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Over the past decade coronary stents have been widely used in clinical field. They are manufactured using a variety of biomaterials ( http://www.scientific.net/AMR.123-125.315) . These stents are used in the coronary artery in a condition called coronary heart disease, in which plaque builds up inside the coronary arteries causing a hindrance in the flow of oxygen rich blood to the heart which is a consequence of high Blood pressure, diabetes or smoking. During the treatment it augments as a tube placed in the coronary artery that supplies blood to the heart so that the arteries are kept open.
A coronary artery stent is generally a small stainless mesh tube that is positioned in a shrunken state and escalated upon a balloon catheter. The stent opens up and pushes itself against the coronary arteries wall as the balloon is inflated. The procedure here is known as percutaneous coronary intervention (PCI).A variety of biomaterials are bein employed for the manufacture of stents of which stainless steel being the most common biomaterial in seven of the eight FDA approved stents. Titanium, Platinum, Iridium, Tantalum, Nitinol and magnesium alloy are the materials that have been employed recently for the preparation of the same .( http://www.scientific.net/AMR.123-125.315)But except for in acute myocardial infarction the stents have shown a least probability of increasing survival except that they reduce chest pain. Except for small arteries a stent is placed after angioplasty so that the blood flow is ensured because with its use the chance for an artery to get closed is only 10-20%.
Coronary Stents were introduced in the early 1990s and they have drastically improved the outcome of percutaneous coronary intervention in obstructive coronary artery disease.The stents available up to today can be classified manly as bare metal stents(BMS) and newer drug eluting stents(DES).Though DESs have been introduced only a few years ago (http://www.eu-acme.org/europeanurology/upload_articles/Case%20Study%20of%20the%20month%20July.pdf) John Robert Dugan of Shelbyville developed bare metal stents which were the first type among the earlier coronary stents.Absorbable stents(metal or polymer) and stents which do not elute drugs and with biocompatible surface coatings are in development(http://en.wikipedia.org/wiki/Coronary_stent). Angioplasty balloons were used in the periods between 1977-1987.Stent concepts grew from the interventional cardiologists experience with such angioplasty balloons.In most cases wall of the coronary artery became weak after ballon dilatation and chances for the artery to collapse after the ballon was deflated was high.So in such cases the only way to repair the problem was an emergency bypass graft surgery on the patient.Tools during surgery were miniaturized so that they could be delivered via catheter.One such device was the coronary stent which could be delivered via catheter and inflated in the coronary arter.In US JulioPalmaz and Richard Schatz and others in Europe developed their own designs of stentsAt Toulouse in France Jacques Paul and Ulrich Sigwart inserted the first stent into human coronary artery in 1986.United states approved the first Palmaz-Schatz stent in 1994.Within the next 10 years several types of bare metal stents were developed and the improvements were such that they could be more flexible and easy to deliver to the narrowing.( http://www.ptca.org/des.html)...On August 3 1994 FDA approved the first device to clear and open hold an artery. In this a stainless steel device was placed in the coronary artery so that it would stay open. Improvements to prevent blockages via materials and medicines made them a safe and beneficial advancement to medicine. (http://www.ehow.com/facts_7171801_history-coronary-stents.html)..
General Design considerations in coronary stents:
Its known that foreign materials on being implanted into human body results in inflammation,trauma with immune response and end up in scarring or healing.Coronary stent material must be elastic proficient for expansion accommodating.It must also be biocompatible.Cytotoxic chemical buildup and chronic inflammation can result if the materials used in coronary stents are not biocompatible.Stainless steel forms the platform for nearly all stents as it's the least expensive one. Austenitic stainless steels, especially 316L, are most widely used for implants..However the compatibility of stainless steel with human body is not efficient as a result of which restenosis and thrombosis follows their implantation.Other problem involved with the use of stainless steel is that they pose a difficulty to some types of imaging like magnetic resonance. Alternative platform materials like titanium, gold,tantalum alloy, Nitinol, and different types of polymer are being employed by researchers for the construction of the same.It must be noted that an ideal coronary stent is one that does not form the ground for any human reaction.Gold was considered as biocompatible highly visible and usually inert for some time.The newer variations of cobalt chromium which was actually developed for use in watch springs later on proved to be effective to be used in coronary stentsTantalum a shiny,flexible and highly radio opaque metal though more brittle than stainless steel is resistive to corrosion.Some polymers too have been used for the creation of stents.A condensation polymer silicone must presents high tensile/coil strength, inner to outer diameter and biodurability .It also induces low rates of tissue traumaThough there is an induction of sludge in 20%-30% of patients who have been treated with polyethylene and polyurethane stents these materials are also used.Protein adherence and biofilm formation are also encouraged by theses materials.Though polyurethane is a very reactive stent material it has good coil and tensile strength.Polymers used for construction of stents are expanding on a dail basis with relation to their different functional characterstics.Some main properties taken into consideration are biodegradable bioabsorbable or bioerodible characterstics of polymers.A major component like an enzyme or microbe makes biodegradable and bioabsorbable stents appropriate for short term uses as they get degrade after some time.A water insoluble polymer that has been renewed into a water soluble material is known as a bioerodible polymer.The risk of restenosis is reduced with biodegradable stents as an antirestinonic drug is released into surrounding tissue from its coating with the degradation of the stent.Polysters polyorthoesters and polyanhydrides are examples of biodegradable polymers.Restenosis and thrombosis rate can be reduced by biocompatible collagen.Drug delivery is also aided with the help of anticoagulants and fibrinolytic agents that are attached to collagen(http://mediligence.com/blog/2009/06/11/materials-used-in-stent-construction/ ) …..... Drug Eluting stents are used for the main issue of reducing restenosis and promotes a drug in the site where the stent is placed.FDA must approve any stent before it reaches the market.A regulatory assessment of any drug eluting stent is done by FDA after studying data and thorough inspection of each components constituting the stent alongwith analysis of it as a whole ie including the drug.The consequences of systemic clinical exposure to the stent is considered and clinical performance of drug and stent is concluded.The regulatory consideration are unique to every combination product of the stents.Since these drug eluting stents are a combination of two different types of regulated components ie a drug and a stent they are known as combination products and are subject to 503(g) of Federal Food Drug and Cosmetic act.Center for Devices and Radiological Health(CDRH) or Center for Drug Evaluation and Research(CDER) are the agencies to which this combination product is assigned and they do the premarket review and regulation which are based on determination of products primary mode of action…..It was then determined by the agency that for current drug eluting stents in which patency of coronary artery is maintained by the component and addition of drug increases safety and effectiveness of the naked stent so as to prevent restenosis must be primary mode of action.So CDRH along with the consultation help from CDER was given responsibility for the premarket review and regulatory responsibility of coronary drug eluting stents.
Application Requirements by FDA
Product Classification - Drug Eluting stents are regulated as Class III devices and should have approval of PMA.The PMA application must contain scientific evidence that gives assurance of the effectiveness and safety of DES if used accordance with its labeled indication.Non clinical animal and human clinical testing form the basis of such evidences.
IDE application requirements:An application must also be submitted to Investigational device Exemption(IDE) for approval as FDA determines DES to pose a significant risk.If there is a requirement of IDE application then clinical trial on humans must not be started until FDA has provided approval in the United States.Sponsors who promote such studies must ensure that they agree to the IDE regulations and those of the institutional review boards.An informed consent must also be obtained.
IND Application Requirements
Potential toxicities of drug can be fully characterized by preclinical and clinical evaluation of the drug substance alone.In US studies of an investigational drug on humans must only be done with an IND application which should illustrate the intended use of stent in combination with the drug.
PMA Application Requirements
The safety and effectiveness of finished drug eluting stent must be provided clearly so as to meet the standard of approval in a PMA application.A Modular PMA application program can also be considered due to the typical need of vast amount of non clinical information.Such applications have different modules that are submitted at different times with the completion of each requirement.
Selection of relevant components must be done very thoroughly for the development of a new DES which is intended for clinical useDrug substance released must also be considered.Testing must be limited to animals and in vitro until relevant results suggest that human testing is permissible under IDE.
Selection of the drug polymer or carrier along with stent platform is the starting step for development of a stent.A known platform may be selected as the stent or a new design may be developed .Polymer or carrier that is selected must have ability to control drug elution and should be able to conform the platform of stent without a change in shape.The compatibility of the polymer with arterial tissue must also be considered
The aim of the drug substance must be to reduce the growth of neointimal hyperplasia which occurs as a result of injury caused by the stenting procedure.It should not prevent ultimate reendothelialization of the stented artery.Another important factor is the selection of drug dose.Drug quantity to be delivered must be carefully analyzed so as to choose the lowest effective dose.This helps in reducing potential toxicities.The identified dose is the optimal dose.
Substance selected as drug should be carefully evaluated of its safety profile,chemistry and mechanisms of action.Toxicities that may occur and exposure levels at which they occur can be analyzed from in vitro and animal testing.No Observed Adverse Effect Level(NOAEL) must be established from animal toxicology testing.Analysis of animal toxicology to drug substance is very critical in understanding the adverse effects following stent implanatation.NOAEL which is determined from animal studies must be used to select the starting dose.
Device testing requirements
The counting and sizing methods must be described and validated.Artifacts from the test system must be minimized. Quantity of samples used should be specified with each test.Sample specification must be justified scientifically.In the characterization process the stent is expanded to its nominal and maximum deployed diameter.Fatigue and durability are also tested along with their stimulated use.
Quality control forms the next step.In this every part of product that has been manufactured as a part of the batch released is tested.
This is followed by Stability testing in which mostly aged samples are evaluated using stimulated use test condition.
The Corrosion potential of the stent is considered with respect to the component used for its construction.Here the base stent substrate too is evaluated and potential for galvanic corrosion is also addressed.
Degradable Coatings if present are evaluated and their nature of degradability too has to be specified.both in vitro and in vivo degradation profile of the polymer must be characterized.
In accordance with ISO 10993 a Biocompatibility test must also be performed
Animal Safety Studies must also be performed.The Standards For Evaluation states that other than in critical situations the artery selected for placement of stent must have no prior injury.based on current clinical standard of care antiplatelet therapy must be administered throughout clinical study when needed.A comparison must be done on the studies conducted on each stent type.(
316L stainless steel is mostly used for the crafting of stents.Some examples are the Cordis Crossflex stent,Guidant multilink stent and Medtronic Bestent.Subacute thrombosis,restenosis,bleeding complications,corrosion and redialation of stented vessels are some of the disadvantages included with the use of stents made of steel.
Gold as we know is a biocompatible,highly visible and a usually inert material.Though high visibility and flexibility were shown by Gold Plated Hybrid stents they were expensive.Medtronic's Bestent can be described as a serpentine mesh of stainless steel that had no welding point and two radioopaque distil gold markers which allowed precise positioning of the stent.Cobalt chromium nickelmolybdenum iron alloy is marketed under trademark names of Conichrome,Phynox and Elgiloy currently stent. A stent Schneider Wallstent is made of cobalt chromium alloy.
Another shiny flexible and highly radio opaque metal is Tantalum.It has high ductility and corrosion resistence though its more brittle than stainless steel.Though with tantalum viewing and supporting characterstics are ideal there are more other biocompatible options.Nitinol is a biocompatible super-elastic shape memory alloy used for the construction of stents.This is an alloy with 55% nickel and 45% titanium.The rate of corrosion is also low here.There is also a difficulty in the manufacturing of this alloy.
The next possibility is Polymeric Stents.Polymeric endoluminal paving and shape memory polymers coupled with biodegradable stents comprise most materials of polymer stents.The first organic material that was cosen for stenting was Silicone.This is a condensation polymer.An advantage of this sstent was that tissue trauma rates induced is low.But it had poor tensile/coil strength,biodurability and inner to outer diameter ratio.Bilary stents that used polyethylene or polyurethane have also been used in patients.The disadvantages included with this was the encouragement of protein adherence,biofilm formation and entrapment of bile crystals and food particles.There was a sludge induction in about 20-30% of the patients.The advantages was that it has good tensile strength and good biodurability.Its one of the most reactive materials present.Biodegradable and Bioabsorbable polymers are used for construction of stents.In cases where the use is temporary or short-term biodegradable implants find their application.If degradation products are removed by cellular activity then the terms Bioabsorption and Bioresorption are implied.A water insoluble polymer which is transformed into a water soluble one under physiological conditions is called bioerodible polymer.Steady degradation,permeability and moderate tensile strength must be the basic requirement of any Biodegradable drug delivery system.Biocompatibility,hemocompatibility and good hemodynamics nust accompany structutral support in any stent.The problem with current biodegradable stents is that they usually induce thrombosis and vascular injury.Stack designed the Duke Bioabsorbable stent which was the first biodegradable stent.A decrease in thrombosis has been shown by Collagen products that are biodegradable throughout their lifecycle and the ability to bind anticoagulants or fibrinolytic agents aids its capacity for drug delivery.Providing the product with a more hydrophilic backbone/endgroups,more porosity,less crystallinity and smaller oversize are some factors that can accelerate polymer degradation.Conditions for a polymer to be ideal is that its strength stays to maximum until tissue heals,does not leave traces after the body metabolizes it,the shelf life is acceptable,sterilization is easy and does not bring about a detrimental inflammatory or toxic response in the body. There is an unevenness of remaining material after degradation process in case of biodegradable materials and this is a concern while using biodegradable stents.Providing a smooth surface using polymeric endoluminal paving can be a good solution for this.Shape Memory Polymers was another polymeric possibility that was developed by Dr. Andreas Lendlein and Dr. Robert Langer.The polymer may be heated or cooled into myriad shapes after the polymer is synthesized(http://web.mit.edu/murj/www/v11/v11-Features/v11-f5.pdf).The ability of a material to induce normal response within the host must be the key factor while selecting coronary stents.On the process of designing a coronary stent the main factors to be considered are photostability,biocompatibility,moisture sensitivity,reaction to gases,temperature stability,and effect on safety/effectiveness.( http://www.slideshare.net/mariam1020/drug-eluting-stents-des)
Stents aim at restoring local perfusion and coronary perfusion reserve.But there is a chance for the stent to grant new properties into the segment of the artery and subsequently induce biological responses like intimal hyperplasia.There is also a possibility of mechanical damage to the arterial wall during stenting process if there is an over expansion of balloons used during angioplasty.There is also a chance for occurrences of scratches in arterial wall during the transport of the stent to its site.Biomechanical and biochemical actions can occur as a result of this damage and chances for localized inflammation,arterial inflammation and thrombus formationa re high.A reduction in global heart muscle perfusion and potentially infarction can occur after this stenting purpose due to various factors.
Coronary stents fall within the range of MDD.Article 1.4 and Article 9 of the MDD leads to classification of coronary stents as Class III medical devices.Clinical data is evaluated with the characterstics of the stent and its side effect under normal conditions.A positive benefit/risk profile of device that illustrates the indications and limitations of use of the stent as illustrated by the manufacturer must be the objective of the clinical investigation.Coronary stents that include some sort of medicinal substance are further referred to a member state designated competent authority like the European Medicines agency for additional scientific opinion.
Before performing a clinical investigation on a stent its very essential that a preclinical assessment must be done which should include
1)Test for Biocompatibility(EN-ISO 10993 series)
2)Bench testing in line with EN14299
3)Studies on Animals(EN 14299,EN ISO 14630,EN 12006-3)
4)With Drug Eluting Stents suitable analysis of medicinal substance along with interaction between device and medicinal substance,pharmacodynamics and characterisation of time release profiles.
5)EMEA Guide line must also be followed.
6)ISO Standard (ISO 25539-2) there is also the testing of uniformity of drug distribution that must also be analyzed.
To analyze if a device is suitable for the purpose it was actually designed for the main aims of performing clinical investigation according to MDD are
1)verification of performance of device with respect to the purpose claimed by manufacturer(Under Normal Conditions)
2)To find out any detrimental side effects and review weather the risks when weighed aganist intended purpose of device are less(this too under normal conditions).
Another important aspect that must be considered are the presence of coexistent pathologies like diabeties or hypertension that can complicate coronary artery disease so coronary stents must be designed as such.Specific clinical data must always be present to support various claims.During clinical investigation various side/adverse effects along with those identified by risk management process must be illustrated clearly in the information supplied along with the device.
A critical aspect that is to be ensured is that the combination product of drug and device in the stent must be up to date with current good modern practice requirements.
Sterilization should be the next issue that must be addressed.PMA should analyze the technique used for sterilization and should certify that the sterility assurance level(SAL) is achieved.Generally a SAL of 10-6 is obtained by sterile devices 2158,and if this is not met a valid explanation must be illustrated along with a detailed explanation of the risks it may cause on patients.The validation 2160 in sterilization must be carried out in respect with an accepted standard or comparable method.
Package Integrity testing should be done so as to show the capability of package to susatain the sterility of product that it contains.The processes involved in package integrity testing mainly comprises of a whole package physical integrity test followed by a seal integrity test.Further tests must be conducted so as to ensure that the package will be able to withstand pressures that it may have to undergo during transportation.ISO 2248 and ISO 8318 has some test methods which are appropriate for testing package integrity.
The next aspect that must be put into evaluation is the Shelf Life of the product.Acclerated aging must be provided to the product and it must be noted if the product is able to maintain its functionalities to the maximum throughout the period expected and promised by the manufacturer.( http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM228704.pdf )
FUTURE ASPECTS OF CORONARY STENTS
In the future metals will be replaced by polymers and more biocompatible materials for the construction of stents.Though this may assist local drug delivery this will come with a chance of inflammatory response.( http://www.ncbi.nlm.nih.gov/pmc/articles/PMC484374/pdf/heart00019-0018.pdf )
Polymers rather than metals could be used as the chief
constituent of stents. This might facilitate local drug delivery
but could lead to an inflammatory response. The
excellent current results of clinical trials suggest that stents
may not need local drug delivery systems. But these were
trials in patients with stent favourable lesions (< 15 mm
long) in large vessels (> 3 mm in diameter) and most
patients seen in routine clinical practice have lesion characteristics
that are not stent favourable (long or thrombotic
lesions, small vessels). Such patients are likely to
benefit from effective local drug delivery.
The clinically apparent biological adverse processes
associated with stent implantation are subacute stent
thrombosis and intimal proliferation. Intimal proliferation
is more likely to be of long-term clinical importance and
the incidence of stent thrombosis seems to be declining.