Coronary diseases (CDs) are the most frequent cause of morbidity and mortality in today’s sedentary life style. The coronary arteries, primarily supply blood to the heart muscles, later on become hardened and narrowed down due to the build-up of cholesterol with other material, called plaque, on the inner walls of the arteries. Lack of blood flow through these arteries further leads to insufficient supply of oxygen in the heart muscles subsequently followed by chest angina, acute coronary syndromes and atherosclerotic plaques. Further, several interrelated processes like change in the composition of lipids, oxidative stress, inflammatory responses, vascular smooth cell and platelet activation, thrombus formation, dysfunctioning of endothelial tissue, and genetic aspects are the other key factors responsible for the awful cardiovascular diseases.

Upto 1970’s, the common surgical interventions to restore blood flow were coronary artery bypass graft surgery (CABG). Later on in 1977, the less invasive percutaneous transluminal coronary angioplasty (PTCA), balloon angioplasty or percutaneous coronary intervention (PCI), was introduced by Gruntzig as a therapeutic procedure and a minimally invasive means to reopen the stenotic (i.e., narrowed) coronary arteries of the heart. PTCA initially showed extremely favourable and good clinical results as it significantly improved the blood flow by reducing luminal obstruction but later on encountered certain limitations too. A part of this procedure was to apply the hydrostatic pressure of magnitude of 6-8 bars on the walls of the artery in an attempt to clear the blockage. This blockage many a times leads to cracking of the walls of the artery while peeling off the inner layers with the cholesterol plaque thus impeding the blood flow, possibly leading to coronary occlusion and myocardial infarction. A deep intramural thrombus is formed by the aggregation of platelets release procoagulant factors like platelet-derived growth factor, tomboxane A2, adenosine diphosphate. This is then followed by proliferation and extracellular matrix synthesis by smooth muscle cells ultimately leading to neointimal hyperplasia which may have an increased rate of re-narrowing due to growth of scar tissue in the stent, a condition called restenosis.

Bare Metal Stent (BMS): To surmount these problems, Puel and Sigwart in 1986 inserted a thin metallic wired mesh-like device, called as a “stent”, into the stenotic artery to prevent or relieve obstruction and to restore blood flow through (Figure 1). Stent enables to improve blood flow to the heart muscle and reduce the pain of angina. The widespread use of coronary stents has reduced this incidence of restenosis by as much as nearly 50 per cent. About three-fourths of the patients undergoing balloon angioplasty will have a stent placed as a part of the therapy. BMS are further classified as a) balloon expanding (BX), b) self-expanding (SX) and c) balloon expandable, super elastic (BXSE) stents. The BX stents are manufactured in the crimped state and expanded to the vessel’s diameter by inflating a balloon thus plastically deforming the stent. The SX stents on the other hand are manufactured at the vessel's diameter and are crimped and constrained to smaller diameter until the intended delivery site is reached where the constraint is removed and the stent is deployed. Efforts have been undertaken to combine some of the advantages of BX and SX stents by creating BXSE stents that are super elastic that are unloaded during expansion. Prevalence of in-stent restenosis (ISR) (Figure 2) has often been detected employing various exercise stress tests, performed after six to twelve months of stent’s placement. This type of restenosis is greatly reduced using anti-clotting therapy during and after the treatment. Over the years, several generations of BMS have been developed in succession, each one proving to be more durable, flexible and easier to deliver to the narrowing than the previous version(s).

 Drug-Eluting Stents: In 2001, a drug-eluting stent (DES) was introduced as a strategy to minimize major challenge imposed with percutaneous coronary interventions employing BMS, i.e., in-stent neointimal formation. These DESs are coated with medications that are slowly released to fight against the proliferation of cells that may block the artery (Figure 3). It significantly reduces the need of repeated procedures to clear the scar tissue around the stent as the medication is delivered directly to the site of the artery blockage. Development of DES has been pioneered through a combination of the increased understanding of the biology of restenosis, the selection of drugs that target one or more pathways in the restenotic process, controlled-release drug delivery strategies, and the use of the stent as a delivery platform.

First-generation DES: US-FDA approved first-generation DES, i.e., Cypher™?, sirolimus-eluting stent and Taxus™?, paclitaxel-eluting stent which effectively surmounted ISR.

Second-generation DES: The safety of first-generation DES has been limited by suboptimal polymer concentration and mechanical properties to control the release of anti-proliferative agents, delayed stent endothelialisation, inflammatory responses, leading to thrombosis, local drug toxicity and biocompatibility issues. As a consequence, in recent years, there is the launch of the second-generation DESs with additional improvements like better deliverability, novel anti-proliferative agents with reduced doses, radiopacity, flexibility, and radial strength employing cobalt-chromium platform, thus allowing thinner struts of about 80 µ-90 µ. The widely used DES of this category is Xience V™ featuring two polymer layers; a primer adhesion layer of poly(n-butylmethacrylate) and a drug reservoir of poly(vinylidene fluoride cohexafluoropropylene) combined with everolimus. While the other popular one is Endeavor™ with phosphorylcholine as polymer and zotarolimus as drug. The second-generation DESs were found to be better than first-generation DES w.r.t. the anti-proliferative agents, polymer used and the stent frame. Lower thrombosis rates with anti-restenotic efficacy and long term safety measures were observed with the use of the second-generation DES.

Preparation of DES: Most of the DESs contain a metal scaffold surrounded by a polymer matrix containing the drug. The type, composition and the thickness of the polymer coatings dictate drug eluting kinetics and sustained release of the drug over a period of weeks or months. Stents are generally coated by simple “dip” or spray coating of the stent with a polymer, and, at times, with a drug too.

Polymers used for coating stents can be broadly classified into (a) non-biodegradable polymers, e.g., polyethylene-co vinyl acetate, polyn- butyl methacrylate, poly (styrene-b-isobutylene b-styrene), polyurethane, silicone, polyethylene terepthalate etc (b) biodegradable polymers, e.g., polylactic-co-glycolic acid (PLGA) or polylactic acid (PLA) or their copolymers etc. (c) biological polymers, e.g., phosphorylcholine, hyaluronic acid and fibrin. Generally, a non-erodible polymer is recommended to be used for long term applications because the fragments that break off from erodible polymer coating may undergo bulk erosion and be phagocytised by macrophages leading to release of inflammatory cytokines.

Drug release mechanism from the DES
The drug release from the DES occurs through several approaches, namely diffusion from polymer, diffusion through rate limiting coating, swelling or erosion of coating, hydrolysis or enzymatic action from polymer, drug-loaded in nanoporous reservoir in stent, coating or between coating layers, or bioerodible polymer stent.

 Drug-Eluting Balloon (DEB) Technology: It offers an attractive option for the treatment of restenosis, without the risk of thrombosis. Paclitaxel was identified as the primary drug for DEB because of its rapid uptake and prolonged retention. In small clinical randomized trials, paclitaxel-coated balloons have been shown to be safe and effective in reducing restenosis among patients with coronary ISR.

Advances in DES:
DES sSystems with bioabsorbable polymers: The bioabsorbable or biodegradable stents constituted the next major breakthrough, offering a potential solution to avert risks associated with currently available DES. A multitude of new stents has been investigated incorporating fully biodegradable polymers like PLA and PLGA, which are fully metabolized to water and carbon dioxide, leaving behind only a healed natural vessel.

 The BioMatrix™ stent is a novel DES that incorporates the S-Stent platform, a thin, stainless steel, laser-cut, tubular stent with 16.3 per cent to 18.4 per cent metal surface area. The anti-proliferative drug is biolimus A9, a highly lipophilic, semisynthetic sirolimus analogue.

 CardioMind™ is a 0.014-inch guide wire–based stent delivery platform combining a limus drug in a biodegradable polymer matrix on nitinol platform with electrochemical dissolution principle for stent release.

 Nevo Cordis™ is a cobalt-chromium stent dotted with “reservoirs” that can be loaded with one or more drugs and polymers to release drug more specifically, potentially in various doses or formulations. The biodegradable polymer is impregnated with sirolimus.

 Elixir Medical Corporation, USA is currently working with two pharmaceutical agents, novolimus, a metabolite of sirolimus, and myolimus, a sirolimus analogue. These are designed to optimize safety and efficacy through the combination of a cobalt chromium stent platform, a low polymer loading with controlled release and a low pharmacological drug dose. Two bioabsorbable polymers allow release of the drug in 2 to 4 weeks and bioerode over a period of three  to nine months.

 The ReZolve™ stent integrates a proprietary drug-eluting polymer and a novel design to create a stent with metal-like performance out of a polymer material. Unlike permanent metal alloys, the REVA polymer dissolves from the body after healing of the artery has occurred, leaving additional treatment options available in the future. Another unique feature of the polymer is that it is visible under x-ray, allowing the stent to be visualized during the implant procedure and during follow up. Other bioresorbable polymer stents are invisible and require permanently attached radiopaque markers to aid in their placement.

Limitations of bioabsorbable polymeric stents
The bioabsorption rate is relatively slow and may still result in restenosis with a significant degree of local inflammation. These stents are radiolucent which may impair accurate positioning.

Polymer-free DES systems
To overcome the limitations of biodegradable polymers, some alternatives are currently being tested. Most of the time, modifications in the surface of the platform are necessary to carry the anti-proliferative drug. The Amazonia Pax Minvasys™ and BioFreedom™ are a few names in this domain. Also, endeavour is being made to load dual drugs on these DES (DDDES) which may control the drug release kinetics. Ideally, a drug for preventing vascular smooth muscle cells proliferation which is released for the first few weeks, and then the second therapeutic agent promoting re-endothelialization would be released after a month. Attaining such tailored release kinetics from a thin layer on a stent is yet to be a reality. This is an upcoming field in interventional cardiology and long-term data as well as larger controlled trials are still to be poured in literature. The sojourn of the various treatments of stents has been attempted to be projected in Figure 4.

Future prospects: Owing to its phenomenal success in the treatment of coronary diseases, DES has been extended for the treatment of stenosis of the carotid artery, biliary track, sinus ostia and esophagus. Nevertheless, even after such advances in the field, the domain is subject to the critical examination of the complication, risk assessment, understanding the pathophysiological characteristics and an improved understanding of the coronary vascular response to injury. The magnitude and time course of the increased risk of stent thrombosis along with a lot many clinical studies are required to determine the ideal duration of antiplatelet therapy after stent implantation. Longer-term post-marketing surveillance is certainly required to determine the unanticipated adverse events that will inevitably occur as a result of the late stent thrombosis. Federal agencies are acting appropriately by taking expeditious action to understand the areas where uncertainty still remains.