STENTS – NEW MATERIALS ANDTECHNOLOGIES FOR THE FUTUREAuthors: Dr. Phil Jackson & Dr. Chris Pickles                     0
1 IntroductionStents are expandable meshed tubes used either to reinforce body vessels possessing weakwalls or to increase...
4 Application of supporting technologies in stent developmentsCERAM has been deeply involved in delivering supporting tech...
FEA uses a 3-D representation of a target shape (figure 1) which is "meshed" (figure 2) todivide it into small areas (2D) ...
In addition to machining, bare stents are frequently ‘passivated’ both to reduce theircorrosion potential and to improve t...
For coated stents, the coating layer thickness (be it primer coat, top coat or both together)  can also be measured using ...
stents (Abbott) were recently in the news and represent a highly attractive concept; forexample, the ability to avoid pote...
right time either naturally or by triggering mechanisms internally and/or externally and tomake the degradation in a way s...
Queens Road, Penkhull, Stoke-on-Trent,                                   Staffordshire ST4 7LQ, United Kingdom            ...
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Ceram stents white_paper

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In this paper we will review some of the technology being used in the development of new
stents and how, in particular, computational modelling and material characterisation are
helping to improve clinical outcomes. Finally we will look at the future perspectives for next
generation stent technology.

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Ceram stents white_paper

  1. 1. STENTS – NEW MATERIALS ANDTECHNOLOGIES FOR THE FUTUREAuthors: Dr. Phil Jackson & Dr. Chris Pickles 0
  2. 2. 1 IntroductionStents are expandable meshed tubes used either to reinforce body vessels possessing weakwalls or to increase the internal diameter of a body vessel to allow an improved flow of fluidssuch as blood or urine. The use of arterial stents in particular has grown significantly overthe last 20 years due to an ageing population and to a change in diet which has led to anincrease in cardiovascular illness. Estimates vary, but it is predicted that coronary stents willhave a market value of $7.2bn by 2012 and will continue to grow at a rate of 6% per annumthereafter. In 2009 over a million US citizens received angioplasty/stent interventions.In this paper we will review some of the technology being used in the development of newstents and how, in particular, computational modelling and material characterisation arehelping to improve clinical outcomes. Finally we will look at the future perspectives for nextgeneration stent technology.2 Stents and coronary diseaseIn the treatment of coronary artery disease, stents offer a less invasive alternative to theCoronary Artery Bypass Graft. It is estimated that for every bypass operation, there are fourinstances of stents being employed as an alternative approach. Stents are fabricated bylaser cutting shaped sections from a metal tube. In use, an opening is made in the patient(groin, arm or neck) and a catheter used to guide a deflated balloon inside a stent to thecorrect position in the artery. X-rays and dye flow are used to identify the area of the arterysuffering from plaque build-up and for associated stent positioning. Once positioned, theballoon is inflated, causing the stent to expand and therefore the plaque to be pushed backagainst the inner walls. Upon deflation and withdrawal of the balloon the stent remains inplace. In some instances, balloon inflation inside the artery is performed without a stent (toassist initial widening) and then a stent is subsequently used.3 Coronary stent typesPrior to the use of stents, angioplasty alone was attempted. However, it was seen that therewas a high chance (25-50%) of restenosis (re-thickening in artery walls) occurring. The firststents were Bare Metal Stents (BMS) and still led to a tendency for restenosis, albeit at alower (15-25% chance) level. Thrombosis (blood clot formation) is also a typical, if relativelyinfrequent, consequence of stent emplacement. In order to reduce or eliminate theseresponses, Drug Eluting Stents (DES) were developed and have been shown to be excellentin reducing the re-narrowing of arteries by up to 70%. However, there is claimed to be alonger-term risk of blood clotting when a DES is used, requiring patients to take clot-preventing drugs for 6 months following the operation. Four DES platforms have beenapproved by the FDA and these represent the current state-of-the-art for clinical use.Whilst the majority of stents are balloon-expanding the development of self-expanding typeshas been done using so-called memory alloys1 such as Nitinol. This type of stent is oftenshaped to a diameter greater than the artery it is inserted into. By then crimping and feedingit inside a catheter it can be directed to the relevant part of the artery. Once released fromthe constraints of the catheter it expands and pushes into the inner arterial wall where it isable to conform to the shape of "non-straight" sections of artery. 1
  3. 3. 4 Application of supporting technologies in stent developmentsCERAM has been deeply involved in delivering supporting technology for the developmentof stents over the last 15 years. In particular this has included the areas of computationalmodelling and material characterisation. 4.1 Computational modelling Computational modelling can provide useful information to the stent design process. Both Finite Element Analysis (FEA) and Computational Fluid Dynamics (CFD) have been used in the pursuit of improved stent designs. Figure 1: 3-D representation of a stent geometry Figure 2: Meshing associated with a section of the geometry illustrated in figure 1 2
  4. 4. FEA uses a 3-D representation of a target shape (figure 1) which is "meshed" (figure 2) todivide it into small areas (2D) or volumes (3D). By applying physical data to the model,the impact of external factors (e.g. heat, pressure) on shape or internal stresses can bepredicted. Figure 3 shows predicted stress development as a stent is enlarged viapressure applied from within the stent cavity. In the design of stents FEA has been usedto explore numerous "what if" scenarios around novel stent geometries, thicknesses andalloy chemistries. Such models can predict how stent diameters increase as a function ofballoon pressure. They can also predict properties such as radial strength and stentstiffness. In addition, they can play an important role in designing stents for bifurcation:One option for bifurcation is to expand a stent at the appropriate point in the main vesselto leave a suitably-sized hole in the stent positioned exactly where a second vesselbranches off. A second stent can then be fed through the hole and expanded. FEA canpredict the size of hole created as a function of balloon pressure. When employing CFD, the mesh is used to represent imaginary points within a given liquid volume. In so doing, the mesh predicts the properties of the fluid passing each point. Predictions can be made about where the fluid moves over time and changes in its physical properties. CFD modelling has been invaluable (in combination with an FEA model of an inserted stent) in predicting the improvements in blood flow attainable via stent interventions.Figure 3: FEA analysis using colour mapping toillustrate stress development during stent expansion4.2 Material characterisationStents comprise a range of materials which are invariably modified in some way or otherin order to improve functionality and/or biocompatibility. The ability to understand thematerial chemistry and its physical profile, be it intentionally introduced or merely that ofthe as-received state, is absolutely fundamental to ensuring efficacy in stent deploymentin the patient. Using state-of-the-art material characterisation techniques CERAM hasdelivered critical insights into material composition in all areas of stent structure, be it themetal substrate or the drug-eluting coating, both pre- and post-use.The metal substrate is invariably an alloy which has been machined in some way. Thesecomponents are often subject to a cleaning process where detached but re-depositedresidues and machining lubricant residues are removed. Validation of the effectiveness ofsuch cleaning processes is carried out by measuring the quantity of such residues stillremaining on the surface after cleaning, rinsing and drying and also the quantity ofresidual cleaning agents. This is carried out using a surface-specific spectroscopicmethod which is sensitive to all the elements (apart from H) to an accuracy of 0.1 atomicper cent. The method uses a bespoke combinatorial algorithm to generate a single figurecleanliness parameter known as the cleanliness index (CI). 3
  5. 5. In addition to machining, bare stents are frequently ‘passivated’ both to reduce theircorrosion potential and to improve their biocompatibility (this latter for bare metal stents).Passivation is a process of controlled oxidation using either thermal or chemical treatmentor a combination of both. It is important to know the depth of the passivation treatment (figure 4) to establish that it has been successfully achieved. This can be High Depth Resolution SIMS Profile measured using surface mass spectrometry operating in depth profiling 1.E+06 60 Ni mode. The substrate surface is 56 Fe continuously sputtered with an ion beam 52 Cr and the material so removed continuously 72 FeO mass analysed to establish the depth of Signal Intensity (Arbitrary Units) 68 CrO 18 O oxidation achieved. The technique is 1.E+05 12 C depth resolved to nanometre precision. Where the stent is to be coated, as with drug-eluting stents, the surface asperity of the bare stent needs to be controlled to 1.E+04 ensure that an even coating can be achieved (whilst retaining sufficient roughness to allow for the effective keying of the coating). This has consequences for the thickness of coating required, as 1.E+03 will be seen below. Surface roughness is 0 5 10 15 measured using a non-contact white light Depth / nm interferometric method which generates a 3D image of the surface with nanometre Figure 4: Secondary Ion Mass resolution in the vertical dimension and Spectrometry (SIMS) analysis, indicating allows an area surface roughness the relative level of key elements as a parameter to be generated for the area function of depth in a passivated metal sampled (figure 5). Surface of coated stent Surface of bare metal stent Figure 5: 3-D profiling (light interferometry) comparing surface roughness of a stent strut before and after coating – 2D image with ‘thermal’ z-axis colour scale 4
  6. 6. For coated stents, the coating layer thickness (be it primer coat, top coat or both together) can also be measured using white light interferometry. In this application a surface image is generated by focussing alternately on the substrate surface and the coating surface then subtracting the two data sets pixel by pixel to generate a coating thickness 3D image. This can be measured directly to give an average coating thickness or presented as a line profile to show the variation in thickness along, or across/around, the stent dimensions with nanometre resolution. The reader will have gathered that this process generates a 3D roughness image for the outer surface of the coated stent which is, in itself, an important characteristic in relation to the deployment of the stent in the patient. Fig. 6: Thickness Map - Statistical Fig. 7: Line profile along stent axis Method - Measure two ends and - mean thickness 4.4 microns middle with 120o rotation As noted earlier, coated stents carry slow release anti-rejection drug entities which are distributed throughout the coating layer. Such stents are routinely tested in vitro to establish the kinetics of the slow release performance of the coating under repeat elution exposure. The distribution of the drug moieties within the coating - particularly with depth - is of prime importance in establishing the potential efficacy of the slow release mechanism in practice. This can be measured using depth profiling mass spectrometry. The method allows for the continuous depth measurement of drug, coating and substrate simultaneously as the coating is sputtered with an incident ion beam. In this way the depth to which drug molecules are depleted after elution exposure is directly known. In tests at CERAM it has been shown that for certain drug/coating combinations it is possible for drug elution to be restricted to the outermost few microns of the coating despite the fact that several microns of coating need to be applied in order to ensure a minimum coating thickness at all points due to the surface roughness of the substrate.5 Trends in stent R&DGiven that the first bare metal stent entered the market in 1994, the technology is far frommature. At the Transcatheter Cardiovascular Therapeutics conference held in Scranton,USA in November/December 2009 the next generation of stent technologies was discussed.Whilst drug eluting stents will be improved through the use of what are described as more‘cell friendly’ (i.e. more hydrophobic) coatings and adapted (by using CFD in stent design) tovarying wall sheer conditions, the industry is already well down the road of developingbioresorbable coatings and even bioresorbable stents. Such systems are already on limitedtrial in Europe with FDA trials aimed at 2012 and approval by 2015. Bioresorbable polymeric 5
  7. 7. stents (Abbott) were recently in the news and represent a highly attractive concept; forexample, the ability to avoid potential (metal) stent fracture during restenosis (andassociated migration of stent fragments) is a desirable goal. In using all-polymer stents thateventually fully dissolve, a fine balance is required between having a structure that remainsstrong enough to open the artery for a given time period but which will then dissolve at adesirable rate. There is also the issue of the by-products that are created duringbiodegradation - they must be formed at a rate that the body can deal with. Polymers arealso versatile, in that drug chemistry can be bonded to the polymer backbone, as opposed tobeing dispersed within the polymer chains.An alternative bioresorbable material is magnesium and its alloys. These have been trialledbut shown to offer no particular advantages versus existing BMS, DES.There are still other areas under study including thinner struts which are important in termsof giving improved stent flexibility, a reduced cross-sectional profile within the vessel andpotentially reduced restenosis (due to reduced vascular trauma). Cr-Co alloys could offerstrength advantages for thinner stents. Sandwich structures, such as a tantalum layer placedbetween stainless steel layers, could also be a route to greater strength. Manufacturingmetal stents via additive layer manufacturing could offer flexibility in terms of more complexgeometries.Reducing restenosis remains important and concern that ion release from the metalsemployed in stents assists restenosis has led to work on alternative coatings to reduce ionrelease. Silicon carbides, carbon coatings, titanium nitride/oxide and sputtered indium oxidehave all been trialled as routes to reducing the incidence of restenosis and/or thrombosis.The need to improve coatings for drug elution (see above) has given rise to research oninorganic coatings. Polymer coatings often require a bond layer to induce compatibility.Parylene coatings can be used to link metal to polybutylmethacrylate co-polymer coatings.Inorganic coating solutions under investigation include nano-porous alumina layers and sol-gel hydroxyapatite layers.A recent paper3 discussing the role of nano-ceramics for drug delivery points, in general, to anumber of benefits of these over polymers. Although focussing on particulates, theconclusions are relevant to nano-particulates as coatings. Ceramic nano-particulates areknown to have longer biodegradation times, allowing longer-term release of associateddrugs. Unlike polymers, ceramic nano-particles do not swell as a result of changes totemperature or pH. Such swelling can be associated with sudden undesirable bursts ofreleased drugs. The high surface area to volume ratio of nano-particles (or nano-porousstructures created from particles) offers scope for retaining higher levels of drug. There iscurrently a great deal of interest in calcium phosphate nano-materials for drug release.There is evidence to show that this chemistry offers sustained release of drugs oversignificant time periods and the ability to offer discrete “on-off” release triggered by astimulus such as ultrasonics.CERAM is currently developing novel, nano hydroxyapatites containing one or moresubstituent chemistries. Although aimed initially at the bone replacement market, this IPRand technology could potentially have applications in the area of drug-delivering stentcoatings. Another approach under investigation is to make biodegradable ceramic stents byemploying polymer as a binder. Bioceramics of very high porosity of nanometre scale havebeen successfully developed at CERAM. The challenge is to make the stent degrade at the 6
  8. 8. right time either naturally or by triggering mechanisms internally and/or externally and tomake the degradation in a way so as not to produce any degraded materials that wouldblock the blood vessel.SummaryStents have played a vital role in improving patient quality-of-life without resorting to majorsurgery. Even with a history of barely 25 years, significant improvements have been made tocombat the twin threats of restenosis and thrombosis. It is clear that by embracing polymersand polymer-ceramics as well as metals, together with nanotechnology, stent developmentswill continue for many years.References1. T.W. Duerig et al. Min Invas Ther & Allied Technol 2000, 9(3/4) p 235-2462. O’Brien and Worrall. Acta Biomaterialia Vol 15, p 945-9583. Lei Yang, B.W.Sheldon, T.J. Webster, Am Cer Soc Bull, Vol 89, No.2, p24-31 7
  9. 9. Queens Road, Penkhull, Stoke-on-Trent, Staffordshire ST4 7LQ, United Kingdom tel: +44 (0)1782 764428 or +44 (0)845 026 0902 fax: +44 (0)1782 412331 email: enquiries@ceram.com web: www.ceram.com/medicalCERAM IS THE TRADING NAME OF CERAM RESEARCH LIMITED. REGISTERED IN ENGLAND. NO.:1960455. REGISTERED OFFICE AS ABOVE. 8

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