The time taken for food to transit through the gastrointestinal tract varies on multiple factors, including age, ethnicity, and gender. [ 27 ] [ 28 ]  Several techniques have been used to measure transit time, including radiography following a  barium -labeled meal, breath  hydrogen  analysis,  scintigraphic  analysis following a  radiolabeled  meal, [ 29 ]  and simple ingestion and spotting of  corn kernels . [ 30 ]  It takes 2.5 to 3 hours for 50% of the contents to leave the stomach. [ medical citation needed ]  The rate of digestion is also dependent of the material being digested, as food composition from the same meal may leave the stomach at different rates. [ 31 ]  Total emptying of the stomach takes around 4–5 hours, and transit through the colon takes 30 to 50 hours. [ 29 ] [ 32 ] [ 33 ]


The gastrointestinal tract forms an important part of the  immune system . [ 34 ]


The surface area of the digestive tract is estimated to be about 32 square meters, or about half a badminton court. [ 19 ]  With such a large exposure (more than three times larger than the  exposed surface of the skin ), these immune components function to prevent pathogens from entering the blood and lymph circulatory systems. [ 35 ]  Fundamental components of this protection are provided by the  intestinal mucosal barrier , which is composed of physical, biochemical, and immune elements elaborated by the intestinal mucosa. [ 36 ]  Microorganisms also are kept at bay by an extensive immune system comprising the  gut-associated lymphoid tissue  (GALT)


There are additional factors contributing to protection from pathogen invasion. For example, low  pH  (ranging from 1 to 4) of the stomach is fatal for many  microorganisms  that enter it. [ 37 ]  Similarly,  mucus  (containing  IgA   antibodies ) neutralizes many pathogenic microorganisms. [ 38 ]  Other factors in the GI tract contribution to immune function include  enzymes  secreted in the  saliva  and  bile .


Beneficial bacteria also can contribute to the homeostasis of the gastrointestinal immune system. For example,  Clostridia , one of the most predominant bacterial groups in the GI tract, play an important role in influencing the dynamics of the gut's immune system. [ 39 ]  It has been demonstrated that the intake of a high fiber diet could be responsible for the induction of  T-regulatory cells  (Tregs). This is due to the production of  short-chain fatty acids  during the fermentation of plant-derived nutrients  such as  butyrate  and  propionate .  Basically, the butyrate induces the differentiation of Treg cells by enhancing  histone H3   acetylation  in the promoter and conserved non-coding sequence regions of the  FOXP3  locus, thus regulating the  T cells , resulting in the reduction of the inflammatory response and allergies.


The large intestine contains multiple types of  bacteria  that can break down molecules the human body cannot process alone, [ 40 ]  demonstrating a  symbiotic  relationship. These bacteria are responsible for gas production at  host–pathogen interface , which is released as  flatulence . Intestinal bacteria can also participate in biosynthesis reactions. For example, certain strains in the large intestine produce vitamin B 12 ; [ 41 ]  an essential compound in humans for things like DNA synthesis and red blood cell production. [ 42 ]  However, the primary function of the large intestine is water absorption from digested material (regulated by the  hypothalamus ) and the reabsorption of  sodium  and nutrients. [ 43 ]


Beneficial  intestinal bacteria  compete with potentially harmful  bacteria  for space and "food", as the intestinal tract has limited resources. A ratio of 80–85% beneficial to 15–20% potentially harmful bacteria is proposed for maintaining  homeostasis . [ citation needed ]  An imbalanced ratio results in  dysbiosis .


Enzymes  such as  CYP3A4 , along with the  antiporter  activities, are also instrumental in the intestine's role of  drug metabolism  in the detoxification of  antigens  and  xenobiotics . [ 44 ]


In most  vertebrates , including  amphibians ,  birds ,  reptiles ,  egg-laying mammals , and some  fish , the gastrointestinal tract ends in a  cloaca  and not an  anus . In the cloaca, the  urinary system  is fused with the genito-anal pore.  Therians  (all mammals that do not lay eggs, including humans) possess separate anal and uro-genital openings. The females of the subgroup  Placentalia  have even separate urinary and genital openings.


During  early development , the asymmetric position of the bowels and inner organs is initiated (see also  axial twist theory ).


Ruminants  show many specializations for digesting and  fermenting  tough plant material, consisting of  additional stomach compartments .


Many birds and other animals have a specialised stomach in the digestive tract called a  gizzard  used for grinding up food.


Another feature found in a range of animals is the  crop . In birds this is found as a pouch alongside the esophagus.


In 2020, the oldest known fossil digestive tract, of an extinct wormlike organism in the  Cloudinidae  was discovered; it lived during the late  Ediacaran   period  about 550 million years ago. [ 45 ] [ 46 ]


A through-gut (one with both mouth and anus) is thought to have evolved within the  nephrozoan  clade of  Bilateria , after their ancestral ventral orifice (single, as in  cnidarians  and  acoels ; re-evolved in nephrozoans like  flatworms ) stretched antero-posteriorly, before the middle part of the stretch would get narrower and closed fully, leaving an anterior orifice (mouth) and a posterior orifice (anus plus  genital opening ). A stretched gut without the middle part closed is present in another branch of bilaterians, the extinct  proarticulates . This and the  amphistomic  development (when both mouth and anus develop from the gut stretch in the embryo) present in some nephrozoans (e.g.  roundworms ) are considered to support this hypothesis. [ 47 ] [ 48 ]


There are many diseases and conditions that can affect the gastrointestinal system, including  infections ,  inflammation  and  cancer .


Various  pathogens , such as  bacteria  that cause  foodborne illnesses , can induce  gastroenteritis  which results from  inflammation  of the stomach and small intestine.  Antibiotics  to treat such bacterial infections can decrease the  microbiome  diversity of the gastrointestinal tract, and further enable inflammatory mediators. [ 49 ]  Gastroenteritis is the most common disease of the GI tract.


Diverticular disease  is a condition that is very common in older people in industrialized countries.  It usually affects the large intestine but has been known to affect the small intestine as well.   Diverticulosis  occurs when pouches form on the intestinal wall.  Once the pouches become inflamed it is known as  diverticulitis .


Inflammatory bowel disease  is an inflammatory condition affecting the bowel walls, and includes the subtypes  Crohn's disease  and  ulcerative colitis . While Crohn's can affect the entire gastrointestinal tract, ulcerative colitis is limited to the large intestine. Crohn's disease is widely regarded as an  autoimmune disease . Although ulcerative colitis is often treated as though it were an autoimmune disease, there is no consensus that it actually is such.


Functional gastrointestinal disorders  the most common of which is  irritable bowel syndrome . Functional constipation and  chronic functional abdominal pain  are other functional disorders of the intestine that have physiological causes but do not have identifiable structural, chemical, or infectious pathologies.


Several symptoms can indicate problems with the gastrointestinal tract, including:


Gastrointestinal surgery  can often be performed in the outpatient setting.  In the United States in 2012, operations on the digestive system accounted for 3 of the 25 most common ambulatory surgery procedures and constituted 9.1 percent of all outpatient ambulatory surgeries. [ 50 ]


Various methods of imaging the gastrointestinal tract include the  upper  and  lower gastrointestinal series :


Intestines from animals other than humans are used in a number of ways.  From each species of  livestock  that is a source of  milk , a corresponding  rennet  is obtained from the intestines of milk-fed  calves .   Pig  and  calf  intestines are eaten, and pig intestines are used as  sausage  casings. Calf intestines supply  calf-intestinal alkaline phosphatase  (CIP), and are used to make  goldbeater's skin .
Other uses are:


In medicine,  infusion therapy  deals with all aspects of fluid and medication infusion, via  intravenous  or  subcutaneous  application. A special  infusion pump  can be used for this purpose. [ 1 ]


A  fenestrated  catheter is frequently inserted into the localized area to be treated.


There are a range of delivery methods for infusion of drugs via  catheter :


Infusion therapy has a range of medical applications including sedation, anesthesia, post-operative analgesic pain management, chemotherapy, and treatment of infectious diseases


Advantages of infusion therapy over other non-site-specific delivery methodologies are primarily efficacy through precision of medication delivery.


New standards for infusible pharmaceuticals have been achieved in recent years with the advent of pre-filled, ready-to-use, dose-specific products. Advanced aseptic presentation, with hermetically sealed containers, allows predictable sterility, ease of use, improved control, and lower total costs. Essentially, systematizing the delivery mechanism and standardizing the delivery container. [ 2 ]


Infusion therapy involves the administration of medication through a needle or catheter. Typically, "infusion therapy" means that a drug is administered intravenously or subcutaneously. The term may pertain where drugs are provided through other non-oral  routes of administration , such as  intramuscular injection  and  epidural administration  (into the membranes surrounding the spinal cord).


Until the 1980s, patients receiving infusion therapy often had to remain in an  inpatient setting  for the duration of their therapy. New technologies and heightened emphasis on  cost containment  in  health care , as well as developments in the clinical administration of the therapy, led to strategies to administer infusion therapy in alternate settings (at clinics and at home) [ 3 ]  in an effort to reduce hospital readmissions.


Insufflation  ( Latin :  insufflare ,  lit.   'to blow into') is the act of blowing something (such as a gas, powder, or vapor) into a body cavity. [ 1 ]  Insufflation has many medical uses, most notably as a route of administration for various drugs.


Gases are often insufflated into a body cavity to inflate the cavity for more workroom, e.g. during  laparoscopic surgery . The most common gas used in this manner is  carbon dioxide , because it is non-flammable, colorless, and dissolves readily in blood.


Gases can be insufflated into parts of the body to enhance  radiological imaging [ 2 ]  or to gain access to areas for visual inspection (e.g. during  colonoscopy ). [ 3 ]


Oxygen can be insufflated into the nose by  nasal cannulae  to assist in respiration.


Mechanical insufflation-exsufflation  simulates a cough and assists  airway mucus clearance . It is used with patients with neuromuscular disease and muscle weakness due to central nervous system injury. [ 4 ]


Glossopharyngeal insufflation  is a breathing technique that consists of gulping boluses of air into the lungs. It is also used by  breath-hold divers  to increase their lung volumes. [ 5 ]


Positive airway pressure  is a mode of  mechanical  or  artificial ventilation  based on insufflation. [ citation needed ]


Pump inhalers  for  asthmatics  deliver aerosolized drugs into the lungs via the mouth. However, the insufflation by the pump is not adequate for delivery to the lungs, necessitating an active inhalation by the patient. [ citation needed ]


Insufflated gases and vapors are used to ventilate and oxygenate patients ( oxygen ,  air ,  helium ), and to induce, assist in or maintain  general anaesthesia  ( nitrous oxide ,  xenon ,  volatile anesthetic agents ).


Positive airway pressure  is a mode of  mechanical  or  artificial ventilation  based on insufflation.


Nasal insufflation is the most common method of  nasal administration . Other methods are nasal inhalation and nasal instillation. Drugs administered in this way can have a local effect or a systemic effect. The time of onset for systemic drugs delivered via nasal administration is generally only marginally slower than if given intravenously.


Nasal administration can also be used for treatment of  children  or patients who are otherwise alarmed or frightened by needles, or where  intravenous  (IV) access is unavailable.


In the 18th century, the  tobacco smoke enema , an insufflation of tobacco smoke into the rectum, was a common method of reviving drowning victims. [ 6 ]


An  intracavernous  (or  intracavernosal )  injection  is an  injection  into the base of the  penis .  This injection site is often used to administer medications to check for or treat  erectile dysfunction  in adult men (in, for example, a  combined intracavernous injection and stimulation test ). [ 1 ]  The more common medications administered in this manner include Caverject,  Trimix  ( prostaglandin ,  papaverine , and  phentolamine ), Bimix (papaverine and phentolamine), and Quadmix (prostaglandin, papaverine, phentolamine, and either  atropine  or  forskolin ). These medications are all types of  vasodilators  and cause  tumescence  within 15 minutes.
Common side effects include  priapism , bruising, fibrosis,  Peyronie's disease , and pain. [ citation needed ]


Priapism is also often treated with intracavernous injections, usually with  sympathomimetic  vasoconstricting drugs like  adrenaline  or  phenylephrine . [ citation needed ]


Intracerebroventricular injection  (often abbreviated as ICV injection) is a route of administration for drugs via injection into the  cerebral ventricles  so that it reaches the  cerebrospinal fluid  (CSF). This route of administration is often used to bypass the  blood-brain barrier  because it can prevent important medications from reaching the central nervous system. This injection method is widely used in diseased mice models to study the effect of drugs, plasmid DNA, and viral vectors on the central nervous system. In humans, ICV injection can be used for the administration of drugs for various reasons. Examples include the treatment of  Spinal Muscular Atrophy  (SMA), the administration of chemotherapy in  gliomas , and the administration of drugs for long-term  pain management . ICV injection is also used in the creation of diseased animal models specifically to model neurological disorders.


Intracerebroventricular injection has been used to inject drugs that induce a diseased state to create animal models for a variety of diseases. Of these,  Alzheimer's disease  (AD) animal models are heavily represented in the literature.


ICV injection of  Streptozotocin  has been used to create a metabolic model of Alzheimer's disease. This protocol works by damaging the control level of cerebral glucose metabolism to mimic Alzheimer's disease symptoms. An early sign of AD is glucose hypometabolism and impaired insulin signaling has been seen in AD patients. Streptozotocin has also largely been used to create diabetes animal models, by injecting either intravenously or intraperitoneally. [ 1 ]  These ICV injections result in models for the sporadic Alzheimer's disease (sAD) form, rather than familial. A characteristic of sAD is an insulin-resistant brain state (IRBS). Streptozotocin is a beta-cytotoxic drug and by injecting it directly into the cerebral ventricles, the treated mice develop symptoms that align with sAD symptoms in humans. Some of these symptoms include IRBS-associated memory impairment, glucose hypometabolism, oxidative stress, and neurodegeneration. [ 2 ]


More recently, a model for AD that represents both familial and sporadic AD has emerged. In the clinic, as well as independent experiments, an increase in amyloid beta (Aβ) levels in the brain has been seen to cause Alzheimer-like symptoms. To create an animal model of AD, Aβ can be injected using ICV injection. A benefit of this pathogen-induced model is that it shows Alzheimer's-like symptoms, while also exhibiting Aβ pathology. This is present in both familial and sporadic AD, making it a more inclusive model. Additionally, the level of Aβ can be controlled, making it an ideal candidate for AD investigation. However, damage to the brain tissue during ICV injection must be minimized to prevent neuronal injury. This requires a highly trained individual or surgeon. [ 3 ]


Intracerebroventricular injection has also been used to test therapeutics and other drugs in animals. Examples of these studies include injection of  bromodeoxyuridine  for proliferation tracing, Apelin-13 for  cerebral ischemia , and α-interferon for its antiviral and antibiotic properties.


ICV injection of bromodeoxyuridine (BrdU) has been used to determine the effectiveness of this injection method compared to intraperitoneal administration. BrdU is a widely used marker to detect proliferative cells in the brain. It is assumed that the number of labeled nuclei after BrdU administration is an indicator of the intensity of  cell proliferation . In the study, there was an increase in BrdU-positive nuclei in the parenchyma for ICV injection compared to the levels for  intraperitoneal administration . This indicates a greater level of the tracer is introduced when injected directly into the ventricular cerebrospinal fluid. [ 4 ]


Cerebral ischemia/reperfusion (I/R) injury is the main pathophysiological process present in  ischemic stroke . Apelin regulates many physiological functions including cardiovascular function, endocrine function, nervous system function, and feeding behavior. This regulation occurs through combination with the  APJ receptor , and this system is present in many brain regions. [ 5 ]  In previous studies, lateral ICV injection of Apelin-13 was done to observe apoptosis during cerebral I/R injury. This route of administration allows for the necessary level of Apelin-13 to reach the brain regions that are impacted by ischemia and hypoxia.


ICV injection of α-Interferon has been used for the treatment of intracranial malignancies in the clinic. α-Interferon has antiviral, antibacterial, and immunostimulatory properties. However, severe central nervous system symptoms occur after injection for ICV, intravenous, and intramuscular routes of administration. Additionally, only .09-.18% of the total Interferon dose was seen to pass through the blood-brain barrier when injected intramuscularly. In one study, intraperitoneal injection of α-Interferon was done on mice and there was no impact on monoamine levels. Another study conducted a similar experiment using the ICV injection method. This study showed reduced monoamine levels in the frontal cortex, in a dose-dependent manner. [ 6 ]  This indicates that ICV injection increases the percentage of the dose that reaches the mouse brain.


In recent years, gene and  cell therapy  therapeutic options have become increasingly present in the clinic. For some of these therapeutics, the administration of the drug directly into the central nervous system is optimal for the treatment of neurological disorders, while avoiding a severe immune response. Additionally, most of the dose is introduced directly into the target area with ICV injection. [ 7 ]  In addition to these therapies, ICV injection has been used for the delivery of  chemotherapies , treatment of carcinomatous meningitis, and other  neurological disorders .


In the design of  gene therapies , the proper  adeno-associated virus  (AAV)  serotype  must be selected. AAV is effective at transporting genetic material in vivo, and there are more than 100 serotypes for AAV that have been identified. Each serotype has a different binding capacity to cell surface receptors. Three serotypes have been identified for their promising specificity to the central nervous system. In a 2017 study, AAV2/1, AAVDJ8, and AAV9 were administered to neonatal mice via ICV injection. The brains of these mice were analyzed for GFP expression following this procedure. The results of this showed that AAV2/1 had higher expression in the cortical layers while penetrating less to the midbrain compared to the AAVDJ8 and AAV9 serotypes. The results indicate that ICV injection of AAV vectors is successful for having a lasting expression of the transgene. [ 8 ]


Primary malignant brain tumors (PMBT) and brain metastases have a high impact on patients with both high morbidity and mortality rates. For patients impacted by this, treatment consists primarily of palliative care. However, multimodal therapy using intra-CSF chemotherapy has shown promise in overt leukemic or lymphomatous meningeosis and primary CNS lymphomas. This form of chemotherapy is less toxic while maintaining similar efficacy to cranial irradiation, by preventing the infiltration and proliferation of leukemic and tumor cells into the leptomeninges. [ 9 ]


In a 2019 study, autologous non-genetically modified adipose-derived stromal vascular fraction (ADSVF) was injected into 24 patients using an ICV injection procedure. Seven other patients were injected through ventriculoperitoneal shunts. These seven patients were being treated for varying neurodegenerative disorders including Alzheimer's disease (AD),  amyotrophic lateral sclerosis  (ALS),  progressive multiple sclerosis  (MS-P),  Parkinson's ,  spinal cord injury ,  traumatic brain injury , and stroke. A total of 113 injections were performed on the 31 patients, with one patient having up to 15 injections over three years. Follow-up was conducted for each participant, with varying follow-up times. One patient developed an infection from their implant, and four patients required hospitalization after their injections. Overall, the results indicate that ICV injections, both single and repeat, are safe. [ 10 ]


Intracerebroventricular injection has also been historically used for pain management. These procedures are primarily focused on refractory head and facial pain, peripheral nerve injury, and other persistent pain conditions.


Six patients with either refractory trigeminal neuralgia or cluster headaches were treated with an ICV opiate infusion pump. Visual analog scores (VAS) were obtained before and after injection to measure effectiveness. When compared, VAS scores improved from an average of 7.8 to 2.8 after the procedure. Most complications that occurred from this procedure consisted of nausea and drowsiness. These symptoms went away after the pump was adjusted. ICV pumps are typically kept in and replaced every four to five years, making the procedure ideal for patients with chronic pain. [ 11 ]


The CTK 01512-2 peptide toxin can act as a  voltage-gated calcium channel  (VGCC) blocker. In previous studies, it was shown to have a prolonged effect on preventing and reducing the processing of harmful stimuli by the central nervous system and peripheral nervous system. To strengthen this finding, the CTK 01512-2 toxin was tested on two models of persistent pain. These models include chronic post-ischemia pain (CPIP) and paclitaxel-induced peripheral neuropathy. Additionally, the peptide was injected using three routes of administration: intravenous, intrathecal, and intracerebroventricular. This approach is beneficial for patients who do not respond to traditional pain management approaches. This also addresses the side effects that occur when using opioid agents. The results of this study showed that pain-reducing effects were observed with all three methods of administration. [ 11 ]


The drugs  gabapentin  and  pregabalin  have long since been used for the treatment of neuropathic pain conditions. The mechanism behind the effectiveness of these drugs is not fully known. However, gabapentin and pregabalin were demonstrated to have supraspinal-mediated analgesic effects after peripheral nerve injury. This is due to the noradrenergic pain inhibitory system that is employed by these drugs, coupled with spinal receptors that produce analgesic effects. The results of this study indicate that ICV injection of these drugs decreases thermal and mechanical hypersensitivity in a murine chronic pain model that has partial ligation of the sciatic nerve. [ 12 ]


Many factors must be considered with intracerebroventricular injection to maintain safety. Some of these factors include osmolarity, pH, volume, and the presence of preservatives in the drug solution. Also, intracranial pressure, cerebrospinal fluid bulk flow rate, and buffering capacity have an impact on the distribution and safety of the injected drug. A major concern of ICV injection is neurovascular injury and intracranial hemorrhage. The risk of these conditions increases with each additional injection or "tap". For this reason, if repeated taps are needed, a catheter-based device can be implanted. These devices are connected to a subcutaneous reservoir, the most common being the  Ommaya reservoir . This can be accessed multiple times, with a sterile puncture through the scalp into the reservoir. There is also an associated risk of infection with this method, but it is less likely than other methods of accessing the intraventricular space. Other rare complications with this method include leukoencephalopathy, white matter necrosis, and intracerebral hemorrhage. [ 13 ]


Other complications can occur with this procedure, and they can be divided into infectious and noninfectious categories. Of the noninfectious complications, the most frequently reported were CSF leaks, hemorrhage, catheter malposition, catheter obstruction, and device malfunction. In one study, the most likely cause for device removals was due to infectious complications (73.75 percent). Of the infections, the most common cause was skin flora. The aseptic technique during insertion and handling has been shown to decrease the occurrence of these complications. Also, in some cases of infection, antibiotics could be given through the ICV system, avoiding the need for removal. [ 14 ]


The blood-brain barrier protects the brain by restricting the ability of large molecules to cross the barrier between the blood, CSF, and interstitial fluid of the brain. ICV injection circumvents this barrier, to be able to deliver drugs to the CSF. An ICV device is implanted under the scalp, into the subgaleal space where it is then connected to the ventricles with an outlet catheter. This allows for repeated doses of the drug without having to re-puncture the scalp. [ 14 ]


Production of CSF is at a rate of about .3 mL/minute and occurs at the  ependymal  and  parenchymal  regions and the  choroid plexus . Up to 80 percent of CSF production comes from the choroid plexus, which is present within the lateral, third, and fourth ventricles. The choroid is lined with  epithelium  with tight junctions at the ventricular side of the cells. This comprises the blood-CSF barrier. Whereas the blood-brain barrier is made up of vascular endothelium in capillary beds throughout the CNS parenchyma. [ 13 ]


For insertion in mice, a permanent ICV guide cannula must be inserted 1 mm above the lateral ventricle. A trained surgeon is ideal for insertion, and a stereotaxic frame and bone cement are needed. The cannula is implanted through the hindlimb area of the cerebral cortex. The surgeon must be careful to minimize damage to the surrounding brain tissue during this process. [ 7 ]


A catheter connected to a subcutaneous reservoir is implanted for permanent access in humans. The reservoir used is most commonly the Ommaya reservoir. A 25-gauge needle is used to puncture the scalp into the reservoir. A few milliliters of CSF are withdrawn before injecting the drug. This technique is typically used for long-term drug administration. Rarely will repeated taps be conducted to administer drugs due to the risk of damaging brain tissue. [ 13 ]


Intramuscular injection , often abbreviated  IM , is the  injection  of a substance into a  muscle . In  medicine , it is one of several methods for  parenteral administration  of medications. Intramuscular injection may be preferred because muscles have larger and more numerous  blood vessels  than subcutaneous tissue, leading to faster absorption than  subcutaneous  or  intradermal injections . Medication administered via intramuscular injection is not subject to the  first-pass metabolism  effect which affects oral medications.


Common sites for intramuscular injections include the  deltoid muscle  of the upper arm and the  gluteal muscle  of the buttock. In infants, the  vastus lateralis muscle  of the thigh is commonly used. The injection site must be cleaned before administering the injection, and the injection is then administered in a fast, darting motion to decrease the discomfort to the individual. The volume to be injected in the muscle is usually limited to 2–5  milliliters , depending on injection site. A site with signs of infection or muscle atrophy should not be chosen. Intramuscular injections should not be used in people with  myopathies  or those with trouble clotting.


Intramuscular injections commonly result in pain, redness, and swelling or  inflammation  around the injection site. These side effects are generally mild and last no more than a few days at most. Rarely,  nerves  or blood vessels around the injection site can be damaged, resulting in severe pain or  paralysis . If proper technique is not followed, intramuscular injections can result in localized infections such as  abscesses  and  gangrene . While historically aspiration, or pulling back on the syringe before injection, was recommended to prevent inadvertent administration into a vein, it is no longer recommended for most injection sites by some countries.


Intramuscular injection is commonly used for medication administration. Medication administered in the muscle is generally quickly absorbed in the bloodstream, and avoids the  first pass metabolism  which occurs with oral administration. [ 1 ]  The medication may not be considered 100%  bioavailable  as it must still be absorbed from the muscle, which occurs over time. [ 2 ] : 102–103   An intramuscular injection is less invasive than an intravenous injection and also generally takes less time, as the site of injection (a muscle versus a vein) is much larger. Medications administered in the muscle may also be administered as  depot injections , which provide slow, continuous release of medicine over a longer period of time. [ 3 ]  Certain substances, including  ketamine , may be injected intramuscularly for  recreational  purposes. [ 4 ]  Disadvantages of intramuscular administration include skill and technique required, pain from injection, anxiety or fear (especially in children), and difficulty in self-administration which limits its use in  outpatient medicine . [ 5 ]


Vaccines , especially  inactivated vaccines , are commonly administered via intramuscular injection. [ 6 ]  However, it has been estimated that for every vaccine injected intramuscularly, 20 injections are given to administer drugs or other therapy. [ 6 ]  This can include medications such as  antibiotics ,  immunoglobulin , and  hormones  such as testosterone and  medroxyprogesterone . [ 5 ]  In a case of severe allergic reaction, or  anaphylaxis , a person may use an  epinephrine   autoinjector  to self-administer epinephrine into the muscle. [ 7 ]


Because an intramuscular injection can be used to administer many types of medications, specific  contraindications  depend in large part on the medication being administered. [ 8 ]  Injections of medications are necessarily more invasive than other forms of administration such as by mouth or topical and require training to perform appropriately, without which complications can arise regardless of the medication being administered. For this reason, unless there are desired differences in rate of absorption, time to onset, or other pharmacokinetic parameters in the specific situation, a less invasive form of drug administration (usually by mouth) is preferred. [ 8 ]


Intramuscular injections are generally avoided in people with  low platelet count  or clotting problems, to prevent harm due to potential damage to blood vessels during the injection. They are also not recommended in people who are in  hypovolemic shock , or have myopathy or  muscle atrophy , as these conditions may alter the absorption of the medication. [ 5 ]  The damage to the muscle caused by an intramuscular injections may interfere with the accuracy of certain cardiac tests for people with suspected  myocardial infarction  and for this reason other methods of administration are preferred in such instances. [ 5 ]  In people with an active myocardial infarction, the decrease in circulation may result in slower absorption from an IM injection. [ 9 ] : 368–369   Specific sites of administration may also be contraindicated if the desired injection site has an infection, swelling, or inflammation. [ 9 ] : 368–369   Within a specific site of administration, the injection should not be given directly over irritation or redness, birthmarks or moles, or areas with scar tissue. [ 9 ] : 368–369


As an injection necessitates piercing the skin, there is a risk of infection from  bacteria  or other organisms present in the environment or on the skin before the injection. This risk is minimized by using proper  aseptic technique  in preparing the injection and sanitizing the injection site before administration. [ 9 ] : 369   Intramuscular injections may also cause an abscess or gangrene at the injection site, depending on the specific medication and amount administered. There is also a risk of nerve or vascular injury if a nerve or blood vessel is inadvertently hit during injection. If single-use or sterilized equipment is not used, there is the risk of transmission of infectious disease between users, or to a practitioner who inadvertently injures themselves with a used needle, termed a  needlestick injury . [ 5 ] [ 9 ] : 372


Injections into the deltoid site in the arm can result in unintentional damage to the  radial  and  axillary nerves . In rare cases when not performed properly, the injection may result in shoulder dysfunction. [ 10 ]  The most frequent complications of a deltoid injection include pain, redness, and inflammation around the injection site, which are almost always mild and last only a few days at most. [ 11 ]


The dorsogluteal site of injection is associated with a higher risk of skin and tissue trauma, muscle  fibrosis  or  contracture ,  hematoma , nerve  palsy ,  paralysis , and infections such as  abscesses  and  gangrene . [ 12 ]  Furthermore, injection in the gluteal muscle poses a risk for damage to the  sciatic nerve , which may cause shooting pain or a sensation of burning. Sciatic nerve damage can also affect a person's ability to move their foot on the affected side, and other parts of the body controlled by the nerve. Damage to the sciatic nerve can be prevented by using the ventrogluteal site instead, and by selecting an appropriate size and length of needle for the injection. [ 13 ]


An intramuscular injection can be administered in multiple different muscles of the body. Common sites for intramuscular injection include:  deltoid ,  dorsogluteal ,  rectus femoris ,  vastus lateralis  and  ventrogluteal  muscles. [ 12 ] [ 14 ]  Sites that are bruised, tender, red, swollen, inflamed or scarred are generally avoided. [ 15 ]  The specific medication and amount being administered will influence the decision of the specific muscle chosen for injection.


The injection site is first cleaned using an antimicrobial and allowed to dry. The injection is performed in a quick, darting motion perpendicular to the skin, at an angle between 72 and 90 degrees. The practitioner will stabilize the needle with one hand while using their other hand to depress the plunger to slowly inject the medication – a rapid injection causes more discomfort. The needle is withdrawn at the same angle inserted. Gentle pressure may be applied with gauze if bleeding occurs. [ 16 ]  Pressure or gentle massage of the muscle following injection may reduce the risk of pain. [ 17 ]


Aspirating for blood to rule out injecting into a blood vessel is not recommended by the US  CDC ,  Public Health Agency of Canada , or  Norway Institute of Public Health , as the injection sites do not contain large blood vessels and aspiration results in greater pain. [ 18 ] [ 19 ] [ 20 ]  There is no evidence that aspiration is useful to increase safety of intramuscular injections when injecting in a site other than the dorsogluteal site. [ 6 ]


Aspiration was recommended by the  Danish Health Authority  for  COVID-19 vaccines  for a time to investigate the potential rare risk of blood clotting and bleeding, but it is no longer a recommendation. [ 21 ] [ 22 ]


The Z-track method is a method of administering an IM injection that prevents the medication being tracked through the subcutaneous tissue, sealing the medication in the muscle, and minimizing irritation from the medication. Using the Z-track technique, the skin is pulled laterally, away from the injection site, before the injection; then the medication is injected, the needle is withdrawn, and the skin is released. This method can be used if the overlying tissue can be displaced. [ 23 ]


The deltoid muscle in the outer portion of the upper arm is used for injections of small volume, usually equal to or less than 1 mL. This includes most intramuscular vaccinations. [ 12 ]  It is not recommended to use the deltoid for repeated injections due to its small area, which makes it difficult to space out injections from each other. [ 12 ]  The deltoid site is located by locating the lower edge of the  acromion process , and injecting in the area which forms an upside down triangle with its base at the acromion process and its midpoint in line with the  armpit . [ 15 ]  An injection into the deltoid muscle is commonly administered using a 1-inch long needle, but may use a  5 ⁄ 8 -inch long needle for younger people or very frail elderly people. [ 11 ]


The ventrogluteal site on the hip is used for injections which require a larger volume to be administered, greater than 1 mL, and for medications which are known to be irritating, viscous, or oily. It is also used to administer  narcotic  medications,  antibiotics ,  sedatives  and  anti-emetics . [ 12 ]  The ventrogluteal site is located in a triangle formed by the  anterior superior iliac spine  and the  iliac crest , and may be located using a hand as a guide. [ 15 ]  The ventrogluteal site is less painful for injection than other sites such as the deltoid site. [ 17 ]


The  vastus lateralis  site is used for infants less than 7 months old and people who are unable to walk or who have loss of muscular tone. [ 12 ]  The site is located by dividing the front  thigh  into thirds vertically and horizontally to form nine squares; the injection is administered in the outer middle square. [ 15 ]  This site is also the usual site of administration for  epinephrine autoinjectors , which are used in the outer thigh, corresponding to the location of the vastus lateralis muscle. [ 24 ]


The dorsogluteal site of the buttock site is not routinely used due to its location near major  blood vessels  and  nerves , as well as having inconsistent depth of  adipose tissue . [ 25 ]  Many injections in this site do not penetrate deep enough under the skin to be correctly administered in the muscle. [ 12 ] [ 26 ]  While current  evidence-based practice  recommends against using this site, many healthcare providers still use this site, often due to a lack of knowledge about alternative sites for injection. [ 27 ]
This site is located by dividing the buttock into four using a cross shape, and administering the injection in the upper outer quadrant. This is the only intramuscular injection site for which aspiration is recommended of the syringe before injection, due to higher likelihood of accidental  intravenous administration  in this area. [ 12 ]  However, aspiration is not recommended by the  Centers for Disease Control and Prevention , which considers it outdated for any intramuscular injection. [ 16 ]


Some populations require a different injection site, needle length, or technique. In very young or weak elderly patients, a normal-length needle may be too long to inject properly. In these patients, a shorter needle is indicated to avoid injecting too deeply. [ 28 ]  It is also recommended to consider using the anterolateral thigh as an injection site in infants under one year old. [ 28 ]


To help infants and children cooperate with injection administration, the  Advisory Committee on Immunization Practices  in the United States recommends using distractions, giving something sweet, and rocking the baby side to side. In people who are overweight, a 1.5-inch needle may be used to ensure the injection is given below the  subcutaneous  layer of skin, while a  5 ⁄ 8 -inch needle may be used for people who weigh under 60 kilograms (130 lb). In any case, the skin does not need to be pinched up before injecting when the appropriate length needle is used. [ 29 ]


Injections into muscular tissue may have taken place as early as the year 500 AD. Beginning in the late 1800s, the procedure began to be described in more detail and techniques began to be developed by physicians. In the early days of intramuscular injections, the procedure was performed almost exclusively by physicians. [ 8 ]  After the introduction of  antibiotics  in the middle of the 20th century, nurses began preparing equipment for intramuscular injections as part of their delegated duties from physicians, and by 1961 they had "essentially taken over the procedure". [ 8 ]  Until this delegation became virtually universal, there were no uniform procedures or education for nurses in proper administration of intramuscular injections, and complications from improper injection were common. [ 8 ]


Intramuscular injections began to be used for administration of vaccines for  diphtheria  in 1923,  whooping cough  in 1926, and  tetanus  in 1927. [ 30 ]  By the 1970s, researchers and instructors began forming guidance on injection site and technique to reduce the risk of injection complications and side effects such as pain. [ 8 ]  Also in the early 1970s,  botulinum toxin  began to be injected into muscles to intentionally paralyze them for therapeutic reasons, and later for cosmetic reasons. [ 31 ]  Until the 2000s, aspiration after inserting the needle was recommended as a safety measure, to ensure the injection was being administered in a muscle and not inadvertently in a vein. However, this is no longer recommended as evidence shows no safety benefit and it lengthens the time taken for injection, which causes more pain. [ 29 ]


In animals common sites for intramuscular injection include the  quadriceps , the lumbodorsal muscles, and the triceps muscle. [ 32 ]


Intraosseous infusion  ( IO ) is the process of  injecting   medication , fluids, or blood products directly into the  bone marrow ; [ 1 ]  this provides a non-collapsible entry point into the  systemic venous system . [ 2 ]  The intraosseous infusion technique is used to provide fluids and medication when  intravenous access  is not available or not feasible. Intraosseous infusions allow for the administered medications and fluids to go directly into the vascular system. [ 3 ]  The IO route of fluid and medication administration is an alternative to the preferred  intravascular  route when the latter cannot be established promptly in emergent situations. Intraosseous infusions are used when people have compromised intravenous access and need immediate delivery of life-saving fluids and medications. [ 3 ]


The use of the IV route to administer fluids has been around since the 1830s, and, in 1922,  Cecil K. Drinker  et al. saw that bone, specifically the sternum, could also be used as a route of administration for emergency purposes. [ 4 ]  To continue the expansion of knowledge regarding IO administration, a successful blood transfusion took place in 1940 using the sternum, and afterward, in 1941, Tocantins and O'Neill demonstrated successful vascular access using the bone marrow cavity of a  long bone  in rabbits. [ 4 ]  Because of Tocantins and O'Neill's success in their experiments with rabbits, human clinical trials were established using mainly the  body of the sternum  or the  manubrium  for access. [ 5 ]   Emanuel Papper  and others then continued to advocate, research, and make advances on behalf of the IO administration. [ 6 ]  Once Papper showed that the bone marrow space could be used with comparable success to administer IV fluids and drugs, intraosseous infusion was popularized during World War II to prevent soldiers' deaths via hemorrhagic shock. [ 7 ]  While popular in the field during WWII, the use of IO was not seen as a standard for emergencies until the 1980s, and only so for children. [ 7 ]  With the rise of technology allowing the ease of technique of IO, and a lower risk of complications like bloodstream infections than when using peripheral access, the alternative of IO access has increased throughout the years for adults, as well. [ 7 ]  IO is now recommended in Advanced Cardiac and Pediatric Advanced Life Support treatment protocols, in cases where access via IV cannot be established on time. [ 4 ]


Intraosseous access is indicated in emergency situations, such as when a person experiences some type of major trauma like  shock ,  cardiac arrest , severe  dehydration , [ 8 ]  or severe  gastrointestinal hemorrhage . [ 9 ]   IO access can provide the quickest way to rapidly infuse needed medications and fluids in an emergency situation. [ 8 ]  In people who experience critical trauma and who do not have adequate blood pressure, the IO route doubles the success rate of the peripheral IV route. [ citation needed ]


In addition to the emergency clinical scenario that can call for an IO route to be used, IO access is only indicated when access to peripheral veins is either not possible or delayed. When IV access is either not possible or delayed, other indications for utilizing the IO route include administering  contrast  if needed for radiology scans and drawing blood for laboratory testing and analysis. [ 10 ]  Situations that can result in decreased or delayed  access to peripheral veins, and thus necessitate the use of an IO route to infuse medications and fluids include circumstances such as burns, fluid accumulation ( edema ), past IV drug use, obesity, and very low blood pressure. [ 8 ]


An IO infusion can be used on adult or pediatric populations when traditional methods of vascular access are difficult or otherwise cause unwanted delayed management of the administration of medications. The IO site can be used for 24 hours and should be removed as soon as intravenous access has been gained. Prolonged use of an IO site, lasting longer than 24 hours, is associated with  osteomyelitis  (an infection in the bone). [ 3 ]


The needle is inserted through the bone's hard  cortex  and into the soft marrow interior, which allows immediate access to the vascular system. The IO needle is positioned at a 90-degree angle to the injection site, and is advanced through manual traction, impact driven force, or power driven. Each IO device has different designated insertion locations. The most common site of insertion is the antero-medial aspect of the upper, proximal  tibia  as this site lies just under the skin and is easily located. Other insertion sites include the anterior aspect of the  femur , the superior iliac crest, proximal  humerus , proximal tibia, distal tibia and the sternum (manubrium). [ 1 ]
Although intravascular access is still the preferred method for medication delivery in the prehospital area, IO access for adults has become more common. As of 2010, the  American Heart Association  no longer recommends using the  endotracheal tube  (ET) for  resuscitation  drugs, except as a last resort when IV or IO access cannot be gained. [ 1 ]  ET absorption of medications is poor, and optimal ET drug dosings are unknown. IO  administration is becoming more common in civilian and military pre-hospital  emergency medical services  (EMS) systems globally. [ 11 ]


Intraosseous access has roughly the same absorption rate as IV access, and allows for fluid resuscitation. For example,  sodium bicarbonate  can be administered IO during a cardiac arrest when IV access is unavailable. [ 1 ]  High flow rates are attainable with an IO infusion, up to 125 milliliters per minute. This high rate of flow is achieved using a pressure bag to administer the infusion directly into the bone. Large volume IO infusions are known to be painful. 1% lidocaine is used to ease the pain associated with large volume IO infusions in conscious people. [ 3 ]


Like any medical procedure, intraosseous infusion has some potential complications. In a review by Tyler et al., an analysis across the included studies found the overall complication rate associated with IO infusions to be less than 1% (0.9%). [ 12 ]


Complications include:


Many of these potential complications can be prevented with simple measures like using good technique and keeping the period of IO infusion short by switching to IV as soon as it becomes feasible. [ 14 ]   Bone fracture complications can be decreased by using modern techniques and requiring more regular training in the methods of intraosseous marrow access for infusion. Extravasation can lead to the more serious complication of compartment syndrome. The risk of developing compartment syndrome can be reduced by medical personnel checking the infusion site regularly for any signs of swelling. Swelling could indicate misplacement of the catheter. Avoiding puncturing the same bone in 48 hours can also lessen the risk of developing this complication. The risk of osteomyelitis, while very low ( <1%), can be further lessened by using sterile, hygienic practices and modern devices to make the puncture. Damage to the epiphyseal plate can be avoided by training medical personnel about proper landmarks to be used for determining puncture sites. [ 13 ]


Intraosseous devices allow quick and safe access to the vascular system for fluid and drug administration. After proper education and training, medical professionals can obtain vascular access via the IO route of administration by using one of the multiple devices that have been approved by the FDA for 24-hour use. [ 7 ]  There are several FDA approved IO devices, categorized by their mechanism of action:


Each device is capable of achieving rapid vascular access, despite the mechanism of action, with insertion times comparable to the IV administration route. [ 16 ]


A comparison of  intravenous  (IV),  intramuscular  (IM), and intraosseous (IO)  routes of administration  concluded that the intraosseous (IO) route is the preferred method versus intramuscular (IM) and comparable to intravenous (IV) administration in delivering pediatric anaesthetic drugs. [ 17 ]


Intraosseous infusion (IO) is used in pediatric populations during anesthesia when other intravenous access,  central venous catherization  or  venous cutdown , are difficult to use or cannot be used. When individuals are severely ill and need "rapid, efficient, and safe delivery of drugs", IO is used. [ citation needed ]  When inserting the intraosseous needle into a conscious individual, this can be very painful. For children, anesthesia is not recommended before this procedure for non-emergency situations. Instead, distracting and holding the child is preferred. Intraosseous infusion is used in instances such as, "immediate indication/life-threatening emergency, cardiac/respiratory arrest, acute shock, hypothermia, obesity, edema, thermal injury, etc." [ citation needed ]


For children, the preferred sites of IO are the distal tibia, proximal tibia, and distal femur. The distal end of the tibia is the preferred site because it is easy to access and the most reliable. Depending on the procedure, a variety of needles are used for IO. For example, "standard steel hypodermic, butterfly, spinal, trephine, sternal, and standard bone marrow needles are used." Needles that have a short shaft are preferred and safe. For infants up to 6 to 8 months old, 18-gauge needles are used and for children more than 8 months old, 15- or 16- gauge needles are used. [ 18 ]
A study by Glaeser et al., concluded that individuals who received IO vs. peripheral and central intravenous access were able to obtain much faster and more successful IO access. Another study, by Fiorito et al., observed the safety of IO use during the transportation of critically ill pediatric individuals. Based on the results, they concluded that the use of IO was safe, based on 78% successful placement of  the IO needle and complications that occurred in only 12% of the cases. [ 19 ]


Similarly to adults, contraindications for IO infusion use in pediatrics include bone diseases such as osteogenesis imperfecta and osteopetrosis, and fractures. Others include cellulitis, burns, and infections at the access site. [ 20 ]


Intraperitoneal injection  or  IP injection  is the injection of a substance into the  peritoneum  (body cavity). It is more often applied to non-human animals than to humans. In general, it is preferred when large amounts of blood replacement fluids are needed or when low blood pressure or other problems prevent the use of a suitable blood vessel for  intravenous injection . [ citation needed ]


In humans, the method is widely used to administer  chemotherapy  drugs to treat some  cancers , particularly  ovarian cancer . Although controversial, intraperitoneal use in ovarian cancer has been recommended as a  standard of care . [ 1 ]  Fluids are injected intraperitoneally in infants, also used for  peritoneal dialysis . [ citation needed ]


Intraperitoneal injections are a way to administer therapeutics and drugs through a peritoneal route (body cavity). They are one of the few ways drugs can be administered through injection, and have uses in research involving animals, drug administration to treat ovarian cancers, and much more. Understanding when intraperitoneal injections can be utilized and in what applications is beneficial to advance current drug delivery methods and provide avenues for further research. The benefit of administering drugs intraperitoneally is the ability for the peritoneal cavity to absorb large amounts of a drug quickly. A disadvantage of using intraperitoneal injections is that they can have a large variability in effectiveness and misinjection. [ 2 ]  Intraperitoneal injections can be similar to oral administration in that hepatic metabolism could occur in both.


There are few accounts of the use of intraperitoneal injections prior to 1970. One of the earliest recorded uses of IP injections involved the insemination of a guinea-pig in 1957. [ 3 ]  The study however did not find an increase in conception rate when compared to mating. In that same year, a study injected egg whites intraperitoneally into rats to study changes in "droplet" fractions in kidney cells. The study showed that the number of small droplets decreased after administration of the egg whites, indicating that they have been changed to large droplets. [ 4 ]  In 1964, a study delivered chemical agents such as acetic acid, bradykinin, and kaolin to mice intraperitoneally in order to study a "squirming" response. [ 5 ]  In 1967, the production of amnesia was studied through an injection of physostigmine. [ 6 ]  In 1968, melatonin was delivered to rats intraperitoneally in order to study how brain  serotonin  would be affected in the midbrain. [ 7 ]  In 1969, errors depending on a variety of techniques of administering IP injections were analyzed, and a 12% error in placement was found when using a one-man procedure versus a 1.2% error when using a two-man procedure. [ 8 ]


A good example of how intraperitoneal injections work is depicted through "The distribution of salicylate in mouse tissues after intraperitoneal injection" because it includes information on how a drug can travel to the blood, liver, brain, kidney, heart, spleen, diaphragm, and skeletal muscle once it has been injected intraperitoneally. [ 9 ]


These early uses of Intraperitoneal injections provide good examples of how the delivery method can be used, and provides a base for future studies on how to properly inject mice for research.


Currently, there are a handful of drugs that are delivered through intraperitoneal injection for chemotherapy. They are mitomycin C, cisplatin, carboplatin, oxaliplatin, irinotecan, 5-fluorouracil, gemcitabine, paclitaxel, docetaxel, doxorubicin, premetrexed, and melphalan. [ 10 ]  There needs to be more research done to determine appropriate dosing and combinations of these drugs to advance intraperitoneal drug delivery.


There are few examples of the use of intraperitoneal injections in humans cited in literature because it is mainly used to study the effects of drugs in mice. The few examples that do exist pertain to the treatment of pancreatic/ovarian cancers and injections of other drugs in clinical trials. One study utilized IP injections to study pain in the abdomen after a hysterectomy when administering anesthetic continuously vs patient-controlled. [ 11 ]  The results depicted that ketobemidone consumption was significantly lower when patients controlled anesthetic through IP. This led to the patients being able to be discharged earlier than when anesthesia was administered continuously. These findings could be advanced by studying how the route of injection affects the organs in the peritoneal cavity.


In another Phase I clinical trial, patients with ovarian cancer were injected intraperitoneally with dl1520 in order to study the effects of a replication-competent/-selective virus. [ 12 ]  The effects of this study were the onset of flu-like symptoms, emesis, and abdominal pain. The study overall defines appropriate doses and toxicity levels of dl1520 when injected intraperitoneally.


One study attempted to diagnose  hepatic hydrothorax  with the use of injecting Sonazoid intraperitoneally. Sonazoid was utilized to aid with contrast-enhanced ultrasonography by enhancing the peritoneal and pleural cavities. [ 13 ]  This study demonstrates how intraperitoneal injections can be used to help diagnose diseases by providing direct access to the peritoneal cavity and affecting the organs in the cavity.


In a case of a ruptured hepatocellular carcinoma, it was reported that the patient was treated successfully through the use of an intraperitoneal injection of OK-432, which is an immunomodulatory agent. [ 14 ]  The patient was a 51-year-old male who was hospitalized. The delivery of OK-432 occurred a total of four times in a span of one week. The results of this IP injection were the disappearance of the ascites associated with the rupture. This case is a good example of how IP injections can be used to deliver a drug that can help to treat or cure a medical diagnosis over the use of other routes of delivery. The results set a precedent of how other drugs may be delivered in this way to treat other similar medical issues after further research.


In 2018, a patient with stage IV ovarian cancer and peritoneal metastases was injected intraperitoneally with 12g of mixed cannabinoid before later being hospitalized. [ 15 ]  The symptoms of this included impairment of cognitive and psychomotor abilities. Because of the injection of cannabis, the patient was predicted to have some level of THC in the blood from absorption. This case presents the question of how THC is absorbed in the peritoneal cavity. It also shows how easily substances are absorbed through the peritoneal cavity after an IP injection.


Overall, this section provides a few examples of the effects and uses of intraperitoneal injections in human patients. There are a variety of uses and possibilities for many more in the future with further research and approval.


Intraperitoneal injections are the preferred method of administration in many experimental studies due to the quick onset of effects post injection. This allows researchers to observe the effects of a drug in a shorter period of time, and allows them to study the effects of drugs on multiple organs that are in the peritoneal cavity at once. In order to effectively administer drugs through IP injections, the stomach of the animal is exposed, and the injection is given in the lower abdomen. The most efficient method to inject small animals is a two-person method where one holds the rodent and the other person injects the rodent at about 10 to 20 degrees in mice and 20 to 45 degrees in rats. The holder retains the arms of the animal and tilts the head lower than the abdomen to create optimal space in the peritoneal cavity. [ 2 ]


There has been some debate on whether intraperitoneal injections are the best route of administration for experimental animal studies. It was concluded in a review article that utilizing IP injections to administer drugs to laboratory rodents in experimental studies is acceptable when being applied to proof-of-concept studies. [ 16 ]


A study was conducted to determine the best route of administration to transplant mesenchymal stem cells for colitis. This study compared intraperitoneal injections, intravenous injections, and anal injections. It was concluded that the intraperitoneal injection had the highest survival rate of 87.5%. [ 17 ]  This study shows how intraperitoneal injections can be more effective and beneficial than other traditional routes of administration.


One article reviews the injection of sodium pentobarbital to euthanize rodents intraperitoneally. [ 2 ]  Killing the rodent through an intraperitoneal route was originally recommended over other routes such as inhalants because it was thought to be more efficient and ethical. The article overviews whether IP is the best option for euthanization based on evidence associated with welfare implications. It was concluded that there is evidence that IP may not be the best method of euthenasia due to possibilities of missinjection.


Another example of how intraperitoneal injections are used in studies involving rodents is the use of IP for micro-CT contrast enhanced detection of liver tumors. [ 18 ]   Contrast agents  were administered intraperitoneally instead of intravenously to avoid errors and challenges. It was determined that IP injections are a good option for Fenestra to quantify liver tumors in mice.


An example of how intraperitoneal injections can be optimized is depicted in a study where IP injections are used to deliver anesthesia to mice. This study goes over the dosages, adverse effects, and more of using intraperitoneal injections of anesthesia. [ 19 ]


An example of when intraperitoneal injections are not ideal is given in a study where the best route of administration was determined for cancer biotherapy. [ 20 ]  It was concluded that IP administration should not be used over intravenous therapy due to high radiation absorption in the intestines. This shows an important limitation to the use of IP therapy.


The provided examples show a variety of uses for intraperitoneal injections in animals for in vitro studies. Some of the examples depict situations where IP injections are not ideal, while others prove the advantageous uses if this delivery method. Overall, many studies utilize IP injections to deliver therapeutics to lab animals due to the efficiency of the administration route.


Intrathecal administration  is a  route of administration  for drugs via an  injection  into the  spinal canal , or into the  subarachnoid space  so that it reaches the  cerebrospinal fluid  (CSF). It is useful in several applications, such as for  spinal anesthesia ,  chemotherapy , or  pain management . This route is also used to introduce drugs that fight certain infections, particularly post-neurosurgical. Typically, the drug is given this way to avoid being stopped by the  blood–brain barrier , as it may not be able to pass into the brain when given orally. Drugs given by the intrathecal route often have to be compounded specially by a pharmacist or technician because they cannot contain any preservative or other potentially harmful inactive ingredients that are sometimes found in standard injectable drug preparations.


Intrathecal pseudodelivery is a technique where the drug is encapsulated in a porous capsule that is placed in communication with the cerebrospinal CSF. In this method, the drug is not released into the CSF. Instead, the CSF is in communication with the capsule through its porous walls, allowing the drug to interact with its target within the capsule itself. This allows for localized treatment while avoiding systemic distribution of the drug, potentially reducing side effects and enhancing the therapeutic efficacy for conditions affecting the central nervous system.


The route of administration is sometimes simply referred to as "intrathecal"; however, the term is also an adjective that refers to something occurring in or introduced into the  anatomic space  or  potential space  inside a sheath, most commonly the  arachnoid membrane  of the  brain  or  spinal cord [ 1 ]  (under which is the  subarachnoid space ). For example, intrathecal immunoglobulin production is production of antibodies in the spinal cord. [ 2 ]  The abbreviation "IT" is best not used; instead, "intrathecal" is spelled out to avoid medical mistakes. [ citation needed ]


Intrathecal administration is often used for a single 24-hour dose of analgesia ( opioid  with  local anesthetic ). Caution should be exercised with intrathecal opioids due to the risk of late onset  hypoventilation . The use of intrathecal  morphine  may be limited by severe  pruritus  and  urinary retention . [ citation needed ]


Pethidine  has the unusual property of being both a local anaesthetic and opioid  analgesic , which occasionally permits its use as the sole intrathecal anaesthetic agent. [ citation needed ]


An intrathecal pump system can be used to deliver a local anaesthetic, and/or an opioid and/or an atypical analgesic agent as  ziconotide .


Amphotericin B  is administered intrathecally to treat fungal infections involving the central nervous system infections. [ 3 ]


Currently, only four agents are licensed for intrathecal cancer chemotherapy:  methotrexate ,  cytarabine ,  hydrocortisone , and  thiotepa . [ 4 ]


Administration of any  vinca alkaloids , especially  vincristine , via the intrathecal route is nearly always fatal. [ 5 ] [ 6 ] [ 7 ]


Often reserved for  spastic cerebral palsy ,  baclofen  can be administered through an  intrathecal pump  implanted just below the skin of the abdomen or behind the chest wall, with a catheter connected directly to the base of the spine. Intrathecal baclofen pumps sometimes carry serious clinical risks, such as infection or a possibly fatal sudden malfunction. [ citation needed ]


Treatment of chronic spinal injuries via the administration of  mesenchymal stem cells , [ 8 ]  either from adipose tissue or bone marrow, is experimental, with better results from the former method. Introduction of mesenchymal stem cells promote the microenvironment needed for axonal regrowth and reduction of inflammation caused by astrocytes proliferation and glial scar tissue. [ 9 ]


Animal models have showed improved motor control under the site of injury. A clinical trial also showed statistically significant improved sensitivity under the site of injury in patients. [ 10 ]


Intravaginal administration  is a  route of administration  where the substance is applied inside the  vagina .  Pharmacologically , it has the potential advantage to result in effects primarily in the vagina or nearby structures (such as the  vaginal portion of cervix ) with limited systemic  adverse effects  compared to other routes of administration. [ 1 ] [ 2 ] [ 3 ]


Formulation methods include vaginal  tablets , vaginal  cream , vaginal gel, [ 4 ] [ medical citation needed ]  vaginal  suppository  and  vaginal ring .


It is used as an administration method for issues related to women's health, such as contraception. [ 5 ]  Medicines primarily delivered by intravaginal administration include  vaginally administered estrogens  and  progestogens  (a group of hormones including  progesterone ), and  antibacterials  and  antifungals  to treat  bacterial vaginosis  and  yeast infections  respectively.


Medicines may also be administered intravaginally as an alternative to  oral route  in the case of  nausea  or other digestive problems. [ 5 ]


It is a potential means of  artificial insemination  (referred to as intravaginal insemination or IVI), sometimes used at home without the presence of a professional. [ 6 ]


This  drug  article relating to the  genito-urinary system  is a  stub . You can help Wikipedia by  expanding it .


Intubation  (sometimes  entubation ) is a medical procedure involving the insertion of a tube into the body. Patients are generally  anesthetized  beforehand. Examples include  tracheal intubation , and the  balloon tamponade  with a  Sengstaken–Blakemore tube  (a tube into the  gastrointestinal tract ). [ 1 ]


An  invasome  is a type of artificial  vesicle   nanocarrier  that transport substances through the skin, the most superficial  biological barrier . Vesicles are small particles surrounded by a  lipid  layer that can carry substances into and out of the cell. Artificial vesicles can be engineered to deliver drugs within the cell, with specific applications within transdermal drug delivery. However, the skin proves to be a barrier to effective penetration and delivery of drug therapies. Thus, invasomes are a new generation of vesicle with added structural components to assist with skin penetration. [ 1 ]


Transdermal  drug delivery (TDD) systems aim to deliver drug therapies topically for local and systemic delivery. They have been gaining increasing attention within the field of drug delivery because of their potential to improve  bioavailability , reduce side effects, and avoid  first pass metabolism , compared to oral medications. However, TDD systems face the challenge of overcoming the barrier of the topmost skin layer, the  stratum corneum . [ 2 ]


Transdermal drug delivery systems are methods to transport drug therapies across the skin barrier. The skin is the largest organ of the body and its primary aim is to protect the body against chemical, thermal, radiation, and microbial threats. However, it is not completely waterproof, allowing some exchange of gas, heat, and fluids from its external environment. [ 3 ]


To effectively shield against external injuries, the skin is composed of several layers: the three distinguishing layers are the  epidermis , the  dermis , and the  subcutaneous layer , or hypodermis. The bottommost layer is the hypodermis. It is primarily composed of  adipose tissue . Next is the dermis, a 3-5 mm thick layer made up of fibrous proteins, an interfibrillar gel, salts, and water. The epidermis is the topmost layer of skin and where vascularization ends. Due to the lack of vascularization, the transfer of fluids, nutrients, and waste across the epidermis occurs through the epidermal-dermal junction. [ 4 ] [ 5 ]  The epidermis is further divided into five layers. From innermost to outermost is the germinative stratum, the spinous stratum, the granular stratum, the lucid stratum, and the stratum corneum. The majority of the epidermis is composed of  corneocytes , which develop from the proliferation, differentiation, and keratinization of  keratinocytes . These fundamental skin cells continually renew as they move upwards toward the surface of the skin. [ 3 ] [ 5 ]  The stratum corneum is a 10-15 μm thick layer of dead keratin-rich corneocytes tightly packed within a lipid-rich matrix, often described and depicted as a brick-and-mortar structure. [ 5 ]


Penetration of the stratum corneum is recognized as the largest challenge of TDD. Due to its tight cell structure, it is the rate limiting barrier for drug absorption. Thus, several methods of penetrating the stratum corneum have been explored. A couple of common methods include delivery through the intercellular route and the transcellular route. The roundabout, intercellular route seeks to bypass the corneocytes by transporting molecules through the lipid-rich intercellular space between the cells. The transcellular route seeks to transport molecules directly through the cells of the stratum corneum. In this method, molecules must travel through both corneocytes and the intercellular lipid space. The method of choice is dependent on physical and chemical properties of the transporting compounds; however, the intercellular route is the most common. Thus, the intercellular lipid barrier has been a subject of investigation to allow for greater understanding of how to develop transportation mechanisms of molecules through the stratum corneum. [ 3 ] [ 5 ]


In recent decades, due to the increasing use of therapeutic medications through transdermal pathways, techniques for improving permeation through the stratum corneum have been explored. The primary two routes of exploration have been chemical and physical penetration-enhancing mechanisms. [ 6 ]


A brief overview of physical penetration methods are summarized in the table below.


Chemical characteristics to enhance drug delivery include incorporating salt formations, drug-ion pairs, eutectic mixtures, chemical penetration enhancers, and utilizing  liposomal vesicles . [ 13 ]  Vesicles have shown the ability to be paired with current physical penetration techniques to synergistically improve drug penetration. [ 2 ] [ 14 ] [ 15 ]


Other vesicular systems, such as  liposomes  and  ethosomes , have already been extensively researched and utilized as drug transporters, but the penetration barrier has resulted in studies to modify current vesicles to add characteristics for improved penetration of the stratum corneum. [ 1 ]


Invasome vesicular systems are artificial vesicles composed of  phospholipids ,  terpene , and  ethanol . [ 1 ]  A phospholipid  bilayer  creates the external structure of the spherical particle. Within the bilayer are terpenes. Terpenes are naturally-occurring hydrocarbon chains that are commonly used in aromatics and scent products, but also have been used for the development of pharmaceuticals. Within the center of the terpene-and-phospholipid bilayer is a core that contains an aqueous hydroethanolic solution, along with the relevant drug. [ 1 ] [ 2 ]


Compared with other vesicular systems, the terpenes and ethanol function synergistically to increase the flexibility of invasomes, which allows for a softer, fluidic structure that increases penetration efficacy of the skin barrier. [ citation needed ]


Terpenes are known to be effective  penetration enhancers . They function in invasomes by breaking apart the tight phospholipid structure of the stratum corneum, increasing the permeability of the intercellular space. [ 1 ]


Like terpenes, ethanol has also been shown to disrupt the lipid structure of the stratum corneum, as well as loosening the invasome phospholipid bilayer. Ethanol also softens the lipids which increases the deformability of invasomes, allowing them to flatten to travel through the tight intercellular spaces of the skin. [ 16 ]


The terpenes and ethanol have been shown to loosen the invasome's phospholipid structure, allowing some of the terpenes and ethanolic solution to leak out of the invasome. There, they also separate the lipids of the stratum corneum. The smaller, flexible invasome is then able to travel intercellularly, passing through the stratum corneum to the viable cell layer where the drug is released and reaches systemic circulation. Thus, the terpenes and ethanol work in conjunction to both break up the phospholipids of the invasome they inhabit so they can pass through, as well as loosen the tight cellular matrix of the stratum corneum, giving the already-flexible invasomes an increased penetration ability. [ 16 ] [ 17 ]


Several preparation techniques of invasomes exist, but the most commonly used techniques are mechanical dispersion and thin-film hydration. [ 18 ]


During lipid dispersion, the lipid and organic solvent are added with a drug of choice; then the solution is vortexed and sonicated for five minutes. PBS is added to the solution with additional vortexing, and then an aqueous buffer is used to hydrate the mixture. The spontaneous swelling of the lipids then creates the invasome vesicles, which are finally sonicated,  lyophilized , and experience high-pressure extrusion. [ 18 ]


During thin-film hydration, also known as the conventional film method, [ 16 ]  lipids and drugs are added to ethanol and sonicated. A rotary flash evaporator is used to dry the mixture; nitrogen gas is used to remove harmful residual solvent. The resulting thin lipid films are hydrated using a  PBS , and after cooling the terpene mixture is added to form the invasomes. Finally, the invasome solution is vortexed and ultrasonicated. [ 18 ]


Invasomes have been considered in a range of applications. Apart from cosmetics, they are increasingly becoming a part of pharmaceuticals and drug delivery research. Areas for use include delivery of  immunosuppressive , anticancer, antiacne, contraceptive, erectile dysfunction,  antihypertensive ,  alopecia , and  antipsychotic  drug therapies. [ 18 ] [ 19 ] [ 20 ]


Invasomes can be paired with transdermal delivery methods to target the skin barrier. Examples of these techniques include  transdermal patches ,  microneedles , and creams.


Transdermal patches are medicated adhesives that can be applied to the skin. Compared to conventional hypodermic needles and oral delivery methods, patches allow for controlled release of drugs through the skin using built-in release mechanisms that allow drug reservoirs to discharge. Additionally, patches can be paired with microneedles to increase drug absorption. [ 21 ]


Microneedles are minimally invasive arrays of needles that bypass the stratum corneum. They can range in length from a few micrometers up to 2000 μm, with the needles existing in several forms: solid, coated, dissolving, hollow, and hydrogel-forming. [ 22 ] [ 23 ]


Medical creams have been used for centuries due to their relative simplicity, ease of preparation, and ease of use. They are medically-treated, semi-solid formulations for topical drug delivery. Benefits of creams include increased  patient compliance  and avoidance of first pass metabolism. [ 24 ] [ 25 ]


Isotropic formulations  are  thermodynamically  stable  microemulsions  possessing  lyotropic liquid crystal  properties. [ 1 ]  They inhabit a state of matter and physical behaviour somewhere between conventional  liquids  and that of solid  crystals . [ 2 ]  Isotropic formulations are  amphiphillic , exhibiting selective synchronicity with both the water and  lipid  phases of the substrate to which they are applied. [ 3 ]  Most recently, isotropic formulations have been used extensively in  dermatology  for drug delivery. [ 4 ]


While it is well established that the skin provides an ideal site for the administration of local and systemic  drugs , it presents a formidable barrier to the permeation of most substances. [ 5 ]  Isotropic formulations have been used to deliver drugs locally and systemically via the skin appendages, intercellular and transcellular routes. [ 6 ]


Limb perfusion  is a medical technique that is used to deliver drugs locally directly to a site of interest. It is commonly used in human medicine for administration of  anticancer drugs  directly to an  arm  or  leg . It is also used in  veterinary medicine  to deliver drugs to a site of infection or injury, as well as for the treatment of cancer in dogs. In both cases, a  tourniquet  is used to reduce blood flow out of the area that is being treated.


Isolated limb perfusion was first introduced into the clinic by American surgeons from New Orleans in the mid-1950s. The main purpose of the isolated limb perfusion technique is to deliver a very high dose of chemotherapy, at elevated temperature, to tumour sites without causing overwhelming systemic damage. (Unfortunately, while these approaches can be useful against solitary or limited metastases, they are - by definition - not systemic and therefore do not treat distributed metastases or  micrometastases ). The flow of  blood  to and from the  limb  is temporarily stopped with a  tourniquet , and anticancer drugs are put directly into the blood of the limb. This allows the person to receive a high dose of drugs in the area where the  cancer  occurred. The temperature is also increased to 42C causing an increased uptake of the drug by the tumor.  The combination of high drug dose and high temperature is toxic systemically, thus the isolation of the limb.  Blood flow through the limb is typically achieved using an extracorporeal circuit consisting of cannulae, tubing, peristaltic roller pump, heat exchanger, and pressure monitoring/safety devices.  Care must be used in handling the drugs and waste material as they are extremely toxic.  Among other types of cancer, isolated limb perfusion has been used to treat in transit metastatic melanoma. [ 1 ]


In the early 1990s an alternative technique was developed at the Royal Prince Alfred Hospital in Sydney, Australia: isolated limb infusion. This technique is less complex and uses a minimal invasive percutaneous approach to circulatorily isolate a limb.


Limb perfusion is also used in veterinary medicine, where is it usually referred to as  regional limb perfusion  (RLP). It is most commonly used in large animals, such as horses, cows, small ruminants, and camelids. These species often require large, cost-prohibitive doses of medications to treat  systemically . Regional limb perfusion allows drug dose to be reduced while maintaining therapeutic concentrations at the site of interest, thereby reducing the cost of treatment, localizing application, decreasing systemic side effects, and improving efficacy. [ 2 ]


Horses are sedated and the procedure is performed standing. [ 3 ]  Horses must be sedated, because movement can force blood past the tourniquet and reduce the concentration of drug below the site of the tourniquet. The area of needle insertion is clipped and scrubbed. A wide tourniquet is placed above the site of interest, and a needle inserted into a superficial vein of the limb below the tourniquet. The medication is delivered and the tourniquet is removed after 20–30 minutes. Because of the size of the limbs, RLP is not possible above the elbow or stifle of a horse because of inadequate compression of the underlying blood vessels.


Limb perfusion is commonly used for antibiotic administration in cases of localized infection, such as lacerations,  cellulitis , infection of a synovial structure (joint, tendon sheath, bursa), or  osteomyelitis . [ 4 ] [ 5 ]  RLP has been shown to produce antibiotic concentrations 25-50 times the  minimum inhibitory concentration  in septic joints. [ 6 ]  Antibiotic selection is important. Antibiotics must be approved for intravenous use, and are ideally chosen based on  culture and susceptibility  results.  Concentration-dependent antibiotics , such as gentamicin and amikacin, are best suited for RLP because they have higher efficacy at higher concentrations, while time-dependent antibiotics such as penicillin and ceftiofur may be used, but have a shorter duration. [ 7 ]  However, expense is usually less of a limiting factor because a smaller amount may be used relative to systemic administration.


Limb perfusion of carbapenem antibiotics such as imipenem and meropenem have been studied in horses. [ 8 ] [ 9 ]  However, a retrospective study comparing horses that received meropenem via RLP for orthopedics sepsis to a group of horses that received gentamicin via RLP for the same condition had no differences in outcome. [ 10 ]  This suggests that initial RLP treatments should utilize less critically important antimicrobials for initial RLP treatment such a gentamicin, instead of critically important antimicrobials, such as meropenem. [ 11 ]


In the case of  lameness  in horses, local use of regenerative therapies, such as  stem cells , [ 12 ]  or bisphosphonates such as  tiludronic acid [ 13 ]  are also given by RLP.


In dogs, RLP is also used to deliver chemotherapeutic agents. [ 14 ]


Side effects of RLP are relatively rare when performed correctly. Partial thrombosis of a vein can occur, especially with repeated use of a vein, but complete thrombosis is rare. There may also be localized tissue irritation. Topical application of an anti-inflammatory, such as  DMSO  or  Diclofenac sodium  may be used.


The  Macy Catheter  is a specialized  catheter  designed to provide comfortable and discreet administration of ongoing medications via the  rectal  route. The catheter was developed to make rectal access more practical and provide a way to deliver and retain liquid formulations in the  distal  rectum so that health practitioners can leverage the established benefits of rectal  administration . Patients often need medication when the  oral route  is compromised, and the Macy Catheter provides an alternative for those medications that can be prescribed per rectum. The Macy Catheter is of particular relevance during the  end of life , when it can help patients to remain comfortable in their home. [ 1 ]


The Macy Catheter is a disposable device approved by the U.S.  Food and Drug Administration  (FDA), consisting of a dual-porl-lumen ballooned tube that is inserted by a  clinician  into the  rectum  just past the rectal  sphincter . Once inserted into the rectum, a soft balloon is inflated with water via a balloon inflation valve to hold the device in place. This small, flexible "semi-retention" balloon exerts very little pressure on the rectal wall, and is designed for safety and comfort, while also allowing the catheter to be easily expelled when the patient needs to  defecate . The catheter utilizes a small flexible  silicone  shaft, allowing the device to be placed safely and remain comfortably in the rectum for repeated administration of medications or liquids.


Once in place, the medication delivery port of the Macy Catheter rests on the patient's leg or abdomen, where it is easily accessible for repeated administration of liquid medications in  solution  or  suspension  form. The device stays in place until the patient has a  bowel movement  and expels the retention balloon, or until manually removed after first deflating the balloon.


The Macy Catheter medication port has a specialized  valve  to prevent leakage and is designed to be non-clogging and compatible only with the connectors on oral/ enteral   syringes  (not luer syringes) for safety. The device is FDA-approved to remain in the rectum for up to 28 days. The catheter has a small  lumen , allowing for small flush volumes to get medication to the rectum. Small volumes of medications (under 15ml) improve comfort by not stimulating the  defecation  response of the rectum, and can increase the overall  absorption  of a given  dose  by decreasing pooling of medication and migration of medication into more  proximal  areas of the rectum where absorption can be less effective. [ 2 ] [ 3 ]


The Macy Catheter is intended to provide rectal access to administer liquids and medications. The Macy Catheter can be used in the following clinical situations:


The Macy Catheter provides an immediate way to administer medication or liquids for patients in the home setting when the oral route of medication administration is compromised. Unlike  intravenous  lines, which usually need to be placed in an  inpatient  environment and require special formulation of  sterile  medications, [ 7 ]  the Macy Catheter can be placed by a clinician, such as a  hospice  nurse or home health nurse in the home. Many oral forms of medications can be crushed and suspended in water to be given via the Macy Catheter. The Macy Catheter is useful for patients who cannot swallow, including those near the end of life (an estimated 1.65 million people are in  hospice  care in the US each year [ 8 ] ). Because the Macy Catheter enables a rapid, safe, and lower cost alternative to administration of medications, [ 9 ]  it may also be applicable to care of patients in  long-term care  or  palliative care , or as an alternative to  intravenous  or  subcutaneous  medication delivery in some instances.


The Macy Catheter is clinically indicated for the following scenarios:


1.  Symptom  management at the  end of life , [ 10 ]  including but not limited to:


2.  Bowel obstruction


3. Discharge from  acute care  to the home setting


The Macy Catheter was invented by Brad Macy, RN, BSN, a 22-year veteran  hospice  nurse. Inspired by a patient who was terminally agitated and not responding to a solid form of a rectally delivered medication, Macy administered the same medication in a liquid suspension with a small tube inserted into the patient's  rectum . The patient's agitation rapidly diminished, and the patient was sleeping within 30 minutes. [ 11 ]  After practicing repeated successful interventions involving the application of medication in highly concentrated form to the  distal  one-third of the  rectum , Macy realized the potential implications for  hospice  and  palliative  patients worldwide. With this motivation, he proceeded to develop the Macy Catheter, a device designed and developed for commercial use. [ 12 ]  The commercial product is protected by two issued U.S. patents and received 510(k) clearance from the  Food and Drug Administration  in early 2014. [ 13 ] [ 14 ]


Rectal  drug delivery is an effective route of medication delivery for many medications used at the  end of life . [ 15 ] [ 16 ] [ 17 ] [ 18 ] [ 19 ] [ 20 ] [ 21 ]  The walls of the rectum absorb many medications quickly and effectively. [ 22 ]  Medications delivered to the distal one-third of the rectum at least partially avoid the "first pass effect" through the liver, which allows for greater bio-availability of many medications than that of the oral route.


The rectal route of administration is highly effective as the rectal  mucosa  is highly  vascularized  tissue that allows for rapid and effective absorption of medications. [ 23 ]  Although  intravenous  administration is the most commonly used alternate route in  acute care  settings, [ 24 ]  it is rarely used in  hospice care , given the associated cost and need for a high level of care and training for providers. [ 25 ]  It can also lead to complications such as  infection  and pain. [ 26 ]  Although subcutaneous medication delivery is more common in hospice, it is also expensive and can cause infection, pain and  swelling . [ 27 ]  The rectal route of administration is highly effective as the rectal mucosa is highly vascularized tissue that allows for rapid and effective absorption of medications. [ 28 ] [ 29 ] [ 30 ] [ 31 ] [ 32 ] [ 33 ] [ 34 ]  The Macy Catheter provides a solution to overcome the challenges and leverage the benefits of  rectal administration .


Magnetic-targeted carriers , also known as MTCs or magnetic vehicles, are micro- or nanoparticles that carry an  anticancer drug  to the target site by using an external magnetic field and field gradient to direct the desired drug. Usually, the complex involves microscopic beads of activated carbon, which bind the anticancer drug. A  magnet  applied from outside the body then can direct the drug to the  tumor  site. This can keep a larger dose of the drug at the tumor site for a longer period of time, and help protect healthy tissue from the  side effects of chemotherapy .  [ 1 ]


The use of MTCs as therapeutic agents for oncology treatment has been increasing exponentially over the past decade. Currently the magnetic vehicle composition relies on the properties of the magnetic component, which is usually ferromagnetic, ferrimagnetic or superparamagnetic, owing to their ability of expressing strong magnetization in the same direction of the external magnetic field while also retaining their magnetization once the external magnetic field is removed.  [ 1 ]


Magnetic vehicles have been focusing on the particle size, aiming to have the MTCs in the nanoscale, which is mainly due to the fact that ferromagnetic and ferrimagnetic materials show remnant magnetization with and without the external magnetic field, which in turn causes particle aggregation complications. Very small nanoparticles exhibit superparamagnetic properties, which are able to obtain a high degree of magnetization while being able to avoid the particle aggregation issue caused by remnant magnetization. Iron oxide is a common metal used for this purpose, which is usually used as magnetite, maghemite or a combination of the two, due to their high magnetization values between the different iron oxides. Iron oxide gives the impression of lacking remnant magnetization even though magnetite and maghemite are ferromagnetic due to thermal fluctuations, which mostly accounts for the internal interactions of the particles affecting energy densities. [ 1 ] [ 2 ]


MTCs carry the drug molecules to the tumor site by either having them bound to the surface or by being enclosed within the magnetic vehicle, which can be referred to as the MTC-drug complex. Magnetic-targeted carriers possess unique intrinsic properties, developing magnetic polarization and magnetophoretic mobility once the external magnetic field and field gradient are applied. Selective application of the magnetic field gradient is applied to the target area, which in turn guides the MTC-drug complex to the desired location with a relatively high degree of accuracy, minimum surgical intervention and maximum dose. In order to be able to successfully deliver the drug at the desired tumor location, the magnetic vehicles are responsive to a specific tumor signal, which is commonly a temp- or pH-sensitive release due to the higher temperature and lower pH observed in tumor microenvironments, relative to the rest of the body. [ 1 ] [ 2 ]


Different requirements exist for magnetic nanoparticles involved in site-specific targeting, which are dependent on either physical or biological reasons. The nine different main requirements the magnetic-targeted carrier should possess are the following: 1) Sufficient magnetic moment to overcome drag and yield forces. 2) Superparamagnetism to prevent agglomeration and embolism. 3) Biocompatibility to prevent toxicity, enhance cell survival and reduce inflammatory responses. 4)  Biodegradability  to improve clearance from the body. 5) Capability to act as a carrier and exhibit controlled sustained release. 6) Structural stability to allow delivery of therapeutic agents after reaching target site. 7) Stealth and functional surface characteristics to prolong the circulation half-life, improve colloidal stability, prevent agglomerations and reduce toxicity. 8) Reproducible sizes and shapes for clinical applications 9) Reproducible and scalable methods to allow mass production. [ 1 ]


The most common current clinical application involving a MTC-drug complex is the doxorubicin-magnetic targeted carrier complex, which is composed of a formulation of the anthracycline antibiotic doxorubicin and is bound to microscopic beads of activated carbon. Iron is used as the magnetic-targeted carrier.  [ 1 ]


Magnetic vehicles started being used for drug delivery purposes of chemotherapeutic agents around 1960–1970. MTCs composition has varied over the years and differed between in-vitro and in-vivo studies. Dr. Widder synthesized albumin microspheres in the 1970s encasing Adriamycin, a chemotherapeutic drug, and used magnetite as the susceptible magnetic component to the external magnetic field. One of the first in vivo experiments using magnetic vehicles performed in humans was done by John F. Alksne and his associates in the 1960s, using carbon-coated iron and applied an external magnetic field in order to occlude intracranial aneurysms, which was considered a successful therapeutic once the X-ray results were analyzed. Currently, magnetic nanoparticles, such as iron oxide, take advantage of their multimodality since they can integrate various functionalities, such as imaging agents, targeted-delivery and induce hyperthermia. In addition, iron oxide nanoparticles are being tested in emerging medical fields, such as multimodal imaging, theranostics and image-guided therapies.  [ 1 ] [ 2 ] [ 3 ] [ 4 ]


Microdispensing  is the technique of producing liquid media dosages in volumes of less than one microlitre. The continuing miniaturization in almost all technical areas creates constant challenges for industry, development and research facilities. Microdispensing is one of those challenges. Ever smaller amounts of adhesive, liquid, oil, grease and a multitude of other media must be dispensed reliably and accurately in dosage and placement with short cycle times.  The precise positioning and quantity of fluids such as glue, reagents or any other substance has a great influence on the overall quality of a medical device. A few examples are:


Microdispensing is also used in non-medical applications, like on-demand soda flavoring (the  Coca-Cola Freestyle  and  Pepsi Spire ),  inkjet printing , and  3-D printing .


There are two basic types of dispensing techniques: classic contact dispensing and non-contact dispensing.


In contact dispensing, the drop forms at the exit of a nozzle, and is deposited by contact, while the drop is still on the nozzle. The technique is as old as the wish to divide a medium, stored in a big container, into smaller amounts. A good example for this is applying adhesive with a tube: To apply the adhesive requires contact between the tip of the tube and the part for the bead of adhesive to be transferred. This method has disadvantages:


Despite all of these disadvantages, contact dispensing is still used in the majority of automated processes today, because  of:


Gear pump


Pressure-time systems


In non-contact dispensing, the drop also forms at the end of a nozzle, but far enough away from the target area that the drop separates from the nozzle before it hits. This, too, is a very old technique, as old as squirting liquid from a tube.