoinjectors expires after one year. [ 2 ]   A study in rabbits showed that intramuscular epinephrine has decreased effectiveness  after it expires; that study also recommended that if the drug in an expired device has not started to precipitate (if the solution is not cloudy and has no particles in it) using the expired device is better than no injection at all in an emergency situation. [ 6 ]


The devices contain a fixed dose of epinephrine and a spring-loaded needle (or, in the case of AuviQ, a CO 2 -driven needle) that exits the tip or edge of the device and penetrates the recipient's skin, to deliver the medication via  intramuscular injection . [ 2 ]


People to whom epinephrine autoinjectors are prescribed need to be trained how to use the specific device prescribed. [ 1 ] [ 4 ]   The rate of unintentional injections using these devices is unknown but a 2009 review found that the rate is increasing. [ 7 ]   Unintentional injections are delivered to a finger or thumb around 90% of the time; they cause intense pain locally but usually completely resolve. [ 7 ]   The cause of unintentional injections has been attributed to design flaws, where the device is mistaken for a pen or the user mistakes which end of the device contains the needle. [ 7 ]


The  European Medicines Agency  conducted a review of the safety of devices then on the market and found several factors that determine whether the devices successfully deliver drug into muscle, including "needle length, the thickness of fat under the skin, the way the auto-injector works (e.g., if it is spring loaded or not), the angle at which the device is placed on the skin and the force used to activate the device as well as how well the user follows the instructions for injection." [ 8 ]   It found that how well the user was trained was the most important factor determining successful delivery, and requested companies to develop better training materials for doctors and people to whom the devices are prescribed. [ 8 ]


In 2013, emergency physician  Seth C. Hawkins  and coauthors published a technique for obtaining multiple additional doses of epinephrine from used, single dose autoinjectors EpiPen and Adrenaclick. It was emphasized this was an emergency adaptation of the intended design for austere environments when no additional epinephrine was available. [ 9 ]  In 2016, Robinson and Lareau published a similar technique adapted to used AuviQ autoinjectors. [ 10 ]


Autoinjectors  were originally developed for the rapid administration of  nerve gas  antidotes in kits like the  Mark I NAAK . The first modern epinephrine autoinjector, the EpiPen, was invented in the mid-1970s at Survival Technology in  Bethesda , Maryland, US by  Sheldon Kaplan [ 11 ] [ 12 ]  and was first approved for marketing by the FDA in 1987. [ 13 ]


One of the people who helped in making the EpiPen was Richard B. Toren. He had the idea to use this technology for allergic reactions because his daughter was allergic to bees and had to carry around a complex kit if she was ever stung. He then helped to slightly alter the technology in order to create EpiPen's current design. [ 14 ]


In 1996, Survival Technology merged with a company called Brunswick Biomedical and the new company was called  Meridian Medical Technologies . [ 15 ]  In 1997, Dey, a subsidiary of  Merck KGaA , acquired the exclusive right to market and distribute the EpiPen. [ 16 ] [ 17 ]  In 1998 there was a recall of one million EpiPens, the second such recall in a year. [ 18 ]


In 2001 Meridian and Dey introduced a two-pack version of the EpiPen; at that time the device had $23.9 million in annual sales and accounted for 75% of the market in the United States. [ 19 ]   In 2002  King Pharmaceuticals  acquired Meridian for $247.8 million in cash; [ 17 ]  the deal was completed in January 2003. [ 20 ]  Kaplan continued to improve his designs over the years, filing for example US Patent 6,767,336 in 2003. [ 21 ]


In 2003, Hollister-Stier received approval from the FDA to market an epinephrine autoinjector called Twinject that could deliver two shots of epinephrine, which it had spent ten years developing. [ 22 ] [ 23 ] [ 24 ]   In 2005, it sold the product to Verus Pharmaceuticals, [ 22 ]  which launched the product the same year. [ 25 ]   In March 2008, Sciele Pharma acquired Twinject from Verus [ 26 ]  and later that year, Sciele was acquired by Shionogi. [ 27 ]


In 2007,  Mylan  acquired the right to market the EpiPen from  Merck KGaA  as part of a larger transaction. [ 28 ]  At that time annual sales were around $200 million [ 29 ]  and the EpiPen had about 90% of the market. [ 30 ]


In 2009, Mylan and King started marketing a new version of EpiPen with the same basic mechanism but a stronger spring, better safety features, and clearer markings and instructions; an expert for NBC News estimated that the cost to redesign the device and packaging may have been "several million dollars" and the cost to retool the manufacturing process may have "run into the double-digit millions." [ 31 ]


In 2009,  Teva Pharmaceuticals  filed an  ANDA  to market a generic EpiPen in collaboration with Antares Pharma Inc, a maker of injection systems; Pfizer and King sued them for infringing US Patent 7,449,012 that was due to expire in 2025; [ 32 ]  Pfizer, Mylan, and Teva settled in April 2012 in a deal that allowed Teva to start selling the device in mid-2015, pending FDA approval. [ 33 ]


In 2009, Intelliject, a US startup developing a new epinephrine autoinjector, licensed their product to  Sanofi . [ 34 ]


King was acquired by  Pfizer  in 2010 for $3.6 billion in cash. [ 35 ]


In 2010, Sciele/Shionogi faced a recall of Twinject devices [ 36 ]  and launched Adrenaclick, a modified version of the Twinject that could deliver only one dose. [ 37 ] [ 38 ]


In 2010, European regulators approved Twinject, [ 39 ]  and also approved a new epinephrine autoinjector made by  ALK  and sold under the brand name Jext. [ 40 ] [ 41 ]  Jext was launched in the European Union in September 2011. [ 42 ] [ 43 ]


Also in 2010, Shionogi authorized Greenstone, the  authorized generics  division of Pfizer, [ 44 ] [ 45 ]  to begin selling an authorized generic of Adrenaclick. [ 46 ] [ 47 ]   The media noted that Pfizer, through Greenstone, was marketing a generic epinephrine autoinjector when Pfizer acquired King later that year. [ 48 ]   At that time, King and Mylan's EpiPen had 91% of the global market share for epinephrine autoinjectors and 96% of the US market. [ 48 ]


In 2010, Pfizer and King sued  Novartis ' Sandoz generic unit for patent infringement after Sandoz submitted an ANDA to sell a generic EpiPen. [ 49 ]  In response, Sandoz challenged the validity of the patents, and as of July 2016 this litigation was ongoing. [ 50 ]


In 2011, Pfizer and King sued Intelliject and Sanofi after the companies filed a 505(b)(2) [ 51 ]   New Drug Application  for the product, then known as "e-cue"; [ 52 ]  Pfizer, Mylan and Sanofi settled in 2012 under a deal that allowed the device to enter the market no earlier than November 2012, pending FDA approval. [ 53 ]  In August 2012, the FDA approved the autoinjector, called "Auvi-Q" after the FDA required a name change from "e-cue". [ 54 ]  The device is equipped with a sound chip to provide electronic voice instructions to guide the user in the proper use of the device. [ 55 ] [ 56 ]


In 2012, Mylan launched a program called  EpiPen4Schools  to sell EpiPens in bulk and with discounts to schools; to participate in the program schools had to agree not to buy epinephrine autoinjectors from any other company for a year. [ 57 ]


In December 2012, the  National Association of State Boards of Education  launched a policy initiative designed to "help state boards of education as they develop student health policies regarding anaphylaxis and epinephrine auto-injector access and use", and advocated for state laws protecting school from legal liability for stocking and using epinephrine autoinjectors.   Gayle Conelly Manchin , mother of Mylan's CEO,  Heather Bresch , had become president of the association in 2010, and shortly after had discussed donations from her "daughter's company" to the association.  Manchin had been appointed to the West Virginia state school board by her husband  Joe Manchin , then-governor of the state, in 2012. [ 58 ]


In 2012, Shionogi, the manufacturer of Adrenaclick and Twinject, announced it would stop making them; [ 34 ]  it had sold the rights to the NDA to a company called Amedra Pharmaceuticals. [ 59 ] [ 60 ]


In June 2013, Amedra relaunched Adrenaclick. [ 61 ]  and at the same time, Lineage Therapeutics launched its authorized generic version of Adrenaclick. [ 62 ]  Lineage was a wholly owned subsidiary of Amedra that had acquired the rights to the Adrenaclick authorized generic from Greenstone/Pfizer. [ 63 ]


After successful lobbying from Mylan, [ 29 ]  in 2013, the "School Access to Emergency Epinephrine Act" became law after passing Congress with broad and bipartisan support; it protected anyone from liability if they administered epinephrine to a child in a school (previously, only trained professionals or the affected person were allowed to administer the drug, and were open to liability), and it provided some financial incentives for schools that didn't already stock epinephrine autoinjector to start stocking them. [ 64 ]   Joe Manchin, the father of Mylan's CEO, was a senator at that time. [ 58 ]


In January 2015 Mylan filed a  citizen petition  with the FDA raising concerns about TEVA's ANDA application to market a generic EpiPen and filed an additional supplement later in May; the FDA rejected the petition in June. [ 65 ] [ 66 ]


In March 2015,  Impax Laboratories  acquired the parent company of Amedra and Lineage, and placed Amedra and the Adrenaclick in its Impax Specialty Pharma division; at the same time it acquired Lineage, which it placed, along with its generic version of Adrenaclick, in its Impax Generics division. [ 67 ] [ 68 ]


In May 2015, the Emerade epinephrine autoinjector developed by the Swedish company Medeca was approved in Sweden and Germany; [ 69 ]   it had been approved in the UK in 2013. [ 70 ]    Also in 2015  Valeant , which had licensed the rights from Medeca, abandoned its efforts to get Emerade approved in the US. [ 71 ]


In October 2015, Auvi-Q and Allerject devices were voluntarily recalled by Sanofi in North America. [ 72 ] [ 73 ]  The reason stated by Sanofi was that the products had been found to potentially have inaccurate dosage delivery, which may include failure to deliver drug. [ 74 ]   In February 2016, Sanofi terminated its license to manufacture and market the Auvi-Q, leaving Kaléo (Intelliject was renamed) to consider how and whether to re-introduce the device. [ 75 ] [ 76 ]


The EpiPen had 89% of the market for epinephrine autoinjectors in 2015; [ 57 ]  in the first half of the year it had about 85% share and Auvi-Q had about 10% share. [ 29 ]


In March 2016, Teva's ANDA for a generic EpiPen, which had already faced several delays, was rejected by the FDA. [ 77 ]


In 2015 Mylan had about $1.5 billion in sales of EpiPens, which accounted for 40% of Mylan's profit. [ 29 ]  Mylan had maintained about a 90% market share since it had acquired the product, and had continually raised the price of EpiPens starting in 2009: in 2009, the wholesale price of two EpiPens was about $100; 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 cost of the drug and device to Mylan as of 2016 was about $35. [ 31 ]  In the summer of 2016, as parents prepared to send their children back to school and went to pharmacies to get new EpiPens, people began to express outrage at the cost of the EpiPen and Mylan was widely and harshly criticized. [ 79 ] [ 80 ]     In September 2016, the New York State Attorney General began an investigation into Mylan's  EpiPen4Schools  program in New York to determine if the program's contracts violated  antitrust law [ 81 ]  and the West Virginia State Attorney General opened an investigation into whether Mylan had given the state the correct discount under the  Medicaid Drug Rebate Program  and subpoenaed the company when it refused to provide the documentation the state requested. [ 82 ]  In October 2016, Mylan announced a $465M settlement with the  US Department of Justice  over rebates paid by Mylan to states under the  Medicaid Drug Rebate Program . [ 83 ]


On 5 September 2017, FDA posted a warning letter to the manufacturer, Meridian Medical Technologies. The agency warned Meridian Medical for failing to investigate problems with the devices, recall bad batches, and follow-up on problems found. According to the FDA, the manufacturer of EpiPen devices failed to address known malfunctions in its auto-injectors even as hundreds of customer complaints rolled in and failures were linked to deaths. During an inspection, Meridian employees told inspectors that they weren't allowed to disassemble and investigate complain samples, because they were allowed to do if only it was “approved by management”. [ 84 ] [ 85 ]


On 16 August 2018 the FDA approved the first generic EpiPen from Teva Pharmaceuticals. [ 86 ] [ 87 ]


In an effort to address the supply shortage of EpiPens, [ 88 ]  on August 21, 2018 the FDA approved extending the expiration dates on some products by four months. [ 89 ]


The Sandoz division of  Novartis  announced on 9 July 2019 the availability of Symjepi, a manual epinephrine injection as an alternative to autoinjectors, in 0.3 mg and 0.15 mg versions. [ 90 ]


As of 2015, the following epinephrine autoinjectors were available in various parts of Europe: Adrenalina WZF, Adrenaline (epinephrine) 1 in 1000 solution for injection BP auto-injector, Altellus, Anapen, Emerade, EpiPen, Fastjekt, FastPen, and Jext. [ 91 ]  As of 2018, three branded products were available in the United States: Adrenaclick, Auvi-Q, and EpiPen. [ 6 ]