Several studies have been dedicated towards the development of bioartificial pancreas involving the immobilization of islets of Langerhans inside polymeric capsules. The first attempt towards this aim was demonstrated in 1980 by Lim et al. where xenograft islet cells were encapsulated inside alginate polylysine microcapsules and showed significant in vivo results for several weeks. [ 3 ]  It is envisaged that the implantation of these encapsulated cells would help to overcome the use of immunosuppressive drugs and also allow the use of xenograft cells thus obviating the problem of donor shortage.


The polymers used for islet microencapsulation are alginate, [ 82 ]  chitosan, [ 83 ]   polyethylene glycol  (PEG), [ 84 ]  agarose, [ 85 ]  sodium cellulose sulfate and water-insoluble  polyacrylates  with alginate and PEG being commonly used polymers.
With successful in vitro studies being performed using this technique, significant work in clinical trials using microencapsulated human islets is being carried out. In 2003, the use of alginate/PLO microcapsules containing islet cells for pilot phase-1 clinical trials was permitted to be carried out at the University of Perugia by the Italian Ministry of Health. [ 54 ]  In another study, the potential of clinical application of PEGylation and low doses of the immunosuppressant  cyclosporine  A were evaluated. The trial which began in 2005 by Novocell, now forms the phase I/II of clinical trials involving implantation of islet allografts into the  subcutaneous  site. [ 86 ]  However, there have been controversial studies involving human clinical trials where Living Cell technologies Ltd demonstrated the survival of functional xenogeneic cells transplanted without immunosuppressive medication for 9.5 years. [ 87 ]  However, the trial received harsh criticism from the International Xenotransplantation Association as being risky and premature. [ 88 ]
However, even though clinical trials are under way, several major issues such as biocompatibility and immunoprotection need to be overcome. [ 89 ]


Potential alternatives to encapsulating isolated islets (of either allo- or xenogeneic origin) are also being explored. Using sodium cellulose sulphate technology from  Austrianova Singapore  an islet cell line was encapsulated and it was demonstrated that the cells remain viable and release insulin in response to glucose. [ 90 ]  In pre-clinical studies, implanted, encapsulated cells were able to restore blood glucose levels in diabetic rats over a period of 6 months. [ 91 ]


The use of cell encapsulated microcapsules towards the treatment of several forms of  cancer  has shown great potential. One approach undertaken by researchers is through the implantation of microcapsules containing genetically modified cytokine secreting cells. An example of this was demonstrated by Cirone et al. when genetically modified  IL-2 cytokine  secreting   non- autologous  mouse  myoblasts  implanted into mice showed a delay in the  tumor  growth with an increased rate of survival of the animals. [ 92 ]  However, the efficiency of this treatment was brief due to an immune response towards the implanted microcapsules.
Another approach to cancer suppression is through the use of angiogenesis inhibitors to prevent the release of  growth factors  which lead to the spread of tumors. The effect of implanting microcapsules loaded with xenogenic cells genetically modified to secrete  endostatin , an  antiangiogenic  drug which causes  apoptosis  in  tumor  cells, has been extensively studied. [ 93 ] [ 94 ]  However, this method of local delivery of microcapsules was not feasible in the treatment of patients with many tumors or in  metastasis  cases and has led to recent studies involving systemic implantation of the capsules. [ 95 ] [ 96 ]


In 1998, a murine model of pancreatic cancer was used to study the effect of implanting genetically modified  cytochrome P450  expressing feline  epithelial  cells encapsulated in cellulose sulfate polymers for the treatment of solid tumors. [ 97 ]  The approach demonstrated for the first time the application of  enzyme  expressing cells to activate chemotherapeutic agents. On the basis of these results, an encapsulated cell therapy product, NovaCaps, was tested in a phase I and II clinical trial for the treatment of pancreatic cancer in patients [ 98 ] [ 99 ]  and has recently been designated by the European medicines agency (EMEA) as an orphan drug in Europe. A further phase I/II clinical trial using the same product confirmed the results of the first trial, demonstrating an approximate doubling of survival time in patients with stage IV pancreatic cancer. [ 100 ]  In all of these trials using cellulose sulphate, in addition to the clear anti-tumour effects, the capsules were well tolerated and there were no adverse reactions seen such as immune response to the capsules, demonstrating the biocompatible nature of the cellulose sulphate capsules. In one patient the capsules were in place for almost 2 years with no side effects.


These studies show the promising potential application of cell microcapsules towards the treatment of cancers. [ 42 ]  However, solutions to issues such as immune response leading to inflammation of the surrounding tissue at the site of capsule implantation have to be researched in detail before more clinical trials are possible.


Numerous studies have been dedicated towards the development of effective methods to enable  cardiac  tissue regeneration in patients after  ischemic  heart disease. An emerging approach to answer the problems related to ischemic tissue repair is through the use of stem cell-based therapy. [ 101 ]  However, the actual mechanism due to which this stem cell-based therapy has generative effects on cardiac function is still under investigation. Even though numerous methods have been studied for cell administration, the efficiency of the number of cells retained in the beating heart after implantation is still very low. A promising approach to overcome this problem is through the use of cell microencapsulation therapy which has shown to enable a higher cell retention as compared to the injection of free  stem cells  into the heart. [ 102 ]


Another strategy to improve the impact of cell based encapsulation technique towards cardiac regenerative applications is through the use of genetically modified stem cells capable of secreting angiogenic factors such as  vascular endothelial growth factor  (VEGF) which stimulate  neovascularization  and restore  perfusion  in the damaged ischemic heart. [ 103 ] [ 104 ]  An example of this is shown in the study by Zang et al. where genetically modified xenogeneic CHO cells expressing VEGF were encapsulated in alginate-polylysine-alginate microcapsules and implanted into rat myocardium. [ 105 ]  It was observed that the encapsulation protected the cells from an immunoresponse for three weeks and also led to an improvement in the cardiac tissue post- infarction  due to increased angiogenesis.


The use of monoclonal antibodies for therapy is now widespread for treatment of cancers and inflammatory diseases. Using cellulose sulphate technology, scientists have successfully encapsulated antibody producing hybridoma cells and demonstrated subsequent release of the therapeutic antibody from the capsules. [ 45 ] [ 46 ]  The capsules containing the hybridoma cells were used in pre-clinical studies to deliver neutralising antibodies to the mouse retrovirus FrCasE, successfully preventing disease.


Many other medical conditions have been targeted with encapsulation therapies, especially those involving a deficiency in some biologically derived protein. One of the most successful approaches is an external device that acts similarly to a  dialysis machine , only with a reservoir of pig  hepatocytes  surrounding the semipermeable portion of the blood-infused tubing. [ 106 ]   This apparatus can remove toxins from the blood of patients suffering severe  liver failure . Other applications that are still in development include cells that produce  ciliary-derived neurotrophic factor  for the treatment of  ALS  and  Huntington's disease ,  glial-derived neurotrophic factor  for  Parkinson's disease ,  erythropoietin  for  anemia , and  HGH  for  dwarfism . [ 107 ]  In addition, monogenic diseases such as haemophilia, Gaucher's disease and some  mucopolysaccharide disorders  could also potentially be targeted by encapsulated cells expressing the protein that is otherwise lacking in the patient.


Cervical drug delivery  is a route of carrying drugs into the body through the  vagina  and  cervix . This is a form of localized drug delivery that prevents the drugs from impacting unintended areas of the body, which can lower side effects of toxic drugs such as  chemotherapeutics . Cervical drug delivery has specific applications for a variety of female health issues: treatment of  cervical cancer , pregnancy prevention, STD prevention, and STD treatment.


Viscous  mucus  secreted by glands in the cervix presents a unique environment for drug delivery.  Due to its ability to retain substances and slowly release them, it holds potential to be used as a natural, noninvasive drug delivery system.  The mucus can act as a reservoir for compounds that destroy pathogens. [ 1 ]   However, the cervical mucus also presents a barrier to drug delivery as it can be really thick, making it difficult to permeate the mucus barrier. [ 2 ]  The mechanisms for penetration and bioactivity of the cervical mucus must be understood to utilize the mucus’s potential as a drug delivery system. [ 1 ]   Due to the changes in viscosity and water content of the mucus during the stages of the  menstrual cycle , this poses a particularly complex consideration. [ 3 ]   For example, the cervical mucus will be thicker when a woman is not  ovulating  in order to prevent sperm from being able to penetrate the mucus barrier, which also in turn makes in more difficult for penetration of drug delivery systems.


The vaginal environment is slightly acidic, with  pH  ranging from 3.8 - 4.5 based on multiple factors such as age, natural bacteria, and stage of menstrual cycle. [ 4 ]   Due to the variety in possible pH values, this poses an interesting consideration for drug delivery.  Absorption and release of drugs is often influenced by pH, so if the pH is changing through the menstrual cycle, different combinations could be needed at different times to achieve the most effective drug delivery system.


Some  hormonal birth control  methods utilize cervical drug delivery methods.  The earliest example of such dates to 1850 Ancient Egypt when acadia gum was inserted into the vagina, releasing  spermicidal  components. [ 5 ]   Examples in the modern era include  vaginal rings  and  intrauterine devices  (IUDs) that release hormones into the reproductive system to prevent fertilization.  Vaginal rings are plastic ring-shaped devices that are inserted into the vaginal canal and slowly release hormones such as estradiol or progestin.  Hormonal IUDs are T-shaped devices inserted into the uterus, releasing progestin over extended periods of time. These hormones work to thicken the cervical mucus to prevent sperm from penetrating and reaching the  fallopian tubes . [ 6 ]   Copper IUDs are another form of intrauterine devices that release copper ions instead of hormones.  The copper ions are toxic to sperm and therefore prevents successful fertilization. [ 7 ]


The most common application of cervical drug delivery is for treatment of cervical cancer. Due to the direct route provided through the use of cervical drug delivery mechanisms, it proves to be the most effective route with the lowest number of side effects. [ 8 ]   The localized treatment has been suggested as ideal as cancer is treated with highly toxic compounds, such as chemotherapeutics.  The more contained the exposure to these compounds can be, the less negative impacts the patient will endure.  Treatment can be delivered in the form of  nanoparticles , vaginal gels, or films and reach the cervix quickly for ideal response. [ 9 ]  Vaginal gels are easily administered into the vaginal canal to reach the cervix due to low viscosity at room temperature.  When inserted into the body which has a higher temperature, the gels become more viscous, allowing them to reside longer at the cervix and have more sustained release. [ 8 ]   Vaginal films are very thin films inserted into the vagina to release a compound.  They can be maintained for six hours in cervical mucus, meaning they hold potential to treat cervical cancer caused by  Human Papilloma Virus . [ 9 ]  Nanoparticle systems take advantage of the size of nanoparticles  to encapsulate the drugs and pass through the mucus barrier. [ 8 ]


Cervical drug delivery serves as a route for compounds to prevent and treat  sexually transmitted diseases  (STDs). Prevention of STDs for women can be achieved by administering preventative compounds into the vaginal canal prior to intercourse. One method researched is the use of a CAP technology that remains stable in the vaginal environment, but breaks down in the presence of human semen, releasing a drug to destroy STDs. [ 10 ]  This application of cervical drug delivery would be useful for prevention of STDs in women without interfering with the bodily environment until there is potential for infection.  STDs can also be treated through cervical drug delivery methods.  Antibiotics for STD treatment are often administered into the vagina in the form of creams or gels.


Hormones to increase fertility are also often delivered through the cervical route.  While this is less common than applications for birth control, it essentially utilizes the same concepts.  Hormones influence the natural menstrual cycle, so instead of using hormones that prevent ovulation, hormones are used to encourage ovulation, such as follicle-stimulation hormones (FSH) and luteinizing hormones (LH).  Fertility lubricants are the most common example of fertility treatments delivered through the cervical route.  These lubricants are designed to mimic a pH and viscosity that is conducive for sperm to reach the fallopian tube. [ 11 ] [ 12 ]  Studies are being done to combine the properties of fertility lubricants with fertility increasing hormones to lead to more direct and efficient treatment.


Vaginal rings are most commonly used for birth control purposes but can also be used to release compounds that treat and prevent STDs as well. The rings come in one standard size that fits most women [ 13 ]  and are made of flexible materials that contain the desired compound, whether that be hormones for birth control or other compounds for STD treatment. These substances are then slowly released over an extended period of time, typically a month.  This is a convenient drug delivery method because they can easily be inserted and removed and do not prohibit intercourse.  For birth control purposes, the vaginal ring is removed after 3 week and a new one is inserted a week later.  Vaginal rings are also often used to treat symptoms of menopause, and these rings are replaced after a 3 month use. [ 14 ]   STD prevention and treatment through the use of vaginal rings is a newer application of such a device, but holds an advantage as a low maintenance option for women in areas with less access to regular healthcare. [ 15 ]


Vaginal  suppositories  are forms of medications that are inserted into the vagina in a solid form, but melt from body heat to release the substances. [ 16 ]   Common uses for them are to treat yeast or bacterial infections.  Hormones are often delivered in this form for treatment of  menopausal  or menstrual related issues.  Spermicide can also be delivered as a suppository when inserted prior to intercourse for birth control purposes.  Insertion of vaginal suppositories uses a mechanism and applicator similar to that of a  tampon .  If there is no applicator available, they can be inserted with two fingers pushing them into the vaginal canal as far as is comfortable.


Vaginal gels are forms of medication that are water-based.  They are applied using a plastic applicator to distribute the gel throughout the length of the vaginal canal.  These gels tend to have release kinetics that are fast acting, which makes them useful for treatment of irritations.  Antibiotics are often distributed in the form of a gel for treatment of common infections, including sexually transmitted infections (STIs).  The gels also have the benefit of being lubricating, which grants additional relief to symptoms of dryness and itching that is common with vaginal infections. Gels that are in the form of liposomal structure have been shown to retain substances for extensive periods of time, making them useful for slow release of drugs administered through the cervical drug delivery route [ 17 ]


Vaginal films are soluble, thin sheets of medication that are inserted into the vagina where they dissolve and release the substances.  Typical uses include delivery of contraceptive substances or antibiotics for infections. These films are inserted by simply pushing them into the vagina with one’s fingers.  There they dissolve quickly upon interaction with natural vaginal fluids. [ 18 ]


Bioadhesives  are substances that naturally stick to live tissue.  Currently, studies are being done on bioadhesives adhering to cervical mucous membranes to allow for an extended release period.  The drug would be released with mucus to create a localized treatment with high effectiveness. This is anticipated to be highly useful for treatment of cervical cancer.  Bioadhesives can come in multiple forms, such as films, tablets, or gels. [ 19 ] [ 18 ]   The appeal of bioadhesives is that they take advantage of the mucous environment surrounding the cervix and utilize it to benefit the drug delivery mechanism.


Coiled-coil drug delivery systems  refer to  drug delivery  systems utilizing  coiled-coil   motifs  capable of delivering disease-treating therapies, imaging agents, and vaccines to patients systemically or  specifically . These systems are a form of  peptide therapeutics  and are capable of being engineered and finely tuned into different types of drug delivery vehicles (such as  liposomes ,  nanoparticle drug carriers ,  polymer hybrid drug carriers ,  micelles , etc.) based on the specific application required. The goal of a coiled-coil drug delivery system is to deliver cargo such as medication, imaging agents, biological molecules, or vaccines efficiently and specifically, in order to maximize the  therapeutic efficacy  and minimize  unwanted side effects . This is achieved through fine-tuning the factors affecting the coiled coil’s  oligomerization , resulting in modular systems that are highly specific for the intended application.


Coiled-coil motifs make up 10% of all  protein  sequences, [ 1 ]  and are utilized naturally by various proteins in both  prokaryotes  and  eukaryotes  to achieve diverse cellular functions. Coupled with the simple  helical  structure of coiled coils which has been widely studied and reported on in literature, engineered coiled coil drug delivery systems are capable of improving drug  pharmacokinetics , reducing unintentional  toxicity  during delivery, delivering drugs in a specific manner,  controlling cargo release , and maintaining high  stability  through transport in the body.


Coiled-coil research began in 1953 when Dr.  Francis Crick  first reported on the theory behind the packing formation of  α-helices  in  fibrous proteins  at the time, which he proposed to consist of alpha helices composed of  heptad  repeats, or seven-residue repeats (a-b-c-d-e-f-g), whereby 2 or more alpha helices twist around each other similar to the strands of a rope. [ 2 ]  In 1972, Dr. Robert Hodges and his colleagues confirmed Dr. Crick’s hypothesis upon sequencing  tropomyosin , further discovering that the heptad repeat consists of two hydrophobic residues at the a and d positions, which stabilize coiled coils and are their basis for formation. This confirmation formed the basis for designing engineered coiled-coil proteins to further investigate and better understand coiled-coil interactions, structures, functions, oligomerization, and other properties. [ 3 ] [ 4 ] [ 5 ] [ 6 ]  Later in 1991, Dr. O’Shea and colleagues obtained the first high-resolution image of a two-stranded coiled-coil at a resolution of 1.8Å. [ 7 ]


Dr. Hodges was the first to suggest the use of coiled coils in a drug delivery system in 1996 when he proposed a two-stage targeting and delivery system based on  heterodimerization , whereby a drug would be conjugated to chain 1 and an antibody would be conjugated to chain 2, such that chains 1 and 2 would form a heterodimeric coiled coil. In this system, the antibody conjugate would hypothetically be delivered first such that it binds to the target location, followed by the administration of the drug conjugate, whose chain 1 would dimerize with the antibody chain 2, resulting in targeted drug delivery. [ 8 ]  Since then, hundreds of investigations have been reported in the literature discussing novel drug delivery systems consisting of various coiled coil  supramolecular assemblies , such as fibers, hydrogels, and nanostructures. [ 9 ]


Typically, a coiled-coil motif consists of 2-7 alpha helix strands coiled together, each of which consists of a 7-residue repeat (a-b-c-d-e-f-g) called a heptad. Heptads are unique in that positions a, d are occupied by  hydrophobic residues  – typically  Leu ,  Ile , or  Val . [ 9 ]  Positions e, g are typically occupied by charged or  polar residues  – typically  Lys  or  Glu . Through this pattern, individual helices become  amphipathic , such that when oligomerized, a hydrophobic core forms between the a, d residues of the helices, along with interhelical  ionic interactions  that aid in stabilizing the oligomer that forms between the e and g residues of the helices (see figure 1). The number of heptads in a molecule is variable and can be modified based on specific applications of coiled-coil systems. For example, sequences with fewer heptads consisting of a, d hydrophobic residues can prove to be more stable than sequences with more heptads containing a mixture of polar and non-polar residues at the same positions. [ 5 ]  Thus, the hydrophobic core of a coiled-coil motif is considered a dominant factor affecting the  stability  of the motif. Additionally, the hydrophobic core residues affect the  specificity  of the coiled-coil motif, such that the specific pairs of a, d residues determine the number of alpha helices that compose the coiled-coil system. For example, in the case of the GCN4 leucine zipper protein, mutants with the a, d pair of I, L resulted in a two-stranded coiled-coil, while a pair of I, I resulted in a three-stranded coiled-coil and a pair of L, I resulted in a four-stranded coiled coil. [ 10 ]  Thus, the oligomerization selectivity can be tuned on a coiled-coil motif by choosing the appropriate amino acid residues in positions a, d.


The polar residues on positions e, g of a heptad also contribute to the stability and specificity of the coiled-coil motif due to the electrostatic interactions such as  salt bridges  with e, g residues on other heptads, though to a lesser extent compared to residues in the a, d positions. [ 9 ]  However, e, g residues are capable of conferring  heterospecific  properties to a coiled-coil motif, such that a system can be designed whereby strands prefer hetero-oligomerize as opposed to homo-oligomerize. [ 9 ]


Coiled coils may be either left-handed or right-handed coils – although the majority of coiled-coil proteins found in nature consist of heptads and are left-handed since the handedness of coiled coils opposes the handedness of the alpha helices that comprise them. [ 11 ]  Right-handed coils have been reported in the literature to contain 11 residue repeats known as  undecad  repeats (a-b-c-d-e-f-g-h-i-j-k) or 15 residue repeats known as  pentadecad  repeats (a-b-c-d-e-f-g-h-i-j-k-l-m-n-o), both of which could feature larger hydrophobic cores and larger cavities that would be useful in drug delivery systems to load larger cargo. [ citation needed ]


Coiled-coils are used as non-covalent  polymer-drug conjugates  to link  drugs  to  polymer backbones . The goal of these types of systems is to attach multiple drugs to a non-toxic backbone such that drugs can be stably transported throughout the body and  released at a controlled rate  once at the target location.  Doxorubicin ,  paclitaxel , and  campothecin  are examples of drugs typically used with polymer-drug conjugate systems. Hetero-dimeric coiled-coils motifs can be utilized in such systems, whereby one strand would be conjugated to the polymer backbone network, while the other strand would be conjugated to the drug of choice. The coiled-coils would then oligomerize, followed by the  administration of the drug system  into the body, whereby the stability of the coiled-coil in physiological conditions would ensure the intact delivery of the drug to the target. Upon  cellular uptake  at the target site, coiled-coil system would be exposed to a decrease in  pH  associated with the acidic environments of  endosomes  and  lysosomes , triggering the  dissociation  of the coiled-coils, resulting in drug release. Dr. Harm-Anton Klok and colleagues were the first to investigate the usage of coiled coils as linkers in polymer-drug conjugate systems, whereby they utilized the parallel heterodimeric E3/K3 coiled-coil system (known for its stability at physiological pH and dissociation at pH 5, resulting in E3 homotrimers along with K3 unimers [ 12 ] [ 13 ] ) to link cargo to a p oly(N-(2-hydroxypropyl)methacrylamide) (PHPMA) -based polymer backbone. Klok et al. proved the intracellular uptake of cargo via  endocytosis , along with cargo release as a result of coiled-coil dissociation. Dr. Ondřej Vaněk and colleagues utilized the same E3/K3-PHPMA system to attach an antibody to the polymer backbone to target the delivery of the drug system, which was successful in vitro. [ 14 ]


Coiled-coil polymer hybrid drug delivery systems can also be used in drug-free macromolecular therapeutic (DFMT) applications, whereby a coiled-coil-based system would be used to induce  apoptosis  in target cells. Specifically, Dr.  Jindřich Kopeček  and colleagues attempted to induce apoptosis in  CD20 -positive  non-Hodgkin's lymphoma   B-cells  by mimicking the induction of apoptosis typically caused by the recognition of secondary antibodies to the CD20 antigen. In this case, apoptosis was induced upon the oligomerization of a PHMPA copolymer-conjugated coil to the anti-CD20 FAB fragment-conjugated coil (which would recognize and bind CD20). [ 15 ]  The coiled-coil motifs used in this system were the  anti-parallel  heterodimeric CCE/CCK coiled coils, which consist of  pentaheptad  repeats. This system was found to be successful at inducing apoptosis in those cells  in vitro , providing an alternative to the anti-CD20 antibody drug  Rituximab . Further studies have shown the efficacy of this system in vivo whereby malignant B-cells implanted in the  bone marrow  of mice were eradicated completely. [ 16 ]


Coiled-coils can be used to create  nanoparticle drug delivery systems  capable of delivering drugs or other biological molecules with increased targeting and controlled release due to their biocompatibility, stability, and targeting properties. Self-assembled cage-like particles (SAGE) utilize coiled-coils along with  disulfide linkers  to create hollow  nanoparticles  of diameters in the range of 100nm. [ 17 ]  SAGE consists of two separate coiled-coil motifs: a ~20 residue heptad homotrimer motif (CC-Tri3) and a ~20 residue heptad heterodimer motif (CC-Di-A / CC-Di-B). Each CC-Tri3 would be bound to either a CC-Di-A or a CC-Di-B via a disulfide linker, such that each time CC-Di-A and CC-Di-B would oligomerize together, hexagonal networks would form with pores of 5-6nm in diameter: CC-Di-A – CC-Tri3 – CC-Di-A – CC-Di-b – CC-Tri3 – CC-Di-B. Self-assembly would result in further oligomerization between the heterodimer motifs, which would eventually result in the formation of a hollow nanoparticle sphere. The final diameter of the nanoparticle would depend on the length linker used, along with the size of the coiled-coil motifs used. [ 17 ]  SAGE has been applied in the field of  antigen delivery , whereby Dr. Andrew Davidson and colleagues modified 3 SAGE systems described above with the antigenic peptides  tetanus toxoid ,  ovalbumin , and  hemagglutinin  individually. The investigators found that SAGE systems were nontoxic  in vivo , and were capable of eliciting  CD4 T cell  and B cell responses in the case of the tetanus toxoid and ovalbumin systems while eliciting a CD8 T cell response with the hemagglutinin system. [ 18 ]    Some advantages to using SAGE systems for antigen presentation include the ability to remain stable and functional after functionalization with cargo, the ability to modify and tune  cellular uptake  properties, and the modularity of the platform which could potentially be used to present multiple antigens at the same time, resulting in increased  antigen immunogenicity . [ 18 ]


Another type of coiled-coil nanoparticle system is the self-assembling protein nanoparticles (SAPN). SAPN differs from SAGE in that SAPN utilizes trimeric and  pentameric  coiled-coil motifs. [ 19 ]  This change results in the self-assembly of a symmetrical  polyhedral  16nm  nanoparticle  composed of 60 monomer building blocks. The small size of SAPN allows the nanoparticle system to resemble viruses in shape and size, which is beneficial to antigen presentation. [ 9 ]  Specifically, SAPN has been utilized by Dr. David Lanar and colleagues to develop a P. falciparum malaria vaccine whereby B and CD8-T cell epitopes of the disease were modified into the SAPN coiled-coil motifs. In vivo results showed that a long-lasting immune response was generated in the mice for up to 13 months, capable of preventing malaria infection in vaccine-treated mice. [ 20 ]


Convection-enhanced delivery  ( CED ) is method of drug delivery in which the drug is delivered into the brain using  bulk flow  rather than conventional diffusion. This is done by utilizing  catheters  inserted into the target region of the brain and utilizing pressure to deliver the therapeutic to a target region. CED has been used to delivery drugs to the  central nervous system  (CNS) for diseases such as  cancer ,  epilepsy , and  Parkinson's disease . [ 1 ] [ 2 ] [ 3 ]  CED has been used to deliver drugs to the CNS for its ability to bypass the  blood–brain barrier  (BBB) and target specific regions for targeted treatment, but current techniques using CED have failed to progress past clinical trials due to a variety of physical limitations associated with CED itself.


The blood brain barrier (BBB) has historically proved to be a very difficult obstacle to overcome when aiming to deliver a drug to the brain. In order to overcome the difficulties in delivering therapeutic levels of drug past the BBB, drugs had to either be  lipophilic  molecules with a molecular weight below 600 Da or be transported across the BBB using some sort of  cellular transport system . [ 4 ]  In the 1990s, a research group led by Edward Oldfield at the  National Institutes of Health  proposed utilizing CED to deliver drugs and molecules too big to bypass the BBB to the brain. [ 5 ]  CED is also useful to delivery drugs that have poor diffusive properties and allows for targeted placement of the catheter used to deliver the drugs. A vast majority of current clinical studies using CED are currently using CED as a method to treat  brain tumors  that are inoperable or have shown little response to conventional therapies.


CED is a method of drug delivery in which a pressure gradient is created at the tip of a catheter to use bulk flow rather than diffusion to delivery drugs into the brain. Diffusion has been limited by the diffusivity of the tissue, and can be expressed using Fick's law,

 J
 =
 −
 D
 ∇
 C

 {\displaystyle J=-D\nabla C}

 , where J is diffusion, D is the diffusivity of the targeted tissue, and

 ∇
 C

 {\displaystyle \nabla C}

  is the concentration gradient of the drug. Diffusion is can only be modified by the concentration gradient of a drug, meaning that in order to deliver drug to large parts of a tissue, high concentrations of a drug are needed in order to promote diffusion, which can result in toxicity. In comparison, bulk flow is limited only by Darcy's law, defined as

 v
 =
 −
 K
 ∇
 p

 {\displaystyle v=-K\nabla p}

 , where v is velocity, K is the hydraulic conductivity of the molecule, and

 ∇
 p

 {\displaystyle \nabla p}

  is the pressure gradient. Using bulk flow to deliver a drug can mean a drug can be delivered further into a target tissue with higher pressure, resulting in lower concentrations and less risk of drug toxicity. [ 6 ]


To perform a CED treatment, catheters are inserted through burr holes drilled into the skull. Treatments can use multiple catheters for a single delivery if that is required. The catheters are inserted into the interstitial space of the brain using image guidance. Once the catheters are placed at the desired site, the catheters are connection to an infusion pump which is used to create the pressure gradient for bulk flow. Infusion rates are typically set to 0.1-10 μL/min and the drug is delivered into the interstitial space, displacing any extracellular fluid. [ 5 ]  CED can result in delivery of drug centimeters deep into the tissue from the delivery site, rather than the millimeters deep that would result from delivery of drugs via diffusion. [ 5 ]


Current clinical trials exploring the use of CED to date have not resulted in any FDA approved treatments. These clinical trials have mostly been focused on using CED to treat glioblastoma and only two studies have been able to progress to stage 3 clinical trials. The first study began in 2004 and was comparing the efficacy of  cintredekin besudotox  delivered using CED and  gliadel  for the treatment of glioblastoma multiform. [ 7 ]  Results from this study showed similar survival rates between the two groups, but patients who were given CED treatment had higher rates of  pulmonary emboli . The second stage 3 clinical trial began in 2008 and was delivering  trabedersen  via CED to treat anaplastic astrocytoma  glioblastoma . [ 8 ]  This trial was terminated early due to the inability to recruit enough trial participants and efficacy of CED in this treatment was not established. These two studies have been the only major clinical trials which have compared the efficacy of CED treatment to current clinical standards for treatment.


While CED clinical trials have primarily explored treating brain tumors, other conditions involving the brain have also been investigated in clinical trials. To date there have been 2 registered clinical trials, both in stage 1, which aim to use CED to treat Parkinson's disease. The first trial, which was registered in 2009, was withdrawn in 2017 for unknown reasons. [ 9 ]  The other clinical trial, which reached completion in 2022, delivered an  adenovirus  (AAV2) encoding for a  glial cell line derived neurotropic growth factor  (GDNF) directly into the brain using CED. [ 10 ]  GDNF is known to protect neurons which produce dopamine. Parkinson's disease has been shown to decrease the amount of dopamine which can be produced in the brain, so researchers hope to be able to decrease the side effects of Parkinson's disease by protecting neurons which produce dopamine. While results from this study have not been published as of April 2022, the pre-clinical research done in a Parkinson's disease model rhesus monkey showed that CED treatment with AAV2-GDNF resulted in neurological improvement without significant side effects. [ 11 ]


Even though current clinical trials have not yet resulted in an FDA approved treatment, there is still plenty of research being done on delivering different types of therapeutics and treating different diseases being done. One of these areas of research is the visualization of the region of treatment. One research group was able visualize the regions of the brain that received drug from bulk flow mixing the desired drug with  Gd-DTPA , a common  MRI contrast agent . [ 12 ]  This allowed researchers to immediately take an MRI post CED treatment to assess if the drug was reaching the targeted area. Research has also tagged nanocarriers of their therapeutic with the MRI contrast  gadoteridol  for real time treatment imaging. [ 13 ]  Other than MRI contrasts, it has been shown to be possible to tag a therapeutic microcarrier with a radiolabeled or fluorescent molecule that can then be excited during imaging. The biggest limitation of this drug distribution visualization is that this technique only works  ex vivo.  One research group was able to optimize their liposomal design using this technique, showing the usefulness of this technique. [ 14 ]


While a common use of CED is to directly deliver drugs to the brain, it is also possible to deliver non-chemical therapeutics, such as proteins or growth factors, using CED. There are several types of microcarriers which have been used for CED, including nanospheres, nanoparticles, liposomes, micelles, and dendrites. [ 15 ]  Nanocarriers have several unique benefits for delivering therapeutics compared to conventional drug solutions. Firstly, nanocarriers can be modified to create an optimal carrier for the system that is being developed. These modifications can include tagging them for imaging, size, charge,  osmolarity ,  viscosity , and changes in surface coating. [ 15 ]


The other large area of research being done currently on CED is the translation of CED from being used for brain tumors to other brain diseases. The primary conditions being researched for non-cancerous treatments include Parkinson's disease and epilepsy. Animal model research using CED to deliver therapeutics to the brain to treat Parkinson's disease have shown 3 promising therapeutics for treatment. Researchers for these therapeutics have typically used adenovirus carriers for therapeutics since many drugs used to treat Parkinson's disease currently are not chemical based but rather gene therapy or protein based. [ 16 ]  Current research areas focus on using GDNF, a growth factor which protects dopamine producing brain cells,  glutamic acid decarboxylase  (GAD), which is another therapeutic that helps to protect dopamine producing brain cells, and  neurturin , which is a GDNF homolog. [ 16 ]  Another reported use of CED is in the treatment of epilepsy. Current epilepsy treatments are too large to pass through the BBB, so utilizing CED to delivery these drugs is currently one of the only ways to target the brain. The two primary antiepileptic drugs (AEDs) being delivered using CED in research are  conotoxin   N-type calcium channel  antagonists and  botulinum neurotoxins . [ 2 ]  Results from these studies showed promise in reducing the risk of seizures for up to 5 days when treated with calcium channel antagonists and up to 50 days when using botulinum  neurotoxins   [ 17 ] [ 18 ]


While there has been promise in the use of CED to delivery drugs directly into the brain, there are some drawbacks with it. A vast majority of studies to date have failed to have consistent delivery from patient to patient for technical reasons surrounding the usage of CED. Incorrect placement of catheters can result in a less effective treatment with increased risks of leaks from the brain into other parts of the central nervous system (CNS). Another, more common occurrence is the incidence or reflux of the drug back into the catheter. Reflux can cause leakage into unintended areas as well as decrease the true volume of drug delivered. [ 6 ]  CED catheter improvements are currently being researched, with some research groups modifying the tips of the catheters to prevent reflux. The design of a balloon tipped catheter for use in CED has been proposed, and results showed that drug was successfully delivered into the brain using the balloon tipped catheter without any complication. [ 19 ]  Other proposed designs include the utilization of catheters with multiple exit sites, catheters with porous tips, and catheters with tips that are smaller than the rest of the catheter. [ 20 ]  New catheter designs also aim to allow for a greater flow rate while still minimizing the risk of reflux. [ 13 ]  These improvements to the technical limitations of CED aim to help researchers determine efficacy of a treatment without worrying about failed treatments due to limitations in the equipment of CED. With this in mind, there is a fast growing tech company in Baltimore, Maryland named CraniUS LLC, for which is inventing, designing and engineering the world's first fully-implantable, MRI-compatible, wirelessly-charged, bluetooth-enabled, high-profile craniofacial implant device to provide neurosurgical patients a safe option for receiving direct and chronic medicine delivery to their brain via convection-enhanced delivery; using a novel embedded, microfluidic-pump system and easy port-access system for repeated, transcutaneous filling. |url= http://www.CraniUSmed.com


A  cream  is a preparation usually for application to the  skin .  Creams for application to  mucous membranes  such as those of the  rectum  or  vagina  are also used.  Creams may be considered  pharmaceutical  products, since even cosmetic creams are manufactured using techniques developed by  pharmacy  and unmedicated creams are highly used in a variety of skin conditions (dermatoses).  The use of the  finger tip unit  concept may be helpful in guiding how much topical cream is required to cover different areas.


Creams are semi-solid  emulsions  of oil and water.  They are divided into two types: oil-in-water (O/W) creams which are composed of small droplets of oil dispersed in a continuous water phase, and water-in-oil (W/O) creams which are composed of small droplets of water dispersed in a continuous oily phase.  Oil-in-water creams are more comfortable and cosmetically acceptable as they are less greasy and more easily washed off using water.  Water-in-oil creams are more difficult to handle but many  drugs  which are incorporated into creams are  hydrophobic  and will be released more readily from a water-in-oil cream than an oil-in-water cream.  Water-in-oil creams are also more moisturising as they provide an oily barrier which reduces water loss from the  stratum corneum , the outermost layer of the skin.


Creams are semisolid dosage forms containing more than 20% water or volatile components and typically less than 50% hydrocarbons, waxes, or polyols as vehicles. [ 1 ]  They may also contain one or more drug substances dissolved or dispersed in a suitable cream base. This term has traditionally been applied to semisolids that possess a relatively fluid consistency formulated as either water-in-oil (e.g.,  cold cream ) or oil-in-water (e.g.,  fluocinolone acetonide  cream) emulsions. However, more recently the term has been restricted to products consisting of oil-in-water emulsions or aqueous microcrystalline dispersions of  long-chain fatty acids  or alcohols that are water washable and more cosmetically and aesthetically acceptable. Creams can be used for administering drugs via the vaginal route (e.g.,  Triple Sulfa  vaginal cream). Creams are also used to treat  sun burns .


There are four main ingredients of the cold cream: [ 2 ]


There are many types of preparations applied to a body surface, such as:


Cypher  is a brand of  drug-eluting coronary stent  from  Cordis Corporation , a  Cardinal Health  company. During a balloon  angioplasty , the stent is inserted into the artery to provide a "scaffold" to open the artery. An anti-rejection-type medication,  sirolimus , helps to limit the overgrowth of normal cells while the artery heals which reduces the chance of re-blockage in the treated area known as  restenosis , and reduces the chances that another procedure is required. [ 1 ] [ 2 ]


The Cypher stent was approved for use by the FDA in 2003. [ 2 ]  Following claims of inconsistent manufacturing processes and poor sales,  Johnson & Johnson  have announced that it will stop selling Cypher stents by the end of 2011. [ 3 ]


A  dermal patch  or  skin patch  is a  medicated   adhesive  patch placed on  human skin  to deliver a medication into the skin. This is in contrast to a  transdermal patch , which delivers the medication through the skin and into the  bloodstream .


In 2016, a study from the University of Nottingham was published describing the first  synthetic  spider silk  that is functionally identical to naturally spun spider silk. Using non-natural methionine analog L-azidohomoalanine (L-Aha) and genetically modified E-Coli cells, self-assembling proteins under the conditions needed to create the filament were produced. These conditions had been researched years earlier by J. Johansson and co-workers studying the production of spider silk proteins. The proteins used in the study are a miniaturized version of the silk monomers found in nature that behave the same way; because of the modifications, they were able to express functionalized regions of the protein 4RepCT, which is a self-assembling recombinant dragline silk protein, derived from the nursery-web spider along the axis of the filament. [ 3 ]


Methods of functionalizing the 4RepCT protein have been successful, but not in the way of reliably producing a stable protein functionalization in biologic environments that can also be tuned and modified. Genetic fusion of functional peptide sequences to silk genes and chemical conjugation of functional molecules onto amino acid side chains are the only two methods currently known to achieve a functionalized 4RepCT protein with tunable functionality. The first approach has the advantage that post-translational manipulation of the silk is minimized. Unfortunately, genetic manipulation is challenging due to the high GC (guanine-cytosine) content of the gene which leads to transcription errors. This method also limits the prevalence of functional binding sites to a single ligand-binding site per 25 kDa 4RepCT silk protein. Large adaptor proteins such as antibodies can be used to display more binding sites, but it isn't considered a feasible solution. This method has been shown to produce 4RepCT proteins that have a higher cell adhesion than natural spidroin proteins and have varied antimicrobial properties. The second method, chemical modification of the silk proteins should result in the covalent attachment of several copies of a wide range of organic and organometallic ligands using robust or sensitive linkers depending on the application. The challenge with this method is it is difficult to make the modification of the 4RepCT protein site-specific. Specific site targeting requires the residues to also be modified to be accessible and chemically bioorthogonal to the rest of the silk protein. Cytosine residues are commonly used for this type of conjugation through a Michael addition, but they tend to undergo exchange reactions which makes them unstable for long durations in a biological environment. These two methods are rather outdated but have been useful in validating the fact that 4RepCT can be tuned in the important areas of cellular adhesion, antimicrobial potency, and the type of molecule or drug attached to it. [ 3 ]


Later azide functional groups were conjugated to the N-terminal of a dragline silk protein using EDC/NHS coupling, yielding glycopolymer-conjugated films with enhanced cell adhesion and DNA-silk chimeras with controllable micro-architectures. Armed with this, the researchers in this study investigated the incorporation of 3 L-Aha residues into 4RepCT, yielding

 4
 R
 e
 p
 C

 T

 3
 A
 h
 a

 {\displaystyle 4RepCT^{3Aha}}

 . The azide side chains of L-Aha allow highly specific and efficient site-specific conjugation to a lot different of functional molecules via Staudinger ligation with phosphine reagents, and Copper (I)-catalysed azide-alkyne cycloaddition ( CuAAC ) or Strain promoted azide-alkyne cycloaddition ( SPAAC ) in click reactions. [ 3 ]


CuAAC and SPAAC are both common click reactions which are often interchangeable in click chemistry. It is well known that intracellular Cu(I) is cytotoxic, which means CuAAC is not as common as SPAAC click reactions for research leading to in-vivo applications. The researchers for this study decided to use CuAAC, despite the purpose of this research to have in-vivo applications, for a few reasons. First, the likelihood for copper to be bound by the

 4
 R
 e
 p
 C

 T

 3
 A
 h
 a

 {\displaystyle 4RepCT^{3Aha}}

  protein is low due to the presence of only 2 glutamic acid residues and no histidine residues (two residues with a high affinity for Cu(I)). These residues are present in the thioredoxin; which is the solubilizing fusion partner conjugated to the 4RepCT protein during synthesis. However, this does not cause issues since the thioredoxin is removed in order to trigger the self-assembly reaction with thrombin which results in fiber formation. This removal of the Cu(I) laden thioredoxin removes virtually all copper from the silk structure. The researchers also, through a buffer containing EDTA and by utilizing THPTA (which stabilizes the copper ions), rinsed the fibers resulting in further removal of Cu(I) leaving a <0.1 % by weight trace of copper ions. Secondly, CuAAC outperforms SPAAC in click reactions where proteins with a high cytosine content, such as 4RepCT, are present. The SPAAC process, in the presence of proteins like 4RepCT, will often create ‘clicks’ in off-target sites resulting in the ligand conjugating to the wrong part of the protein and rendering the protein essentially useless. In order to maximize the number of functional sites along the fiber, CuAAC is preferred. [ 3 ] [ 4 ]


This study demonstrated the CuAAC mediated conjugation of

 4
 R
 e
 p
 C

 T

 3
 A
 h
 a

 {\displaystyle 4RepCT^{3Aha}}

  with two different fluorophores and the antibiotic levofloxacin, showcasing the potential of covalently functionalized recombinant spider silk proteins as biomaterials with enhanced properties. The researchers were able to successfully conjugate

 4
 R
 e
 p
 C

 T

 3
 A
 h
 a

 {\displaystyle 4RepCT^{3Aha}}

  with alkyne fluorophores, proving the protein can be functionalized through an azide group while conjugated to the axis of the silk fiber. Their results showed not only an intense uniform fluorescence along the fiber axis but also an intense uniform composite fluorescence when the fiber was decorated with two different fluorophores in a 1:1 ratio. [ 3 ]


To prove the functional azide group could be decorated with a clinically relevant molecule, the researchers attempted to decorate the fiber with glycidyl propargyl ether (an acid-labile linker) and bound Levofloxacin (a gram-positive targeting antibiotic) to it using an ester bond between the epoxide carboxylate groups respectively. They conducted an inhibition zone assay with the functionalized silk fibers against E. Coli NCTC 12242 bacteria where each factor level contained LB media. Their results showed a successful functionalization of the Levofloxacin decorated fiber which maintained an antibiotic persistence across a 3.5 cm radius for 120 hours and a cell density ~50% of other factor levels (LB media only, unfunctionalized silk, and Levofloxacin doped silk) with p ≤ 0.01. A maximum sustained release of Levofloxacin from the fiber of 5 days was achieved. [ 3 ]


Spider silk is one of the earliest known dermal patches. Primarily used for wound binding, the glycoprotein adhesive found on the capture spiral silk, as well as the protein structure of the fiber itself, has mild antibacterial properties. The silk, acting as a local antiseptic, reduced the rate of sepsis and chronic illness. The silk's viscoelastic properties and high tensile strength and toughness aided wound healing in a way similar to surgical tape.


Despite its superiority to current methods of large-surface-area wound care—gauze wrapping, honey vinegar treatments, and systemic antibiotics—and popular dermal patch uses, spider silk has not found its way into clinical practice. Historically the main reason for this is the difficulty of farming, and harvesting the silk. Unlike silkworms, that spin silk for several easy-to-replicate conditions, spiders spin silk for specific purposes such as catching prey, difficult to replicate in laboratory conditions. In addition, spiders generally tend to be cannibalistic, so breeding sufficient numbers becomes difficult. Forced silking yields unsuitable silks. The most popular proposed use case for dermal applications are:


Research shows  silkworm  silk does not possess any inherent antibiotic characteristics, bio-mimicking mechanical properties, and can cause fatal respiratory allergic reactions in some people. [ 5 ]


A 2020 study found that recombinantly produced spider silk proteins self-assemble at the liquid-air interface of a standing solution, forming protein permeable, super strong and ultra flexible membranes. The unforced self-assembly creates a nanofibrilar membrane which supports cell growth. A confluent layer of human skin cells forms within three days, and would be suitable for direct delivery to a patient. [ 6 ]


As silkworm silk is potentially fatal to humans when in contact with vasculature, there is no approved dermal patch, or dermal patch-like, application for silkworm silk.


Dextran drug delivery systems  involve the use of the natural glucose polymer  dextran  in applications as a  prodrug ,  nanoparticle ,  microsphere ,  micelle , and  hydrogel   drug carrier  in the field of targeted and controlled drug delivery. According to several  in vitro  and animal research studies, dextran carriers reduce off-site toxicity and improve local drug concentration at the target tissue site. [ 1 ]  This technology has significant implications as a potential strategy for delivering therapeutics to treat cancer, cardiovascular diseases, pulmonary diseases, bone diseases, liver diseases, colonic diseases, infections, and HIV. [ 1 ] [ 2 ] [ 3 ]


Although there are many  FDA  approved natural polymeric-based drug carriers available for clinical use, dextran has failed to obtain any clinical applications. Research must address several challenges and obstacles associated with dextran before it can become a viable, clinically approved drug delivery strategy. [ 4 ]


Dextran has many favorable properties that make it an ideal candidate for applications as a drug delivery system. As a natural polymer, dextran is  biocompatible  and  biodegradable  in the human body. Dextran can also be chemically modified to produce derivatives at a low cost, which can address a few of the undesirable characteristics including its low mechanical strength and uncontrollable hydration rate [4]. This natural glucose polymer has excellent water solubility and prolonged circulation in the blood as well. [ 5 ]


Dextran prodrugs are chemically linked drug-polymer complexes in which enzymatic processes and  hydrolysis   in vivo  cause the drug to become pharmacologically active. Therapeutic agents can be linked to dextran via an  ester  bond which can be hydrolyzed slowly by  esterases  to produce sustained, stable drug release. Drug-dextran complexes can also be formed by chemical linkage through an amide bond, which is hydrolyzed by amidase. Prodrugs coupled by amide bonds provide much slower drug release than by ester bonds. Succinic acid and glutaric acid carboxyl groups, amino acids, pH and reductivity sensitive  disulfide bonds , and click chemistry are also methods of coupling drugs to dextran. [ 1 ]


These drug-polymer complexes have advantages such as longer drug half-life and improved targeted drug delivery. Dextran prodrugs have potential applications in the treatment of liver diseases, pulmonary diseases, colonic diseases, and cancer. [ 1 ]


Dextran nanoparticles are 1-100 nm sized particles with drug encapsulation capability. The high surface area of these nanoparticles allows more drugs to be loaded and encapsulated, leading to higher drug concentrations at the target site. The small size of these particles also encourages cellular uptake, which makes dextran nanoparticles a potential effective drug delivery system for targeting tumor cells. [ 1 ]


Dextran has indirect applications in nanoparticles as a coating.  Iron oxide  nanoparticles coated with dextran can be loaded with the  microRNA  miR-29a to selectively target breast cancer cells and down-regulate anti-apoptotic genes leading to successful breast cancer treatment. [ 6 ]  Dextran-coated iron oxide nanoparticles loaded with heparinase-like antisense nucleic acid effectively target uterine cancer cells and inhibit tumor growth. Supermagnetic nanospheres composed of iron oxide coated with dextran can be loaded with doxorubicin to effectively target tumor cells and limit off-site toxicity. Gold magnetic nanoparticles coated with dextran can effectively target desired tissue sites with the aid of an externally applied magnetic field. [ 1 ]  Dextran coatings can further improve the drug targeting capability of other types of nanoparticles.


Dextran conjugates are also utilized in nanoparticle drug delivery system formulations. Nanoparticles composted of dextran and stearic acid with a  polyethylene glycol  (PEG) coating can be loaded with antiviral drugs and be effectively internalized by cells. This nanosystem has the advantages of providing protection against immune responses and providing stability to the encapsulated drug. This technology has applications in the treatment of HIV and AIDS. [ 7 ]  Dextran can be grafted with folic acid to develop doxorubicin-loaded nanoparticles. Dextran-folic acid nanoparticles effectively target tumors, reduce off-site toxicity, and prolong blood circulation. Dextran- spermine  nanoparticles loaded with doxorubicin can achieve targeted and sustained drug release in tumors. [ 1 ]


Dextran nanoparticles have advantages such as increased drug-loading capacity, improved cellular uptake, reduce off-site toxicity, and increase local drug concentrations at the target tissue site. The current research indicates that dextran nanoparticles can potentially have applications in the delivery of anti-tumor therapeutics. [ 1 ]


Dextran microspheres are 1 to 250 micrometer sized polymeric particles that can encapsulate drugs. Microspheres composed of dextran have several advantages as a drug delivery system including controlled drug release, localized drug concentration, and reduced adverse reactions. Controlled drug release by these dextran microparticles is achieved by degradation, which is the breakdown of chemical bonds in the molecular structure of the polymeric network. [ 1 ]  Dextran microspheres are formulated in many forms including native dextran, dextran as a cross-linker, dextran conjugates, and chemically modified dextran. [ 1 ] [ 8 ] [ 9 ]


Dextran can be used as a standalone material in microspheres. Dextran microspheres can provide controlled drug release in gastric and intestinal pH environments, which is ideal for targeting of the colon. [ 1 ]


One application of the glucose polymer dextran in microsphere compositions is as a cross-linker. Dextran and oxidized dextran can be used to crosslink gelatin microspheres to reduce gelatin dissolution, which slows the drug release rate. These dextran/gelatin microspheres can be used to provide slow-release of TRAPP-Br, which is a cancer therapeutic. [ 8 ]  Hydrogel microspheres synthesized by using porous chitosan polyelectrolyte complex with dextran sulfate as a cross-linker can deliver hydrophobic drugs to the intestines with high efficacy. [ 1 ]


Dextran can be conjugated with other materials to synthesize microspheres. Dextran grafted with PLGA forms microspheres that can provide effective delivery of insulin in diabetic patients. Dextran/chitosan microspheres efficiently deliver recombinant bone morphogenic protein (rhBMP-2) for the treatment of bone diseases. [ 1 ]


Microspheres can also be developed by chemically modifying dextran. Acetated dextran can be modified with amine groups and grafted with heparin to form microspheres that provide protamine-stimulated, targeted drug release for the delivery of therapeutics to treat cardiovascular diseases. [ 9 ]  Dextran modified with an octyl- group creates microspheres that provide extended release of doxorubicin, which is an antitumor therapeutic. [ 1 ]


Dextran-based microspheres can encapsulate a variety of drugs and provide therapeutic delivery in the treatment of diseases such as cancer, colonic diseases, bone diseases, and cardiovascular diseases. [ 1 ] [ 8 ] [ 9 ]


Dextran micelles are 10 to 100 nm sized amphiphilic polymeric particles which have the advantages of avoiding drug clearance by the kidneys and traveling through blood vessels. [ 1 ]  The core of these micelles are hydrophobic, allowing for loading of hydrophobic drugs into the micelle. The outer shell of the particles is hydrophilic, which allows for long circulation times in the blood. [ 5 ]  Dextran can be conjugated with other materials to form polymeric micelles including stearic acid and cholesterol to further improve sustained release of the loaded hydrophobic drug. The size of the micelles can be controlled by altering the ratio of stearic acid to dextran. [ 5 ]  Dextran micelles can also be formed from conjugation with  polycaprolactone ,  folic acid ,  retinoic acid , and  PLGA . [ 1 ]


Dextran micelles can be synthesized and modified to be stimuli-responsive. These stimuli include pH, temperature, and redox conditions. [ 10 ]  Micelles composed of dextran grafted with deoxycholic acid or polycaprolactone via a disulfide bond are responsive to a redox environment. Dextran micelles conjugated with cholesterol exhibit pH responsiveness when modified with histidine. [ 1 ]  Dextran-benzimidazole conjugate micelles also exhibit pH-responsiveness. [ 10 ]  When the polymeric micelles encounter these stimuli, release of the drug from the hydrophobic core is triggered by various mechanisms depending on the stimuli and the conjugated material. Stimuli-responsive dextran grafted micelles decrease off-site drug toxicity and increase localized drug concentration in the target site. [ 1 ]


Dextran micelles and dextran copolymer micelles can be loaded with a variety of hydrophobic drugs such as doxorubicin, rapamycin, and paclitaxel, indicating a significant application in the delivery of anti-cancer therapeutics. [ 1 ] [ 5 ]


Dextran hydrogels and dextran conjugate hydrogels are heavily cross-linked polymeric networks that have a strong affinity for water. These gels have soft, elastic physical properties and are biocompatible and biodegradable. [ 1 ]  Dextran hydrogels have also been shown to be stable and safe  in vivo . [ 2 ]  Glucose-based polymeric gels have the advantage of being able to be chemically or physically modified to improve targeted drug delivery. [ 1 ]  Swelling is one mechanism by which drugs are released from the dextran hydrogels. Swelling can be reduced by increasing the molecular weight of dextran, leading to a slower drug diffusion rate out of the hydrogel. Swelling can also be lessened by increasing the amount of the conjugated species and introducing ethanol during the cross-linking reaction. [ 2 ] [ 3 ]  Degradation of chemical linkages in the dextran hydrogels is another mechanism by which drugs are released from the polymeric matrices. An increase in degradation of the dextran hydrogel leads to an increase in drug release rate. Degradation of dextran hydrogels specifically is caused by dextranases, which are microbial enzymes mostly located in the colon. [ 2 ] [ 3 ]


The colon is an ideal target for dextran hydrogel drug delivery systems due to the presence of dextranases. Dextran can be cross-linked with diisocyanate to form a hydrogel that can be loaded with hydrocortisone to treat swelling or inflammation in the colon. [ 3 ]  Hydrogels can also be synthesized from crosslinking  epichlorohydrin  (ECH) with dextran. Dextran-ECH hydrogels can be loaded with salmon calcitonin (sCT) to treat bone diseases. Dextran-ECH hydrogels loaded with sCT achieved comparable release rates to other polymeric hydrogels in the colon. [ 2 ]


Dextran conjugate hydrogels can also target other desirable sites. Paclitaxel-loaded dextran-sericin hydrogels can effectively target tumor growth in mice. Hydrogels composed of translocator protein (TSPO) ligands conjugated to dextran have the potential to induce apoptosis in tumor cells via the TSPO receptor on the mitochondria. [ 1 ]  Dextran/polyacrylamide hydrogels with covalently bound silver nanoparticles can effectively release ornidazole to treat infections. Dextran conjugated with oligolactide chains through a disulfide bond can form hydrogels that have potential applications in cancer treatment drug delivery systems. Dextran hydrogels that release drugs in response to an external electrical field can also be synthesized. [ 1 ]


Dextran hydrogel and dextran conjugate hydrogel drug delivery systems have a variety of applications. These gels can be used to release therapeutics to treat cancer, swelling, inflammation, bone diseases, and infections. [ 1 ] [ 2 ] [ 3 ]


Dextran has yet to be approved for any clinical uses in drug delivery due to a wide variety of limitations including heterogeneity, undesirable side effects, and unknown biological pathways. Changes in the molecular weight of dextran have been shown to alter biological activity, indicating a need for separation and purification processes to ensure batch homogeneity. Dextran, although considered relatively safe and nontoxic  in vivo , exhibits a few side effects with the most notable being thrombocytopenia and liver toxicity. The exact biological mechanisms by which dextran-based drug delivery systems act on the drug target must be elucidated as well. [ 4 ]  Dextran-based drug delivery systems have an enormous potential for clinical use in the treatment of a variety of disease states.


Digital medicine  refers to the application of advanced digital technologies, such as  artificial intelligence , machine learning, and big data analytics, to improve patient outcomes and healthcare delivery. It involves the integration of technology and medicine to facilitate the creation, storage, analysis, and dissemination of health information, with the aim of enhancing clinical decision-making, improving patient care, and reducing costs.


Digital medicine encompasses a wide range of disciplines, including techbio, healthtech, and biomedical engineering. It involves the use of digital tools and platforms to collect, store, and analyze patient data, including electronic health records, genomic data, and medical imaging. This data can then be used to develop new analytics and treatment approaches, personalize healthcare interventions, and optimize healthcare delivery.


Digital medicine is evidence-based, and its approach is rooted in rigorous scientific research and clinical evidence. It is designed to augment and complement traditional medical practices, providing physicians and other healthcare professionals with the tools and resources they need to make more informed decisions and provide better care to patients.


Digital medicine is sometimes confused with similar disciplines, including the broader category of  digital health , as well as  digital therapeutics , another digital health subset. Digital health offerings use digital technologies to enhance human health in some capacity but often lacking the required evidence base to qualify as digital medicine. [ 1 ]  Within this broader category, programs that include a prescription medication with an ingestible sensor component are considered digital medicines. By contrast, digital therapeutics are associated mainly with web-based health management tools and stand-alone health apps, generally without a prescription medication element. [ 2 ]


The ingestible sensor component associated with digital medicines was originally approved in 2012 by the U.S. Food and Drug Administration (FDA) through the Center for Devices and Radiological Health via a de novo pathway for novel, low-risk medical devices. [ 3 ]  This approval has been accompanied by FDA 510(k) clearances. [ 3 ]  The ingestible sensor is CE marked in Europe. [ 4 ]  A New Drug Application for the first fully integrated pharmaceutical with ingestible sensor component,  Otsuka Pharmaceutical 's ABILIFY MYCITE® (aripiprazole with Proteus ingestible sensor), was approved by the FDA in November 2017. [ 5 ]


With its approval of the  digital pill , the FDA confirmed that the review of digital medicines includes assessment of the ingestible device component, and that no additional safety and efficacy data is required for the original pharmaceutical. [ 2 ]


Digital medicines are being used for a variety of conditions in commercial and clinical settings. Medications with ingestible sensors are being prescribed in the treatment areas of  hypertension ,  diabetes ,  hypercholesterolemia ,  heart failure ,  Hepatitis C ,  mental health ,  HIV ,  TB  and  organ transplantation . [ 6 ] [ 7 ] [ 8 ]


In January 2016, Barton Health became the first institution to commercially offer digital medicines to patients with  chronic medical conditions . [ 9 ]  In 2016, Children's Health in Dallas, Texas became the first to commercially use digital medicines with  pediatric  patients. [ 10 ]


Bioethicists have expressed concerns around technologies that log and share information about patients’ medication-taking behavior. [ 11 ]   These concerns exist from the perspective of both individual and collective patient rights. However, proponents note that participation in digital medicine programs are voluntary, comply with all applicable laws and standards, and protect patient data in accordance with applicable state and federal privacy regulations, as with other data generated and stored in electronic medical records. [ 12 ]   Experts add that digital medicine programs show promise as a solution to  medication adherence , and help physicians more accurately titrate dosages and determine how well the medication worked. [ 13 ]


A  douche  is a term for a device used to introduce a stream of water into the body for medical or hygienic reasons, or for the stream of water itself. Douche usually refers to vaginal irrigation, the rinsing of the  vagina , but it can also refer to the rinsing of any body cavity. A douche bag is a piece of equipment for douching—a bag for holding the fluid used in douching. To avoid transferring intestinal bacteria to the vagina, the same bag must not be used for both an  enema  and a vaginal douche.


Douching after sexual intercourse is not an effective form of  birth control . [ 1 ]  Additionally, douching is associated with a number of health problems, including  cervical cancer ,  pelvic inflammatory disease ,  endometritis , and increased risk of  sexually transmitted infections . [ 2 ]


The word's first known use is in 1766.  Douche  came into English via  French , from  Italian :  doccia  "conduit pipe" and  docciare  "pour by drops" to douche, from  doccia  water pipe, probably back-formation from  doccione  conduit, from  Latin :  duction- ,  ductio  means of conveying water, from  ducere  to lead. [ 3 ] [ failed verification ]  In French today it means  shower , as it does in many European languages.


Vaginal douches  may consist of water, water mixed with  vinegar , or even  antiseptic  chemicals. Douching has been touted as having a number of supposed but unproven benefits. In addition to promising to clean the vagina of unwanted odors, it can also be used by women who wish to avoid smearing a sexual partner's penis with menstrual blood while having  sexual intercourse during menstruation . In the past, douching was also used after intercourse as a method of  birth control , though it is not effective (see below).


Many health-care professionals state that douching is dangerous, as it interferes with both the vagina's normal self-cleaning and with the natural bacterial culture of the vagina, and it might spread or introduce infections. Douching is implicated in a wide variety of dangers, including: adverse pregnancy outcomes including  ectopic pregnancy ,  low birth weight , preterm labor,  preterm birth , and  chorioamnionitis ; serious gynecologic outcomes, including increased risk of  cervical cancer ,  pelvic inflammatory disease ,  endometritis , and increased risk for  sexually transmitted infections , including  HIV ; it also predisposes women to develop  bacterial vaginosis  (BV), [ 4 ]  which is further associated with adverse pregnancy outcomes and increased risk of sexually transmitted infections. [ 5 ]  Due to this, the  U.S. Department of Health and Human Services  strongly discourages douching, citing the risks of irritation, bacterial vaginosis, and pelvic inflammatory disease (PID). Frequent douching with water may result in an imbalance of the  pH  of the vagina, and thus may put women at risk for possible vaginal infections, especially yeast infections. [ 6 ]


In May 2003, a randomized, controlled, multi-center study was conducted with 1827 women ages 18–44 who were regular users of a douche product and who had been treated recently for a sexually transmitted bacterial infection or bacterial vaginosis. Women were randomly assigned to use either a newly designed and marketed douche product or a soft cloth towelette. There was little or no indication of a greater risk of PID among women assigned to use the douche product (versus soft cloth towelette). [ 7 ]


Antiseptics used during douching disturb the natural balance of bacteria in the vagina and can cause infections. [ 8 ]  Unclean douching equipment may introduce foreign bodies into the vagina. Douching may also wash bacteria into the  uterus  and  fallopian tubes , causing fertility problems. [ 9 ]  For these reasons, the practice of douching is now strongly discouraged except when ordered by a physician for medical reasons. [ 8 ]


Douching after intercourse is estimated to reduce the chances of conception by only about 30%. [ 10 ]  In comparison, proper male  condom  use reduces the chance of conception by as much as 98%. [ 11 ]  In some cases douching may force the  ejaculate  further into the vagina, increasing the chance of pregnancy. A review of studies by researchers at the  University of Rochester Medical Center  (N.Y.) showed that women who douched regularly and later became pregnant had higher rates of  ectopic pregnancy ,  infections , and low birth weight infants than women who only douched occasionally or who never douched. [ 8 ]


A 1995 survey quoted in the  University of Rochester  study found that 27% of U.S. women age 15 to 44 douched regularly, but that douching was more common among  African-American  women (over 50%) than among white women (21%), [ 8 ]  and frequent douching contributes to more frequent bacterial vaginosis among African-American women than the average. [ 4 ]


Medical doctor  Harriet Hall  writes that not only can douching change the  pH  of the vagina and lead to infections, "There is no need ... to cleanse the vagina. It cleanses itself". [ 12 ]


Douchebag  and its variants, or simply  douche , [ 13 ] [ 14 ]  are  pejorative  terms [ 14 ]  referring to an arrogant, obnoxious, or despicable person. [ 15 ]  The slang usage of the term originated in the 1960s. [ 16 ]


A  drip chamber , also known as  drip bulb , is a device used to allow gas (such as  air ) to rise out from a fluid so that it is not passed downstream. It is commonly employed in delivery systems of  intravenous therapy  and acts to prevent  air embolism . [ 1 ] [ 2 ]


The use of a drip chamber also allows an estimate of the rate at which fluid is administered. For a fluid of a given  viscosity , drips from a hole of known size will be of nearly identical volume, and the number of drips in a minute can be counted to gauge the rate of flow. In this instance the rate of flow is usually controlled by a clamp on the infusion tubing; this affects the resistance to flow. However, other sources of resistance (such as whether the vein is kinked or compressed by the patient's position) cannot be so directly controlled and a change in position may change the rate of flow leading to inadvertently rapid or slow infusion. Where this might be problematic an  infusion pump  can be used which gives a more accurate measurement of flow rate.


Drip chambers can be classified into macro-drip (about 10 to 20  gtts /ml) and micro-drip (about 60 gtts/ml) based on their drop factors. For a given drip chamber (when the fluid drips from the hole into the chamber) drop factor means number of drops per ml of the IV fluid. Flow rate can be calculated with the help of the observations from the drip chamber and its drop factor. The unit of flow rate is gtts/min, where gtts means  guttae  (Latin plural noun meaning “drops”).


Drug packaging  (or  pharmaceutical packaging ) is process of packing  pharmaceutical preparations  for distribution, and the physical  packaging  in which they are stored. It involves all of the operations from production through  drug distribution  channels to the end consumer.


Pharmaceutical packaging is highly regulated but with some variation in the details, depending on the country of origin  or the region. Several common factors can include:  assurance of patient safety, assurance of the efficacy of the drug through the intended  shelf life , [ 1 ]  uniformity of the drug through different production lots, thorough documentation of all materials and processes, control of possible migration of packaging components into the drug, control of degradation of the drug by oxygen, moisture, heat, light exposure etc., prevention of  microbial  contamination, sterility, etc. Packaging is often involved in dispensing, dosing, and use of the pharmaceutical product. Communication of proper use and cautionary labels are also regulated. Packaging is an integral part of pharmaceutical product. [ 2 ] [ 3 ]


Pharmaceutical packaging can often be thought of by the segment in the distribution system being encountered and by the functions needed by the user of the package.   Packaging requirements are different. [ 4 ]


Bulk pharmaceuticals can be shipped to another pharmaceutical company for further processing, to a  contract packager  for forming unit packs, to international customers, etc.               Bulk shipments might be in fiber drums (with plastic liners),  bulk boxes ,  corrugated boxes  with liners,  intermediate bulk containers , and other  shipping containers .


Smaller bulk packs can be shipped to pharmacies, particularly compounding pharmacies.  The liquids or powders can be measured and put into primary packages.


Shipments to medical professionals could be at hospitals, nursing homes, veterinarians, dentists, etc.    These packaged  pharmaceuticals are intended to be dispensed and administered by professionally trained and certified personnel.


Drugs under prescription control are sent to pharmacies in  multi-packs  of unit packs or in bottles containing many hundreds of capsules.     Typically  a pharmacist prepares the final form of the unit pack or places a lower count of capsules in a small bottle for the customer.  In a pharmacy, pharmacists are available to answer questions and to ensure that proper documentation is provided.  Internet pharmacies mail the prescribed drugs to the customer; boxes or mailing envelopes are used.  Child resistant packaging is often required on the unit packs; if requested, a pharmacist is allowed put drugs in a bottle with easy open features.


Over-the-counter drugs are sold in drug stores, grocery stores, and diverse retail outlets.  Usually the package needs to have all the usage information available.  Packages often need to have  tamper resistant  features and  child-resistant packaging .


Usually the packaging and labeling of  dietary supplements ,  homeopathic  drugs, and  folk medicines  are not regulated.  Some producers voluntarily follow the regulations for over-the-counter drugs or regional  Pharmacopoeias .


The wide variety of pharmaceutical solids, liquids, and gasses are packaged in a wide variety of packages.  Some of the common primary packages are:


Formed solid  unit doses  of pharmaceuticals ( capsules ,  suppositories ,   tablets , etc.) are commonly packed in blister packs.  In Europe about 85% of solid unit doses are packed in blister packs with only about 20% in North America. [ 5 ]


Blister packs are pre-formed plastic/paper/foil packaging used for formed solid drugs.  The primary component of a blister pack is a cavity or pocket made from a thermoformed plastic. This usually has a backing of  paperboard  or a lidding seal of  aluminum foil  or  plastic film . Blister packs are useful for protecting drugs against external factors, such as humidity and contamination for extended periods of time.


Blister packing machinery is readily available and is suited to validation processes. [ 6 ]


Bottles are commonly used for liquid pharmaceuticals as well as formed tablets and capsules.   Glass is most common for liquids because it is inert and has excellent barrier properties.   Various types of plastic bottles are used both by drug producers as well as by pharmacists in a pharmacy.


Prescription bottles have been around since the 19th century. [ 7 ]  Throughout the 19th and 20th centuries, prescription medication bottles were called  medicinal bottles . [ 7 ]  There are many styles and shapes of prescription bottles. [ 7 ]  Bottles would often include cotton to cushion powdery, breakable pills. In modern times, pills are coated, and thus the inclusion of a cotton ball is no longer necessary. The U.S.  National Institute of Health  recommends consumers remove any cotton balls from opened pill bottles, as cotton balls may attract moisture into the bottle. [ 8 ]


Prescription bottles come in several different colors, the most common of which being orange or light brown due to its ability to prevent  ultraviolet light  from degrading the potentially photosensitive contents through  photochemical reactions , while still letting enough visible light through for the contents to be easily visible. Other common colors include: Clear (for compounds that don't degrade in light), blue, dark brown, green, and various opaque hues. [ 9 ]


Many pharmaceutical products are sensitive to heat or cold. Controlled distribution systems and sometimes  cold chains  are  required.


A mail order or  online pharmacy  usually ships orders by mail services or by small parcel carrier.  The shipment is not temperature-controlled and it may sit in a  mail box  upon delivery.  Conditions can include high or low temperatures outside of the recommended storage conditions for certain products. For example, the  USFDA  found that the temperature in a steel mailbox painted black could reach 136 °F (58 °C) in full sun while the ambient air temperature was 101 °F (38 °C). [ 10 ]   Insulated mailing envelopes are sometimes used.


Larger shipments are sent in  insulated shipping containers  with  dry ice  or  gel packs . A digital  temperature data logger  or a  time temperature indicator  is often enclosed to monitor the temperature inside the container for its entire shipment.


Many dry pharmaceuticals are sensitive to moisture.  Tablets may become unstable and the drug may degrade.  High barrier packaging (including seals) is necessary but, by itself, is often not enough.
 Shelf life  of a moisture-sensitive drug can be extended by means of desiccants. [ 11 ]
Several types of dessicants are available; the type and quantity need to be matched to the particular drug and package.  One common method is to include a small packet of dessicant in a bottle.  Other methods of including desiccants attached to the inner surface or in the material have recently been developed. [ 12 ] [ 13 ]


Counterfeit drugs are a serious problem. People can potentially ingest useless or dangerous drugs without their knowledge. Custom package seals,  authentication  labels,  holograms , and  security printing  can be valued parts of an entire security system. [ 14 ]  They help verify that enclosed drugs are what the package says they are. Drug counterfeiters, however, often work with package counterfeiters, some of whom can be sophisticated. No packaging system is completely secure.


Medication packaging includes a document that provides information about that drug and its use. In the US, this information is overseen by the Center for Drug Research and Evaluation (CDER), a branch of the Food and Drug Administration (FDA).  For  prescription medications , the insert is  technical , and provides information for  medical professionals  about how to prescribe the drug. Package inserts for prescription drugs often include a separate document called a "patient package insert" with information written in  plain language  intended for the  end-user  -- the person who will take the drug or administer the drug to another person. Inserts for  over-the-counter medications  are also written plainly. [ 15 ] [ 16 ] [ 17 ] [ 18 ]


In the US the document is called "prescribing information" or the " package insert " (PI) and layperson's document is called the "patient package insert" (PPI). [ 15 ]   In Europe the technical document is called the "summary of product characteristics" and the document for end-users is called the "package leaflet". [ 19 ]


The bottle or box also has information printed on it, intended for the person taking the medication. [ 18 ]


All aspects of pharmaceutical production, including packaging, are tightly controlled and have regulatory requirements.   Uniformity, cleanliness ( washdown ), sterility, and other requirements are needed to maintain  Good Manufacturing Practices .


Product safety management is vital.  A complete  Quality Management System  must be in place.  Validation involves collecting documentary evidence of all aspects of compliance. [ 20 ]   Hazard analysis and critical control points  is a methodology which has been proven useful. [ 21 ]   Quality assurance extends beyond the packaging operations through distribution and cold chain management; Good  distribution  practice is often a regulatory requirement.  Track and trace  systems are usually required.


With a large portion of  pharmaceutical packaging being outsourced to  contract packagers ,  additional demand is being placed on specialty areas, i.e. specialty dosage forms. [ 22 ]


A  drug-eluting stent  (DES) is a tube made of a mesh-like material used to treat  narrowed arteries  in medical procedures both mechanically (by providing a supporting scaffold inside the artery) and pharmacologically (by slowly releasing a pharmaceutical compound). A DES is inserted into a narrowed  artery  using a delivery catheter usually inserted through a larger artery in the groin or wrist. The stent assembly has the DES mechanism attached towards the front of the stent, and usually is composed of the collapsed stent over a collapsed polymeric balloon mechanism, the balloon mechanism is inflated and used to expand the meshed stent once in position. The stent expands, embedding into the occluded artery wall, keeping the artery open, thereby improving blood flow. The mesh design allows for stent expansion and also for new healthy vessel endothelial cells to grow through and around it, securing it in place. [ 1 ] [ 2 ] [ 3 ]


A DES is different from other types of  stents  in that it has a coating that delivers medication directly into the blood vessel wall. The stent slowly releases a drug to prevent the growth of scar tissue and new obstructive plaque material which caused the original blood vessel stenosis, this clogging of a stent is termed  restenosis . A DES is fully integrated with a  catheter  delivery system and is viewed as one integrated  medical device . [ 4 ] [ 5 ] [ 6 ]


DESs are commonly used in the treatment of narrowed arteries in the heart ( coronary artery disease ), but also elsewhere in the body, especially the legs ( peripheral artery disease ). [ 7 ]  Over the last three decades,  coronary stenting  has matured into a primary minimally invasive treatment tool in managing CAD. [ 8 ]  Coronary artery stenting is inherently tied to  percutaneous coronary intervention  (PCI) procedures. PCI is a minimally invasive procedure performed via a catheter (not by open-chest surgery), it is the medical procedure used to place a DES in narrowed coronary arteries.  PCI procedures are performed by an  interventional cardiologist  using  fluoroscopic imaging  techniques to see the location of the required DES placement. PCI uses larger peripheral arteries in the arms or the legs to thread a catheter/DES device through the arterial system and place the DES in the narrowed coronary artery or arteries. [ 7 ]  Multiple stents are often used depending on the degree of blockage and the number of diseased coronary arteries that are being treated. [ 9 ] [ 10 ]


A drug-eluting stent (DES) is a small mesh tube that is placed in the arteries to keep them open in the treatment of  vascular disease . The stent slowly releases a drug to block  cell proliferation  (a biological process of cell growth and division), thus preventing the arterial narrowing ( stenosis ) that can occur after stent implantation. While such stents can be used in various arteries throughout the body, they are commonly placed in the  coronary arteries  to treat  coronary heart disease . [ 11 ] [ 12 ] [ 13 ] [ 14 ]  DES products are integrated medical devices and are part of a  percutaneous coronary intervention  (PCI) delivery system. [ 15 ] [ 16 ] [ 17 ] [ 18 ]


DES is a medical device with several key properties: it functions as a structural scaffold, physically keeping an artery open to ensure blood flow; the device has specific drug delivery features, and the chosen drug is critical for its effectiveness. The drug, the hallmark compenent of the device, is selected for its suitability in inhibiting  restenosis  and its  pharmacokinetics . Apart from the drug, the materials used in the fabrication of the device are also essential and are carefully chosen for their  biocompatibility  and durability in a biological environment, such as human blood; these materials must also withstand the constant motion of the heart's beat and be suitable for future patient imaging using  magnetic resonance imaging  (MRI) technologies, which employ high  magnetic fields . [ 15 ] [ 16 ] [ 17 ] [ 18 ]


Other components, such as the catheter design, also play significant roles in the device's overall functionality and effectiveness. [ 15 ] [ 16 ] [ 17 ] [ 18 ]


DES are typically composed of metal alloys, most commonly  stainless steel  or  cobalt-chromium , but can also be made of other materials such as platinum-chromium or  nickel-titanium . The stent is often coated with a  polymer  to control the release of drugs. The role of polymers in drug delivery is significant as they regulate the rate at which the drug is released into the surrounding tissue. [ 19 ] [ 20 ]  There are also polymer-free stents where the drug is directly coated on the stent or contained in reservoirs within the stent. [ 21 ] [ 22 ] [ 23 ] [ 24 ]


The design of the stent includes  struts , which are thin wire structures that make up the stent frame. The strut thickness can influence the stent's performance, with thinner struts generally being associated with lower  restenosis  rates and reduced  thrombosis  risk. [ 25 ] [ 26 ] [ 20 ]


Most DES are balloon-expandable, meaning they are mounted on a balloon catheter and expand when the balloon is inflated. [ 27 ] [ 28 ]  There are also self-expanding stents, which automatically expand when deployed. The very first stent, introduced in 1986, was of this type. [ 29 ] [ 30 ] [ 31 ] [ 32 ]


The stent tube mesh is initially collapsed onto the catheter—in this collapsed state, it is small enough to be passed though relatively narrow arteries and then expanded in its destination place, pushing firmly to the diseased artery wall. [ 33 ] [ 34 ]


The pharmaceutical compounds that DES emit are  antiproliferative  agents such as  sirolimus ,  everolimus ,  zotarolimus ,  paclitaxel  and  biolimus . These drugs help prevent the arterial narrowing that can occur after stent implantation. [ 35 ] [ 36 ] [ 37 ]  These drugs are also used for other purposes, that involve moderating the  immune system  or treating cancer. They work by inhibiting cell growth. In DES, they are used in very small amounts and for a short time, and only in the area where the stent is placed. [ 38 ]


There is a distinction between  coronary stents  and peripheral stents. [ 7 ]  While both are used to prevent the narrowing of arteries, coronary stents are specifically for the  coronary arteries , while peripheral stents are for any other arteries in the body. [ 39 ] [ 40 ] [ 41 ]  Peripheral stents are mostly  bare metal  ones; some peripheral DES, of the self-expanding type, are used in arteries of the legs. [ 42 ]


Bioresorbable  DES are made of materials that can be absorbed by the body over time, potentially reducing potential long-term complications associated with permanent stents. [ 43 ]


Atherosclerosis is a chronic disease that affects the large and medium-sized arteries. It is characterized by the accumulation of calcium, fats (such as cholesterol) and other substances in the innermost layer of the endothelium, a layer of cells that line the interior surface of blood vessels. Atherosclerosis is considered to be the most common form of arteriosclerosis, which refers to the loss of arterial elasticity caused by thickening and stiffening of blood vessels. [ 44 ]


Atherosclerosis can begin as early as childhood with the development of small "fatty streaks" within arteries. These streaks are essentially deposits of fat. Over time, these initial lesions grow larger and become thicker, forming atheromas (atherosclerotic plaques). [ 44 ]


Drug-eluting stents (DESs) are used in the treatment of atherosclerosis in both coronary interventions and peripheral arterial interventions: [ 45 ] [ 46 ]


DESs are used in the management of atherosclerosis in both coronary and peripheral arterial interventions. [ 7 ]  They help improve blood flow and reduce the risk of restenosis, thereby improving patient outcomes. The use of DESs is accompanied by appropriate medical therapy and lifestyle modifications to manage atherosclerosis effectively. [ 51 ]


Stenosis of blood vessels refers to the narrowing of the blood vessels, which can restrict blood flow to the organs and tissues. [ 20 ]  This condition is often caused by the buildup of fatty deposits in the arteries, a process also called atherosclerosis. [ 55 ]


In the context of stents, stenosis is a significant concern. Stents are inserted into a narrowed artery during a procedure known as angioplasty. The stents help to open up the narrowed artery and improve blood flow. However, over time, the treated artery can close up again, a condition known as restenosis. [ 20 ]


Restenosis, or in-stent restenosis, is a blockage or narrowing that comes back in the portion of the artery previously treated with a stent. [ 20 ]  Restenosis tends to happen three to six months after the procedure. [ 20 ]  Restenosis is even more likely to occur if a stent would not have been used. [ 20 ]


When restenosis occurs, another procedure may be needed to correct the problem, such as the placement of a DES [ 20 ] [ 55 ]  that gradually release a drug compound that suppresses cellular growth, thereby reducing the potential for blockage within the stent area itself. [ 20 ] [ 55 ]  This therapy significantly reduces the occurrence of adverse events post-stenting. [ 20 ] [ 55 ]


Technically, a DES in a mesh tube implant devices that is used in angioplasty procedures to treat stenosis of blood vessels and prevent restinosis: the stent, which elutes drugs, is implanted into the blood vessel to help keep the vessel open and improve blood flow. [ 56 ] [ 57 ] [ 58 ]  Specifically, drug-eluting stents are used in the treatment of various medical conditions usually at the site of stenotic or occlusive arterial lesions, but one of the primary medical uses is in the treatment of coronary artery disease. [ 59 ]  Stents are inserted into narrowed coronary arteries, where the narrowing is primarily caused by atherosclerosis. Stents are then expanded to open up the narrowed artery. Such stents gradually release a drug compound that suppresses  cellular growth , into the newly stented area, thereby reducing the potential for blockage within the stent area itself. [ 59 ]  Such blockage is termed in-stent restenosis (ISR). This in-stent blockage is most often caused by excessive  cell proliferation  or  thrombi  (blood clots).  Anticoagulation therapy  (blood thinners), has become a standard treatment following the placement of DES. This therapy significantly reduces the occurrence of adverse events post-stenting. [ 60 ] [ 61 ] [ 62 ]


DESs have played a transformative role in the management of coronary artery disease. These stents are tiny, flexible mesh tubes employed during percutaneous coronary intervention (PCI) to address narrowed coronary arteries. What sets them apart is their special coating, which incorporates a drug delivery system that enables controlled release of medication over a specific period, typically within the first 30 to 45 days following implantation. This medication aids in inhibiting the formation of scar tissue within the stent and subsequent re-narrowing of the blood vessel. [ 63 ] [ 64 ]


PCI is a minimally invasive procedure. It involves the placement of a drug-eluting stent (DES) in a coronary artery. This procedure, previously known as  angioplasty  with a stent, is considered non-surgical as it is performed through a small puncture in a peripheral artery, avoiding the need to open the chest wall. While bleeding from the puncture site was once a concern, advancements in PCI practices have mitigated this issue through the use of pressure bands and arterial closure systems. Modern DES/PCI procedures are generally painless, although some mild discomfort may be experienced. [ 65 ] [ 66 ] [ 67 ]  In PCI, multiple DES are sometimes implanted within a single patient; the decision to use multiple stents is typically contingent on the extent of the coronary artery disease present and the number of diseased coronary arteries that require treatment. [ 9 ] [ 10 ]