A Review of Improving the Efficacy of Coronary Stents Using Drug-Eluting Nanoparticles

Abstract

Cardiovascular disease is the leading cause of mortality worldwide, striking the homes of approximately 17.9 million people around the world each year. The most common cases are linked to atherosclerosis, the depositing of fatty plaque within the arteries. The large discrepancies pose the opportunity for much advancement in proposing novel treatments to treat it and replacing it as the world’s leading disease. One of the most recent and once-promising treatments was the use of coronary stents, however, this innovation poses many discrepancies, that if improved would significantly reduce the devastating effects of CVD. The following paper discusses the intervention of coronary stents within the treatment of CVD, and how drug-eluting nanoparticles and nano-surfaces can be used to increase efficiency.

Outline

1. The Circulatory System

2. Blood

2.1The Composition of Blood

2.2 Characteristics of Blood

3. Cardiovascular Disease

3.1 Atherosclerosis

3.2 Arterial Thrombosis

4. Coronary Stents

4.1 Bare Metal Stents

4.2 Bioresorbable Stents

4.3 Polymeric Bioresorbable Stents

4.4 Drug-Eluting Stents

5. The Issue With Coronary Stents

5.1 In-Stent Restenosis

5.2 Stent Thrombosis

5.3 Local Chronic Inflammation

5.4 Stenosis

5.5 Stent Surface Compatibility

6. Stent Coating Analysis

6.1 Magnetron Sputtering

6.2 Pulsed-Laser Deposition

6.3 Matrix-Assisted Laser Deposition

6.4 Molecular Layer Deposition

6.5 Coating Integrity

7. Stent Mechanics

8. Stent Geometry

8.1 Cells

8.2 Struts

8.3 Size

8.4 Stent Designs

9. Nanotechnology

9.1 Drug-Eluting Nanoparticle in Stents

9.2 Nanopatterning

9.3 Nano-Coatings

9.4 Nano-Surfaces

10. Stent Manufacturing

10.1 Laser Cutting

10.2 Water-Jet Cutting

10.3 Photoetching

10.4 3D Printing

11. Conclusion

12. References

1. The Circulatory System

The existence of the circulatory system would not be what it is known as it is today if not for William Harvey’s concept of travelling blood from one side of the heart to another through a wall. However, due to many gaps as well as an absence of microscopes, Harvey left the idea and instead altered it to describe our circulatory system as a system that simply used closed “tubes” to move our blood along the body, but the question still remained of how blood travelled so effectively.

Then, in 1661 Marcello Malpighi discovered capillaries: the smallest of our blood vessels that allow the transfer of blood from an arterial membrane to a venous membrane, and so set the entire foundation of the mammalian circulatory system.

Blood rushes through the human body every second due to our most vital internal organ: the heart. The heart has two pumps that can also be referred to as the left and right heart, which both consist of two chambers. Our blood travels in the heart with fluid mechanical separation due to these pumps. Fluid mechanical separation simply describes the way in which our blood moves from high pressure to low-pressure areas and then to high-pressure areas again all while moving from smaller passages ie. our veins and capillaries to larger passages such as arteries.

2. Blood

Photo by National Cancer Institute on Unsplash

The most vital fluid within our bodies is the blood that is pumped by our heart and rushes through pathways in our body every second of every day; providing our organs with much-needed nutrients and vitamins that would otherwise be halted. Blood is such a unique substance due to its properties and vitalness to organisms and is composed of many different substances that all work together to give blood its properties. Blood also has critical aspects that are integral to our health such as its effectiveness during flow around the body as well as the pressure at which it travels.

2.1 The Composition of Blood

Plasma is composed of 90% water and allows other corpuscular substances such as fats, proteins, electrolytes, minerals, and ions (sodium) to remain embedded as well as dissolved into the 90% component of water; transporting vital nutrients, fluids, and waste around the body.

Now that the liquid component of blood is complete, the solid component comes in, otherwise known as the formed elements. The aspect is essentially varying cells floating all throughout the plasma. These elements include erythrocytes (red blood cells), leukocytes (white blood cells), and thrombocytes (platelets).

Photo by Khan Academy on khanacademy.org

2.2 The Characteristics of Blood

pH Level of Blood

The pH level of blood is based on two ends of a spectrum of acidity and alkalinity ranging from 0 to 14. If blood is too acidic it will be closer to the right end of 0, while more alkalinity means it will be closer to the left end of 14. The pH level of blood is most healthy when it is between 7.35 to 7.45.

When blood has high acidity levels this can cause a series of problems such as nausea, vomiting, and fatigue. Acidic blood is often much darker in colour and can also be recognized under a microscope when the red blood cells are ruptured and irregular in shape. This is caused by ingesting too much sugar, meat, alcohol, and coffee to name a few. It is important to remember that dark red blood can also be caused by low oxygen intake and high carbon dioxide exhalation and the two should not be confused.

Blood is most healthy when it is more alkaline, and it will be a much brighter red colour with healthy red blood cells in their defined shape. Alkaline blood is often associated with a diet that is composed of more fruits and vegetables, which help to add oxygen intake into the blood. However with alkaline blood as well a high level can leave blood deficient in carbon dioxide with too many bases and too few acids, causing respiratory issues and tremors.

Photo of pH Level of Blood by crystalsheal.co.za

Osmotic Balance

Osmotic balance is a critical aspect of blood, which ensures that there is a balance between the blood-brain barrier. Blood requires osmotic balance as it is composed of water, mineral salts, and electrolytes, this balance ensures that each component is present and in appropriate amounts.

Proteins

Blood contains two main types of proteins that help with producing enzymes, antibodies, and hormones, which are albumin and globulin.

Albumin is a globular protein that is water-soluble and semi-soluble in salt concentrations, giving this protein a critical role in blood. It is due to this protein that small molecules that need to remain maintained are removed. These molecules include bilirubin, calcium, and prescription drugs. Bilirubin is a product that is formed when red blood cells rupture and break down, which causes a build-up in the blood. Calcium is also a critical aspect of blood, in which it allows blood vessels to effectively move blood across the body, as it helps with coagulation, however, extremely high levels of calcium can cause extreme clotting in the blood stopping blood flow. Albumin also allows the medications a person may be taking to remain in appropriate amounts and time in the blood as well as being dispersed throughout.

Red Blood Cells

Red blood cells also called erythrocytes are biconcave cells that specialize in the role of transporting oxygen to our tissues. Red blood cells are small and due to their biconcave shape extremely thin in the centre. These properties allow red blood cells to effectively transport oxygen to our tissues. The shape allows for easy flow throughout vessels and increases the surface area to volume ratio so that the cell can receive and release oxygen with its surroundings far more effectively. Red blood cells also lose their nucleus and mitochondria when fully grown. The absence of a nucleus allows more space for hemoglobin; a protein that helps the cell transport oxygen, and without mitochondria, a red blood cell can conserve more oxygen for tissue rather than using it for the growth of the cell.

Since red blood cells are also responsible for taking carbon dioxide from tissues to the lungs, hemoglobin can often bind itself to the carbon dioxide molecules. Red blood cells also carry an enzyme called carbonic anhydrases, which turns CO2 into HCO3 or bicarbonate. From here blood transports this bicarbonate to the lungs, which transforms this bicarbonate so that it can be exhaled as carbon dioxide.

White Blood Cells

Leukocytes can be broken down into two major groups with more specific types within them for a total of five forms of cells. The first group, called granulocytes is composed of cells that have granules present under a microscope, these granules in the cytoplasm are secretory vessels that allow the cell to diffuse substances. The three within these groups are The second known as agranulocytes have an absence of these granules and include monocytes and lymphocytes.

Overall all white blood cells are responsible for defense, however, in these five groups, their roles can be broken down further and more specifically.

Granulocytes are phagocytic, meaning they are the group of white blood cells that secrete neutralizers. Neutrophils, basophils, and eosinophils are most notable with neutrophils secreting a variety of substances to carry out inflammation resolution, which is to neutralize and lower the irritation caused to cells when inflammation occurs. Eosinophils excrete substances that help to counteract the effects of histamine. Although an organic compound that carries out many functions, histamine in the blood is responsible for dilating blood vessels, and basophils excrete heparin; an anticoagulant that slows the probability of blood clots forming within blood vessels.

Platelets

Platelets are also an integral part of blood. By being fragments of cells and not complete cells, platelets also called thrombocytes to break off from large cells called megakaryocytes. Platelets come together as they are sticky and attach themselves to each other to help seal tissue tears in vessels as well as form clots in the blood.

Clotting

Clotting most commonly occurs when blood is exposed outside the body when a cut on the body appears. When this takes place, platelets with rush to the site of the wound and begin to close it off due to their sticky characteristics and this attracts other platelets as well. During this process fibrinogen, which is another protein present in blood plasma and is soluble in water is converted into fibrin, where it loses its water solubility. This creates layers of sticky platelets and fibrin that do not allow further and excessive blood loss. This process is unique to blood and it was described that this takes place at the sites of wounds, however, clotting is possible completely inside the body as well.

3. Cardiovascular Disease

3.1 Atherosclerosis

Atherosclerosis occurs when the artery begins to narrow due to an unhealthy build-up of plaque in the artery. Plaque is sticky and composed of fatty substances such as cholesterol and fats, as well as cellular waste, calcium, and fibrin (a clotting substance). As the plaque builds up in the artery it begins to not only make the passage of blood flow smaller, but also begins to harden. Many problems arise with this, with the largest one being a chance of stroke as blood flow gets cut off.

This illness is a result of many factors that might include a high bad fat intake, little exercise, etc. Currently, treatments for this are heavy prescription drugs that will thin out your blood such as aspirin, which will reduce inflammation in the artery and change plaque consistency. A second treatment also exists aside from prescription drugs known as coronary stent implantation, which is often the best option if a patient has just had a heart attack as it immediately opens the artery to restore blood flow back to the heart.

3.2 Arterial Thrombosis

Thrombosis in the artery is caused by irritation (adhesion and activation) of fibrinogen, and platelets. Thrombosis also known as blood clots can take place in the artery when certain parts of the blood thicken, often this happens if a proper diet is not in maintenance, causing more red blood cells, more white blood cells, or too many platelets causing the blood to thicken. More obvious reasons to why blood clotting will occur in the artery are if the artery goes through an injury, although very rare arteries can become injured if they are not healthy they can interfere in other parts of the body and become damaged.

Clots like this, however, can be difficult as they have two parts, blood cells that are aggravated in large quantities and inflamed as well as stressed platelets that form this cluster that become very difficult to move especially in an artery where volume is already very small.

4. Coronary Stents

Coronary stents have been one of the many innovations and treatments developed for heart disease. In their earliest forms, coronary stents were described by the method in which they were inserted into arteries known as (POBA) or “plain old balloon angioplasty). With balloon angioplasty, a bare-metal stent was placed into the artery with a catheter and then expanded with medical balloon expansion where it permanently remained to allow for blocked passages to become open resulting in smooth blood flow. In today’s day and age, however, stents have taken many forms with improvements in shape, materials, and functions. Although stents have offered a solution to arteries clogged with plaque, they still pose much room for improvement.

4.1 Bare Metal Stents

Through the years many new ideas and designs have been made in regard to coronary stents. However, the first stents developed are known as bare-metal stents (BMS). BMSs were constructed with simple stainless steel with mixtures of cobalt-chromium, platinum-iridium alloys, as well as tantalum, and even nitinol to name a few. Although the first surgery in which this stent was placed showed an overall improvement in arterial health and blood flow, the stent posed many problems as well. For example, the highly foreign surface of the stent did not react well to the artery and caused severe tissue hyperplasia as well as the development of restenosis.

Despite these disadvantages BMSs have shown an efficient recovery time of the endothelium of an artery, being 12 weeks, this is significant as the endothelium a thin layer that covers in the inner of our heart and blood vessels become damaged due to a stretching of the artery, however, BMSs have shown the damage recovery time to be manageable.

As it is known, blood cells that are known as platelets are what allow blood to clot, and so aspirin therapy and clopidogrel are often given once the bare metal stent is inserted so that clotting does not occur. These are known as antiplatelet drugs and both have to be given on a schedule of six to twelve months after insertion.

Types of Bare Metal Stents

There are two types of bare-metal stents. The first type is balloon-expandable stents and the second is self-expanding stents.

Balloon expanding involves a catheter with a small medical balloon inserted with the stent inside of the artery. Once the components are inserted the catheter which is a rubber tube inflates the balloon with air or sometimes sterile water. Once the fluid starts to expand the balloon the stents begin to expand inside of the artery, beginning with the ends and then lastly the middle to ensure the stent stays in a proper position. The benefit of having a balloon expand the stent is that the radial strength is extremely high, which reduces the chances of the stent moving along the artery. However, with any stent, the possibility of crumpling still exists due to high compression, which is why these stents are best suited to be placed inside of the torso area.

Self-expanding stents are often more desirable for placement as they work with the contraction and release of muscles. These stents work particularly well in areas outside of the torso where they are least likely to move and remain properly placed due to external pressures. Self-expanding stents are most often made of nitinol an alloy composed of nickel and titanium. An issue that exists within these stents, however, is that they pose the possibility of obstruction due to a lower radial strength. Self-expanding stents also do not have the ability to be opened larger if it is small in the artery, and so this can pose issues.

4.2 Bioresorbable Stents

The introduction of bioresorbable stents was revolutionary as they had the ability to be dissolved within the body easily. Within bioresorbable stents two options existed of having the entire stent homogenous ie. the entire stent would gradually dissolve within the artery or simply the outer coating would be able to dissolve. This is because the initial coating would then be loaded with a drug that would slowly be released into the artery.

Due to a very effective dissolving capability, these stents must be applied with specific biodegradable as well as biocompatible materials and alloys. The most often used alloys consist of iron, magnesium, and zinc. The polymers used include poly-L-lactic acid, poly-L-glycolic acid, polyorthoester, polycaprolactone, fibrin, hyaluronic acid, phosphorylcholine, or polyethylene oxide/polybutylene terephthalate, and these are all able to be absorbed safely into the human body. The timing for this differs based on each person, however, generally after a few months, the stent will begin to degrade.

Due to their incredible degrading ability, bioresorbable stents avoid the variables of dangerous foreign reactions, are a permanent device located inside the artery, and are desirable for those who need surgeries often.

However, in comparison to bare metal stents, bioresorbable stents lack strength and will completely dissolve into the artery after one to two years. After this dissolving, the artery will no longer be held in place with a stent, and so this poses the possibility of the artery narrowing once again.

Bioresorbable Stent Layers

One of the latest designs of a bioresorbable stent is one that excretes nitric oxide (NO) into arterial vessels. Using this stent as a model, the most integral parts of the stent can be seen. The first layer is a bioresorbable scaffold which is essentially the foundation of the stent, being the main polymer that has the ability to resorb. Secondly, a resorbable coating, and lastly NO-nanoparticles are incorporated into the coating. This is as far as BRSs have come, so it is important to take a closer look at each layer.

4.3 Polymeric Bioresorbable Stents

Polymeric bioresorbable stents when created were a significant upgrade from BRSs as they allowed for a more focused aspect of local drug delivery. Polymeric biodegradable stents incorporate a biodegradable polymer along with polymeric nanoparticles with an emphasis on how both prospects can best be combined. Currently, the most often used polymer for the manufacturing of biodegradable stents is Poly-L-lactic acid (PLLA). PLLA is highly effective in biocompatibility within the body as it has low toxicity levels and excellent absorption rates. PLLA is so safe it can also be used in food handling, however in different forms, PLLA can be highly toxic to the human body. As a vapour or liquid PLLA has the ability to be extremely toxic if inhaled or absorbed. Although this is avoided since PLLA has a significantly high melting point it is unlikely of it moving into these states within the body.

PLLA incredibly has the ability to be manufactured without any toxic or waste products. PLLA is effectively dissolved in the body through a process that takes anywhere from twelve to eighteen months with the Krebs cycle, this results in this reaction to form carbon dioxide and water, which are then absorbed by the artery. However, these advantages are often short-lived as a study conducted showed that these stents still lack mechanical properties, such as mechanical strength in which a stent implanted after three months rapidly lost its strength causing many disturbances within the artery. A lack in mechanical strength can cause the patient discomfort as well as pose the possibility for it to move from its place in the artery.

There have been numerous variations of biodegradable polymers that each have benefits in treating factors such as drug release and inflammation. This is because along with PLLA, poly(3-hydroxybutyrate) and poly(ε-caprolactone) have been highly used within bioresorbable stent research. Among the stents a number of biomimetic polymers have also been used modeling from natural aspects in nature, these are known as phosphorylcholine (PC) and poly(vinylidene fluoride)-hexafluoropropylene (PVDF-HFP). Other variations include a stent that due to the variation in polymer also has a slower drug-release pattern, made with poly (iodinated desaminotyrosyl-tyrosine ethyl ester) and is a carbonate stent with sirolimus. In addition to this one of the latest designs in BRSs is one made with poly-anhydride and coated with salicylic acid and sirolimus which helps to reduce any inflammatory characteristics as well as proliferative which means the spread or multiplication of cells that the stent can impose.

The lacking in this generation of stents still resides even with the many generations in aspects such as mechanical strength, effective degradation, and dissolving of the stent, as well as the absence of any toxic waste products that can harm the artery.

4.4 Drug-Eluting Stents

Through each generation, it was quickly realized that due to the high risk of inflammation, clotting, and proliferation, stents need to exhibit characteristics to counteract these effects, which is where loaded stents began to emerge.

As a general classification, these stents involve often anti-inflammatory or anti-thrombotic drugs that lie on the surface of the stent or are incorporated into a coating that is then released into the blood vessel. The first generation in this category was made of stents that had sirolimus and paclitaxel excretion and were composed of a biodegradable polymer that although lowered inflammation vascular healing time was much longer.

Other created stents being the second generation within this category were composed of zotarolimus- and everolimus-eluting properties and significantly reduced hypersensitivity, were highly flexible, and had an appropriate amount of recoil as well as compliance, meaning its loss of stiffness was not as severe.

Bioresorbable drug-eluting vascular scaffold stents were then developed as they had the ability to completely dissolve and the entire stent had the ability to act as a drug holder, however, this stent type still lacks a difficulty in implantation within blood vessels.

After seeing the value of a bioresorbable stent and the mechanical strength of a metal stent. Combining these two characteristics was one of the most optimal options. A bioresorbable metal stent was developed made of magnesium as well as a mixture of other metal elements. Magnesium is present in the human body at a total of approximately 25g. The dissolving of the magnesium was beneficial as it effectively dissolved after four-month, without inflammation, and also offered a magnesium supplement to arterial tissue, which is beneficial for growth.

As a part of this category, stents were also developed that use DNA miRNA, and siRNA, as well as nanoparticles, to enhance drug-emitting properties. Although incorporating these properties can make the stent design and structure far more complicated, one of the most feasible and effective designs developed was made by a 3D printer, which printed a PLLA stent and later had a coating of sirolimus-loaded PDLLA (Poly DL Lactide) nanoparticles put on it.

However, as promising as the effects of incorporating nanoparticles are in stents, most designs have leaned towards a simple coating, as it can become difficult to effectively carry this out in the stent. An example of this is using the drug sirolimus, which reduces inflammation in tissues. Far more stents have been developed with coatings as it is far easier to omit the polymers required in nanoparticles and add these coatings on a bare-metal stent. However, nanoparticles in stent design still hold great promise and so in order to progress further with this surface modification needs to be looked at. The progress involves looking precisely at where the drug localization would need to occur and positioning this on the stent in this way, how the drug will sit and deposit is also an integral factor. The localization and deposition may consist of a system of microporous surfaces, nanoparticles, or a simple drug reservoir, wherein certain parts of the stent the drug will accumulate and release into the vessel this can be achieved by altering something as simple as the grooves on the stent. Many current designs involve microporous surfaces loaded with sirolimus, using a passive carbon coating to prevent corrosion of the stent.

By looking at the many different variations it can be seen how in each case materials, coatings, and the resulting design of the stent allowed for certain characteristics to be better than the others, so it is crucial to look at each material, coating, and stent design to compare and see which holds more opportunity for improvement.

5. The Issue With Coronary Stents

From the beginning of their creation to reopen arteries it was quickly seen that although created to open the arteries due to the complexity of the artery and blood’s makeup, the stent became a disruptive innovation that could itself begin to cause many issues within.

5.1 In-Stent Restenosis

Restenosis describes the growth of scar tissue in the artery. This can happen when a stent is first implanted into an artery and will form over time depending on the environment of the artery. Since restenosis deals with the muscle tissue present in the artery, the process can be seen as this: once the stent is implanted tissue with actually begin to grow inside of it, and this is fine as this is healthy tissue that will help to keep the stent placed properly in the artery and will allow blood to flow smoothly. This, however, becomes a problem when tissue underneath the healthy tissue can become neointimal as in coarse scar tissue, and begin to narrow the artery. As a foreign object that can react easily with blood, a stent becomes problematic in this sense.

5.2 Stent Thrombosis

Earlier learning about a thrombus we can describe it simply as a cluster of red blood cells, and platelets that have come together and formed a sort of plug, and that these can be signaled if injury occurs or if simply there are too many components in the blood making an imbalance. This can then occur with the variable of the stent as the stent can cause inflammation to the artery as well as possible injury, which will then cause the red blood cells and platelets to rush to the site in defense, resulting in a clot.

5.3 Local Chronic Inflammation

Local chronic inflammation is different from general inflammation that may be caused by the stent as being chronic it lasts much longer and can reappear due to the extent of inflammation caused by the stent when it was implanted or inflated. It is important to remember that over time as the stent sits in the artery can begin to reject its presence and cause inflammation in this way as well.

5.4 Stenosis

Stenosis is caused as a result of the stent when far too much tissue begins to grow inside the stent making the artery more narrow, this happens when the stent can give conditions for the tissue to grow, which is why when looking at improvements it is important to consider drugs that can be added that will not harm the artery but also prevent the growth of smooth muscle and endothelial cells inside the stent.

5.5 Stent Surface Compatibility

Surface compatibility is a topic within the stent that can become quite specific when thinking about drugs and coating that can be added, but simply looking at blood and a simple surface of a stent, a high chance of clotting exists. This is because of blood’s inherent inclination to react quite aggressively to foreign objects and will stick to them forming clusters of blood that over time can form clots and block arteries, so improvement lies in making a surface that does not allow blood to stay on but rather slip off.

6. Stent Coating Analysis

Due to blood’s extreme reactions to foreign objects because of its complicated makeup, the material and coating surrounding the layer are critical. With the correct material and coating, the stent’s effectiveness significantly increases, preventing corrosion as well as strength and clotting of the blood.

Most commonly coating modifications to the stent have been made in relation to the addition or subtraction of different oxides and nitrides of metals. The base of the stent, however, remains in only the accumulation of the foundational metals and polymers. There are many ways in which these substances are accumulated to form the surface and foundational layers of the stent. For now, when discussing the coatings this is known as chemical surface modification as the coating is not always applied but father facilitated through various methods such as magnetron sputtering, pulsed laser deposition, and matrix-assisted pulsed laser evaporation. Coatings and properties within them can also be facilitated through molecular layer deposition, with the most recent and promising featuring salinization features.

For now, although these are ways and processes in which the stent forms this coating, it will be referred to as coatings themselves, as the desired stent properties are achieved with this.

6.1 Magnetron Sputtering

Magnetron sputtering involves depositing a thin film onto a stent using gaseous plasma. To get this thin film onto the stent, the stent is essentially put into a vacuum chamber to avoid the interference of any other gases. The surface is then essentially cleaned, which means all ions in the gaseous plasma corrode the stent, once this has taken place the atoms then travel freely and begin to deposit as a thin film on the stent, most often gases such as Xenon and Argon are used for their versatility.

6.2 Pulsed-Laser Deposition

In a pulsed-laser deposition, a similar result takes place where a thin film is formed on the stent. In this method, however, a vacuum chamber is in common on the later hand a high-energy laser beam is directed through it to achieve the thin film. How this works is the material of the stent, which may be a polymer or a metal is vaporized into a plasma plume. The plasma plume, which is essentially free carbon atoms that do not have a defined structure starts to accumulate onto the stent. This method of deposition can occur in a vacuum although background gases are not entirely avoided, as an example with oxygen, when depositing oxides the film can become fully oxygenated and therefore help to deposit oxides and also oxygenate the thin film.

6.3 Matrix-Assisted Laser Deposition

The last mechanical deposition method known as matrix-assisted laser deposition, is similar to a pulsed-laser deposition in which a laser is used for the ionization of particles onto the stent surface, however, with matrix assistance biomolecules such as DNA, proteins, and peptides can form ions through laser desorption when mixed with organic compounds that can act as a strong crystalline structure that can absorb the wavelength of the directed laser. This method can then facilitate the types of stents seen earlier, that were coated with genes as an example.

6.4 Molecular Layer Deposition

Lastly, molecular layer deposition (MLD) is a relatively new concept in which it involves the foremost understanding of atomic layer deposition (ALD). ALD is a method in which two reactions take place in sequence, which has allowed for the creation of many integral features such as the coating of nanoparticles as well as deposition on porous substrates. With ALD the reactions that take place to form the thin film on the substrate have a special characteristic in which the two sequential reactions that take place are self-limiting. So, once the reaction is no longer experiencing changes in concentration it is inert and will begin to saturate onto the substrate in this case the stent and form the film in a very thin manner, as all other sources will be depleted and so the film can be self-directed in this manner. MLD then is closely identical but molecular substances such as DNA, nanoparticles, and peptides are some of the few varieties.

The method of magnetron sputtering produces a better film with enhanced quality however, can be extremely high cost-wise.

Coatings are an incredibly important part of the stent as they also have the ability to facilitate the rate at which the stent releases biological ingredients such as drugs or anti-inflammatory solvents that may be loaded into or onto the stent.

6.5 Coating Integrity

The coating of a stent plays a major role in its ability to function in the artery safely and effectively without the many issues that can take place. Some of these issues include severe cracking, delamination, and peeling off of the coating, which then gives the opportunity for clotting.

The mechanical stress that is placed upon the stent is often what causes this to take place, and as learned the strut crowns experience this the most, which is why the origin of crackling begins from here. This most often is a result of when the stent is crimped or inflated, although there was no immediate corrosion or peeling of the coating, it was seen that again at the area of the strut crowns, there were micro-sized cracks, that could potentially go on to complete corrosion of the stent, causing structure fracture and serious issues in the artery.

7. Stent Mechanics

Within the mechanical aspects lie many key aspects of the stent that are specially characterized due to their importance in-stent efficiency.

1. The Young’s Modulus
2. Radial Strength
3. Acute + Chronic Recoil
4. Yield Strength
5. Ultimate Tensile Strength
6. Elongation
7. Radial + Axial Flexibility
8. Deliverability
9. Profile
10. Lifetime Integrity

Each of these characteristics plays an important role in the efficacy of the stent, however, often it is due to these characteristics that one can be taken for granted if one is prioritized over the other. All of these factors affect how the stent will be made, what the strut will be like, the material of the stent, shape, as well as size.

The Young’s Modulus characteristics of a stent essentially describes how stiff the material of the stent is. Often numerical equations are used to measure this, thus in cases such as this, it is beneficial to think of YM (Young’s Modulus) as the amount of stress or strain on the material.

As the stent is in a cylindrical shape radius, diameter, and circumference are all integral aspects of the design. In particular, the radial strength ensures that the stent does not easily become compressed and lead to deformation of the stent.

Acute and chronic recoil of the stent describes a stent’s ability to maintain its inflated and solid shape. This is an important factor for two reasons, the first as over a patient’s lifetime the stent will begin to move back into a smaller shape as it is compressed against the artery. Secondly, if the stent is a balloon-inflated one, there is a high chance of little recoil taking place, which can be negative as then it will not sit effectively in the artery.

Yield strength is what expresses the mechanical strength of a material, mechanical strength is extremely important as it is a characteristic of an effective material to withstand load without being compressed significantly or going through plastic deformation, which refers to any material that goes through compression, but it left with a permanent tear, bend, or elongation to name a few.

Ultimate tensile strength is then similarly a measure of how much the stent can withstand but deals with it while the elongation and stretching of the stent may be taking place, both horizontally as well as vertically.

Then speaking of elongation this is a highly discussed factor as the results can often be unpredictable. In studies conducted it was shown that after the implementation of the stent in the artery approximately 67 stents elongated in the artery, with 16 shortenings and 17 having no visible changes.

The axial flexibility of a stent refers to how much the stent can endure axial stiffness, which is how one can measure the amount or quality of deformation a stent may receive from both a shortening in the stent that can be resulted from compression or elongation due to tension in the artery.

The deliverability of a stent is overall how well it can sit and remain in many different artery environment types. This is often because the acidity of arteries can vary based on the alkalinity and acidity of blood as well as arteries can be tortuous which means they can be looped and shaped irregularly with sometimes knots and or kinks, in this case, deliverability becomes vital as well as flexibility as moving a tortuous artery can be extremely dangerous to the patient and they are often corrected during surgery and stent as tortuous arteries are more likely to form clots.

Stent profiling involves finding the maximum diameter of a stent that is not yet inflated or expanded, once this measurement is found the maximum diameter of the artery can also be determined, and this is critical as the artery has an endothelium layer that is very thin and controls many of the artery’s enzymatic controls, such as blood clotting and the immune system of the artery which makes it less susceptible to infection. The endothelium also controls vascular contraction and relaxation, being a flexible membrane in the artery if it wears or tears this would make these contractions and releasing of the muscle extremely difficult.

Lastly, the variable of lifetime integrity is most possibly the most crucial aspect of a stent. When a stent is inputted although its immediate effect of widening the artery is carried out quickly, it is required to keep a stent in for a lifetime, so that the same state of narrowing does not return. Therefore, stents are implanted permanently and are required to have high efficiency in all of the characteristics to effectively last for a person’s lifetime.

Each characteristic discussed is highly significant, however, often if one characteristic is far better than another the others can be compromised, which leaves room for much improvement as we want all of these characteristics to be as efficient as possible, however, some are often overlooked due to design characteristics. Factors such as manufacturing methods, strut shape, stent shape, design, and size as well as material all affect the stent’s mechanical characteristics and integrity.

8. Stent Geometry

8.1 Cells

1. Open Cell Design

An open-cell design is one that has gaps in it, so the cells each cell for example may not be connected to another one but rather have a gap, and this characteristic is quite random, some cells may have it while some may not. Although it may seem that this randomized characteristic serves no purpose it can actually be quite effective with longitudinal flexibility. However, because of the gaps at the bends in the stent, there is a lower drug holding capacity, however as certain parts are inclined more inwards, this can make certain parts hold a larger quantity of the drug.

2. Closed Cell Design

A closed-cell design describes the way in which the stent geometry is implemented so that the shape of the struts when they come together is connected in such a manner that they have their struts connected from the tip at all times so that there are no gaps. A closed-cell design maximizes the effectiveness of the scaffold of the stent, which is simply another term for the structure of the cells. The image below describes this as taking one cell from the image the scaffold is the outermost part of it encompassing the drug and polymer.

With a closed-cell design, the radial strength is also oftentimes much higher making it much more desirable. Part of this has to do with the simple fact that the yielded strength of the stent overall will be higher with a closed-cell rather than an open cell. In terms of plaque buildup, the closed-cell design is more efficient as it lowers the likelihood of plaque prolapse, which is when tissue extrudes from the stent’s struts causing scar tissue. Closed cells also offer efficacy and consistency when bent, and so this can help in aspects such as drug release where the drug will be released consistently as the amount and concentration of the drug in the stent will be the same.

3. Open-Closed Cell Design

Both designs have benefits as well as some downfalls, which is why a design that combines the two was created. A hybrid of the two types of cells can make a significant difference. For example, adding a closed-cell design in the centre while making the outer area open cell can improve core integrity while also including the variable of longitudinal flexibility.

In conclusion, when manufacturing the stent it is imperative that the correct cell type is chosen as it significantly affects the scaffolding, drug reservoirs, mechanical properties, and overall strength. Cell choosing, however, is most imperative for its impact on vascular dynamic bending. This bending was found to occur most often in the bridging part of struts on a stent, and along the axis of the stent both horizontally and vertically the most pressure and force were in the middle cells of the stent, and breakage and fractures are more likely to take place here.

8.2 Struts

Thickness

Prior to new designs in previous stents struts use to be quite thick as this improved ultimate strength, however, thick struts were found to have an adverse effect on the conformability within the artery, and with this, it was very uncomfortable for the patient. Decreasing the thickness of the strut was valuable in many ways such as lowering the chances of neointimal obstruction, which is the formation of scar tissue after the stent is implanted as well as simple inflammation.

Although making struts thinner significantly helped the comfortableness and delivery capability of the stent it also lowered its visibility as making thin struts is when a polymer is involved that can allow thin struts to be manufactured and still hold integrity, but unlike a metal stent one with thin struts will not show up on an x-ray imaging machine. As discussed above once again a stent with thin struts will be significantly lower than one with thicker struts. However, to avoid this alloys with cobalt and chromium have been used to make this effect a little less impactful, however, there is still a significant need for improvement.

Types of Struts

Both round and square-cross section stents have been used most often and both serve their own benefits. Interestingly, the more struts the stent has the more likely restenosis is to occur, so a lower number is more preferred.

Strut Crown

A strut crown is two struts, this can best be explained by imaging a single unit cell of a stent, this is one stent crown as the tip is formed by connecting two sides or struts.

This can be seen exactly here where the tips of when two sides are coming together can be seen as already week. It is due to these weak points’ tendency to be weak that causes breaks and tears in the crown. A key point to take into account for the strut crown is the curvature of radius, which is simply the outward measurement of the curve that is present at the tip of a strut crown. With this the smaller the radius of curvature becomes the more prone the stent becomes to deformation, and for the latter if larger the stent is less likely to be deformed under pressure. What this can then cause is the coating of the stent to lose its strength and properties.

To prevent or to improve this adverse effect some changes can be implemented. One change that can be made is decreasing the number of strut crowns formed. The more straight parts of the struts can also be taken and made to have their maximum curvature of radius, and finally, a better and more efficient type of strut crown can be designed so that deformation does not take place.

Since strain is most severe in these crown areas, it is important to note that strain and the curvature have a special relationship in that they are inversely proportional, so as the strain gets more severe this means that the curvature is smaller. So, for this, we can add flat areas that have a higher radius of curvature or simply areas with higher radiuses of curvature. A higher radius would mean simply stretching the crown out more horizontally, this would then in turn also cause the stent to gain some size horizontally, so this aspect needs to be carefully looked at.

8.3 Size

The general size of a strut is about 100 μm. However, ultrathin struts that are more efficient in conformability can be 60 to 80 μm.

Smaller struts are less likely to break or have weak points than larger struts.

Overall studies have shown that a smaller stent does decrease the risk of clots as well as in-stent restenosis, however, a smaller stent can lack in many mechanical areas, such as strength and integrity.

To conclude struts most generally have the most improvement out of the many stent features. As an example struts are aligned on the vertical axis of the stent, however, studies are investigating how multi-angled struts may be more efficient in adding more strength and integrity. Since the struts play such an important role in the drug reservoirs as well, there is potential in having the struts placed differently, although the best positioning is not yet determined in how we can change this to have a more uniform and smooth releasing of any loadings, other features include curvature, strut crown improvement, etc.

8.4 Stent Designs

Due to how they are implanted in the artery the stents have been given different design names based on this.

1. Overlapping Design

The overlapping design is one that can be very beneficial for better coverage of the artery as well as increased mechanical strength. The overlapping stents go through an especially unique phenomenon where the struts on the stents do not make contact with the surface but with the edges only, it may seem that in the figure above it that one stent is lying on top of the other, however, in this type of design the struts essentially lock into one another, by resting with each other’s edges. This works only because of normal deformations that the stent may go through during the process of planting it into the artery as well as its circular structure plays an important role in it as well, as being in this shape does not give it much already developed strength.

Improvements to this design exist as well, with the most notable being overlapping stents that have sawed teeth essentially on the overlapping area, so that when pressure is applied to the stent with the balloon and catheter the sawed in edges that resemble teeth lock slide on top of each other and then after released they lock with each other. Tests conducted with these overlapping stents showed that the cross-sectional area, which is how large the radius essentially is in this case, or how large the stent is open. With this also little to no plastic deformation took place and there was very little recoil as evidenced by the cross-section. This is why this variation has been given the name

2. Depot Stents

Depot stents are another special type of design as they are not surface modified and so do not have usual obvious drug cavities, as it was found that putting these can lower many of the mechanical properties. Although a physical depot stent of this kind was not created a finite element analysis was used. In this way the improvement of adding very micro-sized drug reservoirs to see if mechanical integrity would improve. In this analysis, they created micro-sized reservoirs that were perfectly sized and spaced out from each other, and what resulted from this was that the strut crowns remained the most strained parts of the stent. However, without the holes or drug reservoirs, it was found that strain was reduced and the pressure was more even across the whole stent.

3. Slotted Tubular Stents

The stent surface in this has certain parts that are “caved” inwards thus the slotted tubes, and with this design, it simply served as another type of design that offered a different method of eluting drugs. With this, the surface is slotted as can be seen in the image above. The slots are micro-scaled and are said to function as antiproliferative agents that help to stop the spread of malignant cells. These properties can also be enhanced by adding a layered carbon coating, which will also increase the hemocompatibility of the drug reservoir that is formed as a result of the slotted surface.

9. Nanotechnology

Nanotechnology is the study of how matter behaves and changes on extremely small scales. This is why nanotechnology has the ability to be used for many purposes such as enhanced and lightweight materials, as well as drug delivery, through organic, inorganic, and synthetic means.

9.1 Drug-Eluting Nanoparticles in Stents

Currently, although there are drug-eluting stents that do help relieve inflammation in arteries the major problem is that these stents have been shown to stop endothelial cells grow; in addition to this they also obstruct the natural endothelial lining in the artery. The endothelial lining releases natural enzymes that help with inflammation as well as contraction and relaxation of the arterial muscle. It is because of this lining that thrombosis is limited in the artery, but with its obstruction, the likelihood of thrombosis increases as well as the formation of scar tissue, as the underlying muscles are touched and the plaque formation can break out causing severe thrombosis. This is why the discussion of incorporating nanoparticle eluting features is necessary as it may help to relieve the stent of these features.

Thrombosis deals with plaque, however, another process occurs known as restenosis, and this is when injury to the artery takes place causing smooth vascular cells to report to the region. A lesion with cells that come together to the site creates this essential structure that is fatal to the vessel and can very quickly cause restenosis. Most easily this can be imagined as a soft structure of cells that are bunched up around weaker or damaged parts of the artery, and so although implanting a stent can reduce the effects, the cells can attach themselves to the stent and move into the parts tightly, which lowers the effectiveness of the stent making its surface stressed this problem also lies in the struts.

Although these have proved to be quite effective the factor of rupture in the endothelial line still occurs, and unless the patient takes further anti-thrombogenic and anti-inflammatory medications, the potential of clotting is very high. Improvement in this area will require a stent that can prevent vascular smooth cell formations around the artery but also exert a substance that can help to regenerate the endothelial cells. In this case, studies have gone significantly into nitric oxide (NO) donors. Donors mean that they are essentially made to release nitric oxide in vivo and in vitro, and the applications of NO are absolutely amazing as they have many functions. One function as an example is the release of prostanoids, which release substances that deal with blood flow, clotting, and inflammation. NO donors also lower the process of platelet clustering and they can produce radicals without oxygen which is critical as a radical which is a highly reactive molecule with unpaired electrons will want to bind with other molecules to find an electron, and this part is fine as long as there is not oxygen as reactive oxygen is lethal to cells as they will react and can damage further substances such as lipids, proteins, and nucleic acids.

So, this is where the intervention of drug-eluting nanoparticles can significantly help, as they can be added on to actively deliver drugs to the targeted areas, so that the endothelium can be healed, plaque can be taken care of and restenosis can be limited.

Currently as can be seen earlier in the paper, most of the stents that can elute drugs are to be classified as DESs, as they use a blended coating to create drug reservoirs that can be released into the artery over a prolonged period of time.

As it was seen how urgent the issue of the obstruction of the endothelium and the possibility of restenosis is, currently those driven through nanotechnology are classified by two properties. The first characteristic is a nano approach to avoid restenosis, and the second is an approach so that the endothelium can be healed, currently, the combination of the two is difficult, and therefore one must be compromised for the other.

For the anti-restenosis method, studies have been conducted using nanoparticles that can deliver small amounts of anti-proliferative and anti-inflammatory drugs that can avoid neointima formation within the stent. Another method includes using the heat excreted by inflammatory cells to activate nanoparticles, the strategy would use this then only when if the nanoparticles were able to detect if inflammation was to occur. Nanoparticles in themselves can also aside from stents have the ability to effectively deliver drugs maximizing the effect of the drug, while also preventing any toxic substances from harming the artery. The question still lies in how we can implement the nanoparticles best with stents so that the artery can accept the stent, and no toxic substances are excreted.

Taking a closer look at re-endothelialization then studies have been conducted using nanofibrous scaffolds of a stent that essentially act as the extracellular matrix in blood vessels, which includes mainly proteins, elastins, and collagen. Another excellent method executed used magnetic nanoparticles that were then attracted to the metal stent, and then from there would release their drugs at the active site. The only condition with this is that this would need to be conducted in a key environment that is under a magnetic field.

In another approach a liposome nanoparticle was loaded with a bisphosphonate, a class of drugs composed of Carbon, Oxygen, Phosphorous, and Hydrogen, therefore making it a phosphonate or a phosphonic acid that is easily soluble in water, which makes it an excellent drug to use as well as its ability to stop the overgrowth of macrophages (white blood cells) and monocytes (white blood cells) which can make their way into the artery and induce clotting if an infection is detected as they fight off bacteria. A test conducted with this significantly reduced the formation of scar tissue and stenosis in the artery. This was carried out through an alendronate liposome, in which a liposome is a type of nanoparticle that mimic the cell membrane of natural cells and is composed of lipids that have a head and tail group and in this certain parts attract and are soluble in water while others are not. The alendronate part in this refers to another chemical group that is a hydrated bisphonate salt, that helps to regulate bone mass, and this is useful in arteries as calcification can take place in arteries and can help to lower the levels softening the artery by lowering serum levels of calcium as well as phosphate so that the growing rate of minerals can be maintained in the artery.

A study conducted used for the reduction of in-stent restenosis used albumin structured nanoparticles loaded with paclitaxel and when used alongside bioresorbable metal stents it was found to avoid toxic excretion, which is extremely useful when considering future applications and improvements.

Another example of a nanoparticle-driven application was using a liposome that held prednisolone, which is a medication that is used to commonly treat allergies or inflammation. This method in particular was made to target chondroitin sulfate proteoglycans (CSPGs), which are more specific parts of the extracellular matrix in the blood vessel, and they are responsible for factors such as cell growth and adhesion, therefore targeting them allows the nanoparticles to actively release the drugs in CSPG concentrated areas that are resulted from stent injuries and help to reduce issues present within atherosclerotic rabbits, on which the test was conducted.

Nanoburrs are a relatively novel polymeric nanoparticle therapy that was created to target IV collagen by encapsulating paclitaxel and having it released over an arterial stenosis present in a rat carotid, which are large arteries on the side of the head and brain. In another approach, similar nanoparticles were loaded with the drug paclitaxel, which is used to target platelet tissue factor, a protein encoded by an F3 that initiates coagulation and is present in subendothelial cells and can become very severe if there is an injury from the stent.

In another approach, the stent was the object involved in helping the nanoparticle find its way to the area. This was done by a developed magnetic nanoparticle loaded with paclitaxel and in addition to high biocompatibility, the magnetic nanoparticle is magnetized towards the stents struts and the arterial tissues with a magnetic field making the transport of the nanoparticles as well as the prevention of resistance quite effective.

A strategy with similar components but a new method used to help regenerate the endothelium utilized cell therapy that was responsive magnetically, and this was done by taking ECs which are endothelial cells that had magnetic nanoparticles loaded into them and then put into the carotid artery of a rat. Then when a magnetic field was applied the particles moved to the target area near the stent and attached themselves there. Although offering promising results the ECs still need further research so that they can be applied on a long-term basis after they have reached the surface of the stent.

In the last two novel methods PDGF, which stands for platelet-derived growth factor since it has quite a large role in restenosis was targeted and therefore imatinib mesylate, which controls and inhibits the growth of the platelets was put to surround a bioresorbable stent that incorporated eluted polymeric nanoparticles and was predicted to inhibit the formation of scar tissue as imatinib mesylate is a PDGF receptor tyrosine kinase, and a receptor tyrosine kinase is a subclass of simple tyrosine kinases that maintains cell and cell communication, therefore regulating cell growth as well.

This was carried out on a pig artery as well as in cell culture and the result from this showed that the imatinib nanoparticles reduced a severe production of smooth muscle cells and this was after the target molecule was shown to be inhibited {phosphorylation of PDGF receptor-β} but there was no effect on the endothelium. On the other hand in the pig artery, there were also promising results in particular for scar tissue formation which was reduced by 50%. Although this did reduce the activity of mitogen-activated protein kinase in the artery, which is a protein kinase derived from amino acids that can help to reduce inflammation, it was seen that the inflammation did not increase and the endothelium was not affected. So, it can be concluded that this method does offer an opportunity for the suppression of inflammation, but also helps to target scar tissue formation as well as the regeneration of the endothelium.

9.2 Nanopatterning

The process of nanopatterning involves manufacturing nano-sized structures across a substrate with the purpose of making the material more biocompatible and helping to promote regeneration of the endothelium. Below is an example of a nanopattern.

So, far nanopatterning has only been looked at with bare-metal stents as the texture significantly increases the coverage of the metal stent, as due to the lack of variety in its functions its best function is to simply reopen the artery, but with nano-patterning on it it attains anti-inflammatory properties.

9.3 Nano-Coatings

Aside from regular coatings that incorporate a blend of a loaded drug or had the stent have drug reservoirs, nano-coatings offer a more consistent and reliable route of transporting the drug to the arterial surface as well as to the stent.

One developed approach was nano-coating which utilized nanopatterning with extracellular matrix proteins. This proves to be quite useful when considering endothelial cells, that are reactive to the nano-scaled components of this matrix as a component of the natural extracellular matrix in the arteries consisting of collagen. In this way, if the fibers in the collagen matrix were to align vertically along the stent this would cause the endothelial cells to follow them. Once the cells align in this manner, they can essentially mimic the mono-endothelial layer of the blood vessel and are aligned with dimensions of a higher length than width, this become important as the second type of endothelial cells, which are not in this monolayer and have a rocky appearance, and within this, the aligned ones are able to produce more nitric oxide and fewer adhesion molecules. This results in a low chance of inflammation and thrombosis. In addition, this method holds a unique characteristic, in which once the endothelial cells are properly aligned on the collagen nanopattern, they do not face stress as well as strain.

In another approach, a breakthrough nanoparticle coating was developed by a team led by Dr. Anna Waterhouse and Dr. Thomas Valentin who developed a slippery Omni-phobic coating for medical devices that repels blood excellently reducing clotting and thrombosis effects.

The coating is a liquid slippery Omni-phobic nanoparticle coating that excellently repels blood off of surfaces preventing clotting and thrombosis. The coating integrating biomimicry was inspired by the Nepenthes pitcher plant which has a natural layer of water that it uses to prevent insects from sticking to the plant, which can cause damage to the plant. In a similar way, the coating was inspired by this to improve SLIPS technology, which stands for slippery liquid-infused porous surface.

The coating is a covalently tethered molecular layer of perfluorocarbon, which is simply an artificially made substance that is composed of fluorine and carbon atoms, in which specifically the fluorine atoms have all replaced hydrogen atoms, and it is extremely useful as the porous surface is not existent with this liquid coating that fills in gaps excellently. With this as well there are substances that briefly resemble blood so that the blood is not reacting with a complete foreign substrate.

In the image above the blue part is the covalently tethered flexible layer of perfluorocarbon and this is holding the red part on the surface which is a liquid film of perfluorocarbon with the ability to stay stable against blood flow.

An issue, however, still lies in the fact that smooth materials although are smooth can still be porous, take an eggshell for example, although quite smooth they are porous and allow small substances to go through. So the team developed a way to improve the SLIPS technology so it can also work effectively so that smooth materials have no porous gaps. How they did this was by essentially after adding the layer of the perfluorocarbon they found that adding a free mobile layer of LP (liquid perfluorocarbon) such as perfluorodecalin, which is a type of perfluorocarbon that is very stable as well as inert. So, with this, you have a tethered perfluorocarbon layer and a liquid layer, that on the outside resembles blood as perfluorodecalin is an FDA-approved blood substitute, which is critical due to blood’s tendency to react with foreign objects.

A key part of the coating is also that the tethered perfluorocarbon layer is able to effectively keep the mobile layer in place even as the blood is rushing onto its surface. Although, the coating has extremely promising applications a current issue still exists in that the LP is able to evaporate at body temperature, and can form toxic gases in the body.

9.4 Nano-Surfaces

The earliest stages of surfaces attempted to be modified with nanofeatures were those with microporous and microstructured surfaces. As discussed above in earlier sections, since stents have a high likelihood of rupturing the endothelial layer, the most desirable stent will stop the rapid growth of vascular smooth muscle, as well as to keep the extracellular mixture of proteins healthy, as they will include important proteins such as collagens, elastins, fibronectins, and laminins. Thus, the stent must be made so that the layer can be restored effectively while also keeping the restenosis possibility in mind.

Some examples of these microporous structure figures are also discussed above bare-metal stents with a microstructured nitinol surface, however, with this again although the materials ie. cobalt-chromium, titanium alloys, and stainless steel. Although these materials have an excellent biocompatibility and versatility metal ions that are released can cause significant inflammation, as well as encourages the growth of neointimal tissue.

As an example, this is a stent’s surface with a nitinol microporous coating on it. Due to the characteristics of the stent itself with nitinol best suiting metal stents as well as the nature of the coating, it can easily be seen why clotting and adhesion of blood are likely.

However, within this, there is also another option that is quite useful in terms of neointimal tissue formation and is quite accessible as well as cheaper, where a coating of specific drugs can be sprayed onto specialized stents such as slotted tubular stents, polymer-free microporous stents, and microstructures surfaces, have pores that can effectively absorb the drug. With a polymer-free surface what happens is that when using a stainless steel material, the absence of this polymer as well as abrasion processes will make the stent have a very unique texture that will allow drugs that will stop cell growth to nicely attach onto the stent and can, in turn, better suppress the formation of neointimal tissue.

Nanoporous and Nanostructured

Then, going into nanoporous and nanostructured surfaces we see how with the addition of nanotechnology even polymer-free stents have the ability to be manufactured with nano-eluting properties, this is significant as with most eluting nanoparticles the polymer in them is what helps to protect what they may be holding so that it is only released onto the active and targeted site, but when working without these nano-properties have been altered to not exactly release drugs themselves but enhance regeneration properties within the artery or slightly carry out these properties but not through original nanoparticle forms, instead, these are nano-surface modifications.

The first example of testing in this area was down with a plain stainless steel stent coated with a nano-thin layer of nanoporous hydroxyapatite, and due to the material having pores 100 um or less they were able to be loaded with sirolimus for suppression of the plaque and will help to stop the artery from narrowing again.

Another example of is using aluminum oxide, as both have been seen to improve the endothelization in the artery. With this, a nano-layer of aluminum is put onto the stent and then it is ionized to make it a porous aluminum oxide. An issue with this however lies in its ability to have debris ejected from the pores, and therefore cause inflammation in the artery, so even though its endothelization properties are highly effective as well as the pores which allow drug-loading and inhibit cell growth need further improvement to be used more widely in arteries.

10. Stent Manufacturing

10.1 Laser Cutting

Laser cutting of stents involves using an accurate and thing laser that can cut materials, particularly metals at micrometres. Laser cutting allows a very complex shape to be accurately engraved on the stent, and can easily reduce thickness without changing many mechanical properties.

10.2 Water-Jet Cutting

In this method of manufacturing water at very high pressures is inclined and then used to cut shapes thinly and accurately. Water-jet cutting can be used to cut various types of materials and is not best suited to the metal as laser cutting is.

10.3 Photoetching

A key characteristic of photo etching is that it is quite cost-friendly, as it involves using a UV light so that an image is fixed onto a surface, then using an etching solution which are acids, the image is followed to sculpt the image into metal, and slowly by removing all excess metal one is left with the design.

10.4 3D Printing

3D printing stents is a relatively new concept, in which the first-ever to be manufactured in this way was a nitinol stent. Since, a 3D printer is quite versatile in terms of the materials that are used in stents, such as metal and polymer can be inputted and the stent can very easily be manufactured.

11. Conclusion

Stents have been an immensely talked about topic for decades within the biomedical field, and they continue to pose many opportunities for improvement.

Many people have credited stents with saving their lives and giving them another opportunity at a life filled with greater quality and happiness, which is why it excites me to think about how we can make this innovation much better than it is now, and cost-efficient so that it can be implemented in places where people need it most.

12. References

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5368670/
2. https://tehj.springeropen.com/articles/10.1186/s43044-021-00170-9
3. https://biomedical-engineering-online.biomedcentral.com/articles/10.1186/1475-925X-4-59
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098574/
5. file:///C:/Users/Admin/Downloads/micromachines-12–00770-v2.pdf
6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238261/#B243-pharmaceutics-12-00349
7. https://hal.archives-ouvertes.fr/hal-00570755/document
8. file:///C:/Users/Admin/Downloads/micromachines-12–00770-v2%20(1).pdf
9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3900802/

Thank you for tuning into this paper! My name is Noorish Rizvi, and I am a 15-year-old incredibly interested in the applications of biomedical innovation particularly in developing countries. Learning how we can improve vital innovations so that they can be more accessible is what excites me the most. :) If you enjoyed reading this, please feel free to reach out on LinkedIn, Twitter, or Instagram!