The intra-vascular stent as a site-specific local drug delivery system

The current review focuses on utilization of a tubular structure (coated or uncoated, balloon expandable or self expanding) known as a “stent” for localized intravascular drug delivery. Emphasis of the review is on technologies currently employed for immobilization and coating for drug onto the stent prior to its placement in various lumen of the body. A brief discussion on stent design, comparison of angioplasty and coronary stenting, and market status complements the review for researchers new to this area.     

An integrated compliant balloon ultrasound catheter for intravascular strain imaging

An integrated compliant balloon ultrasound catheter was developed to allow greater deformations in strain imaging with intravascular ultrasound. A 64-element circumferential array was placed inside a compliant silicone balloon catheter to capture real-time, phase-sensitive radio frequency (RF) data during deformation experiments. Strains over 40% could be applied to normal arterial wall tissue with intracatheter pressures as low as 200 kPa (2 atm). Strain images of a hard-soft rubber phantom, thrombus, and fibrotic plaque were produced using the integrated balloon ultrasound catheter. Results show that this catheter can apply large deformations at low pressures and image various vascular pathologies ex vivo. Potentially, it can serve as a multifunctional, intravascular therapeutic device to guide angioplasty and stent deployment.     

不同材料冠状动脉支架膨胀行为分析

冠状动脉支架作为经皮穿刺冠状动脉成形术中保持病变血管畅通的核心器件,其在手术过程中受球囊作用的扩张特性以及球囊撤出后的反弹行为对支架植入术的成功有着重要的影响.利用有限元的方法系统,建立专有支架单独膨胀和血管支架膨胀模型,分析了316L不锈钢和L605钴铬合金两种材料支架筋尺寸和支架扩张尺度的变化及血管对其膨胀行为的影响.结果显示,支架所选材料是决定支架膨胀行为的主要因素,L605材料支架所需的临界内压力及反弹行为明显大于316L不锈钢支架;材料一定时,增加支架筋的宽度或厚度提高支架迅速扩张临界内压力;支架轴向长度的变化只与结构和最终膨胀状态相关.有限元模拟对支架性能的评价和设计有一定指导意义.     

Drug‐Coated Angioplasty Balloon Catheters: Coating Compositions and Methods

Flow‐limiting stenosis or total occlusion of coronary, cerebral, or peripheral arteries is very common. Minimally invasive treatment with balloon catheters optionally combined with stent implantation immediately relieves symptoms. However, renarrowing of dilated vessel segments due to excessive scar formation frequently reverses the initial success observed soon after treatment. Coating of balloons with antiproliferative drugs is a promising approach to overcome this problem. The coating of angioplasty balloon membranes is a challenging task. It must ensure homogeneous distribution of the antiproliferative agent and adherence to the balloon membrane during handling and on the way to the treatment site in a distant artery, where the agent should be immediately released and transferred to the vessel wall when the balloon is inflated. In vitro and in vivo testing methods are described. The impact of different kinds of balloons, drugs, additives, and coating methods has been investigated, and the results of representative examples including clinically tested products are presented and discussed.     

Internal dosimetry for radiation therapy in coronary arteries

Acute myocardial infarction, which occurs because of the occlusion of one or more coronary arteries, is the most common form of cardiovascular disease. Balloon angioplasty is often used to treat coronary artery occlusion and is less invasive than surgery involving revascularisation of the myocardium, thus promising a better quality of life for patients. Unfortunately, the rate of re-stenosis after balloon angioplasty is high (approximately 30-50% within the first year after treatment). Intravascular radiation therapy has been used with several types of radiation source, and researchers have observed some success in decreasing the rate of re-stenosis. In this paper theoretical radiation dose distributions for monoenergetic electrons (with discrete energies) and photons are calculated for blood vessels of diameter 1.5, 3.0 and 4.5 mm with balloon and wire sources using the radiation transport code MCNP4B. Stent sources employing 32P are also simulated. Advantages and disadvantages of the radionuclides and source geometries are discussed, as well as issues regarding possible benefits to the patients.     

Inorganic materials as drug delivery systems in coronary artery stenting

Recent studies proved coronary stent implantation to be superior over conventional angioplasty in the treatment of coronary artery disease. However, restenosis remains one of the most crucial problems in interventional cardiology. Inflammatory infiltrates and foreign body reactions can be found in the tissue surrounding the struts in stenting. Thrombogenesis, proliferation of α‐actin expressing cells (smooth muscle cells) and hyperplasia of the intima occur. In order to improve the biocompatibility of the stents, new stent designs and stent coatings have been developed. One advantage of stent coating is the combination of mechanical stability of the stent with the biocompatibility of the coating. The coatings are divided into active and passive coatings. Passive coatings improve the biocompatibility of the stent, while active coatings may suppress neointima proliferation by releasing anti‐inflammatory or antiproliferative substances. Immunosuppressive drugs (tacrolimus, sirolimus) and cytostatic drugs (paclitaxel) have been tested in several studies and showed promising results. However, it could also be demonstrated that polymer‐coated stents used as a matrix for drug release reduced the hyperplasia of the intima. However, after dissipation of the immunosuppressants or cytostatics, the presence of the polymer itself lead to a delayed inflammation and proliferation causing restenosis. Thus, efforts have been made to develop inorganic coatings that are suitable for drug loading. One promising approach is a new nanoporous alumina coating. Preliminary tests with this coating revealed favourable loading characteristics and sustained drug release in vivo. The present article provides an overview on different approaches for stent coatings.     

Surface and depth profiling investigation of a drug-loaded copolymer utilized to coat taxus express2 stents

The surface of a styrene-b-isobutylene-b-styrene triblock copolymer, containing a solid-phase drug, was studied by time-of-flight secondary ion mass spectrometry employing 15-keV Ga+ and 20-keV C60+ ion sources. This polymer/drug system has direct application in the cardiac stent arena, where it has been used to treat restenosis or renarrowing of arterial walls after stent or angioplasty procedures. Overall, the results illustrate the successful use of a cluster ion beam for greatly enhancing the high-mass fragment ion and molecular ion intensities from the surface and bulk of the polymer system. The use of C60+ also established the ability to remove common overlayers like poly(dimethylsiloxane), which was not possible using a Ga+ ion source. Furthermore, the use of C60+ allowed depth profiles to be obtained using primary ion dose densities in excess of 6 x 1014 C60+/cm2. Resultant sputter craters reached depths of approximately 2 microm and possessed relatively flat bottoms without the need for sample rotation. AFM and profilometry studies support the relatively gentile removal of surface species via phase contrast and topographic imaging. In addition, the findings suggest that relatively high ion doses do not significantly alter the phase distribution or surface topography of the polymer surface; however, a slight increase in surface roughness was detected.     

Beta radiation exposure of medical staff and implications for extremity dose monitoring

Sealed and unsealed beta radiation sources come into use to a greater extent in radiation therapy, e.g. for treating inflammatory joint diseases by radiosynoviorthesis (RSO), by injecting (90)Y, (186)Re or (169)Er-solutions. Sealed (90)Sr/(90)Y and (32)P-sources or (188)Re-liquid-filled balloon catheter are applied in vascular brachytherapy. Recently, (90)Y-labelled antibodies are being successfully used in radioimmunotherapy (RIT) of malign lymphoma. Such practices require handling of high activities at small distances to the skin. Thus, the medical staff may be exposed to high beta doses. Investigations of the extremity exposure were performed at several workplaces, in particular during RSO treatments. The local skin dose (LSD), Hp(0,07), was measured with thin-layer TLD (LiF:Mg,P,Cu) fixed to the fingers (TLD-tapes). The findings indicate that the exposure of the staff can exceed the annual dose limit of 500 mSv when working at low protection standard. Routine monitoring of the extremity exposures with ring dosemeters appropriate to beta radiation and provided by the approved German dosimetry services was found to be needed. But even monitoring with these official 'beta-dosemeters' does mostly not give suitable results to demonstrate compliance with the dose limit. A study was conducted at RSO-workplaces in order reveal a correlation between doses measured with ring dosemeters and the maximum LSD obtained from the TLD-tapes. The results are discussed and conclusions for routine monitoring are drawn.     

Radiation dose distribution in polymer gels by Raman spectroscopy

The Raman spectroscopy of polymer gel dosimeters has been investigated with a view to developing a novel dosimetry technique that is capable of determining radiation dose within a micrometer of spatial resolution. The polymer gel dosimeter, known as the PAG dosimeter, is typically made up of acrylamide, N,N'-methylene-bis--acrylamide, gelatin, and water. A polyacrylamide network within the gelatin matrix forms in response to an absorbed dose. The loss of monomers may be monitored by corresponding changes to the Raman spectrum. Principal component analysis offers a simple method of quantifying the absorbed radiation dose from the Raman spectrum of the polymer gel. The background luminescence in the spectrum increased significantly with dose and is shown to originate in the glass of the sample vial. The competing effects of elastic scatter, which increases with dose due to the formation of polymer, and sample absorption were quantified and found to introduce errors of up to 5% under certain conditions. Raman spectra as a function of distance from the air-surface interface have been measured for samples that were subjected to doses delivered by a clinical linear accelerator. The depth dose profile thus obtained compared favorably with "gold standard" ion-chamber measurements.     

Biocompatibility of Coronary Stent Materials: Effect of Electrochemical Polishing

Percutaneous Transluminal Coronary Revascularization (PTCR) is now a widely accepted treatment modality for atherosclerotic coronary artery disease. Current multicenter randomized trials comparing PTCR with the more invasive Coronary Artery Bypass Grafting could not show long‐term significant survival differences. During the last two decades progress has been made to further optimize PTCR. The most logic approach to treat atherosclerotic coronary narrowings is to remove the atherosclerotic material using especially developed devices. Several trials, however, could not show a significant beneficial outcome after use of these devices compared to plain old balloon angioplasty. Another approach was to implant a coronary prothesis (stent), scaffolding the diseased coronary artery after PTCA. This approach resulted in a decreased restenosis rate at follow‐up. The beneficial effects of stenting, however, was not found to be related to the inhibition of the neointimal cellular proliferation after vascular injury, but simply to be the mechanical result of overstretching of the treated vessel segment. The most important remaining clinical problem after stenting remains the neointimal hyperplasia within the stent, resulting in a significant stent narrowing in 13 to 30 % of patients. Further efforts to improve the clinical results of coronary stenting should focus on the reduction of this neointimal hyperplasia. Neointimal hyperplasia after stent implantation results from (1) a healing response to the injury caused by the stent implantation and (2) a foreign body response to the stent itself. Factors that seem to influence the neointimal hyperplastic response are genetic, local disease related, stent delivery related and stent related factors. Biocompatibilisation of coronary stents by looking for more biocompatible metal alloys, optimized surface characteristics and optimized stent designs should result in a better late patency. Furthermore drug eluting and radioactive stents are under development in order to decrease the neointimal hyperplastic response.     

Numerical investigation of influence of number of stent cells and type of link on expansion and haemodynamic behaviour of balloon-expandable coronary stent

Coronary stents are tubular, mesh-like structures used to force open clogged artery. Mounted on an inflatable balloon, stent compresses calcified plaque inside atherosclerotic artery with an inflating device, which transfers the load through the compliant balloon, thus maintaining the patency of lumen. One of the contributors for success of angioplasty is type of stents, which mainly differs in its geometrical design. A clinician recommends a stent based on comparative advantages. An ideal stent should be flexible to manoeuver through tortuous artery, easy to expand, provide good scaffolding to the vessel, have less radial recoil and foreshortening, possess uniformity in expansion and induce minimum alteration in physiological blood flow dynamics. In a stent these parameters are in competition with each other and are optimized by trade-offs. The present work tries to sequentially investigate the effect of number of stent cells and type of links on the expansion and haemodynamics behaviour through computational analysis based on finite element and finite volume techniques. The study compares performance within same classes of designs rather than comparing the designs that are completely different form each other. Results show that more number of stent cells in longitudinal direction considerably decrease the radial recoil, but increase the foreshortening effect. Restenosis-prone zones are localized around the stent struts and are predominant during end of systolic phase of cardiac cycle. Shorter links are preferred for better recoil and favourable distribution of wall shear stress while longer links are preferred for favourable foreshortening.     

Biological weighting of absorbed dose in radiation therapy

Absorbed dose is a quantity which is scientifically rigorously defined and used to quantify the exposure of biological objects, including humans, to ionising radiation. There is, however, no unique relationship between absorbed dose and induced biological effects. The effects induced by a given absorbed dose to a given biological object depend also on radiation quality and temporal distribution of the irradiation. In radiation therapy, empirical approaches are still used today to account for these dependencies in practice. In hadron therapy (neutrons, protons, ions), radiation quality is accounted for with a diversity of (almost hospital specific) methods. The necessity to account for temporal aspects is well known in external beam therapy and in high dose rate brachytherapy. The paper reviews the approaches for weighting the absorbed dose in radiation therapy, and focusses on the clinical aspects of these approaches, in particular the accuracy requirements.     

An integrated semicompliant balloon ultrasound catheter for quantitative feedback and image guidance during stent deployment

An integrated balloon ultrasound catheter prototype was designed to image from inside the balloon for real-time guidance during stent deployment. It was fabricated using a semicompliant balloon material (polyethylene) and a 20 MHz, 64-element circumferential ultrasound array. A commercial stent, nominally 4.4 mm in diameter and 12 mm in length, was used for a phantom study and placed along the length of the integrated balloon ultrasound catheter. A rubber phantom was created with an elastic modulus of 175 kPa with a 4.36 mm diameter lumen. Real-time balloon pressure measurements were recorded using a digital pressure sensor, and real-time radio-frequency (RF) data were captured as the balloon was inflated. The slope of the area-pressure ratio (APR) was compared to a reference measure of the balloon and stent expanded in water to determine a measure for optimal stent deployment. The results clearly indicate stent deployment at 11.1 atm using this metric. The APR slope could serve as quantitative feedback parameter for guiding stent deployment to reduce arterial injury and subsequent restenosis. After the stent deployment experiment, RF data were captured as the balloon catheter was moved along the length of the stent in pullback mode to confirm successful stent deployment. Ultimately, an integrated balloon ultrasound catheter could serve as a single catheter intervention device by providing real-time intravascular ultrasound (IVUS) imaging and quantitative feedback during stent deployment.     

Estimation of doses to personnel and patients during endovascular brachytherapy applications

In the last few years coronary endovascular brachytherapy using gamma- and beta-emitting radionuclides has been established as a standard treatment procedure to prevent restenosis after percutaneous coronary interventions. Direct measurements and calculations were made to determine personnel doses and organ doses of patients due to gamma rays of 192Ir and beta rays of 90Sr/90Y and 32P sources. In general, our results show that the dose levels are low compared with the X-ray exposure from angiography. The dose rate from bremsstrahlung at 1 m distance from a device containing a 90Sr/90Y source of 2.3 GBq is 4 micro Sv h(-1). The skin dose from beta rays during source transfer into and from the patient was estimated with the directional dose equivalent H'(0.07) of 10 micro Sv at 1 m distance from the catheter. By maintaining safe distances, the dose levels can be kept well within annual dose limits.     

Radiochromic dye film studies for brachytherapy applications

Commercial radiochromic dye films have been used in recent years to quantify absorbed dose in several medical applications. In this study we present the characterisation of the GafChromic MD-55-2 dye film, a double sensitive layer film suitable for photon irradiation in brachytherapy applications. Dose measurements were carried out with a low dose rate 137Cs brachytherapy source, which produces very steep dose gradients in its vicinity, and therefore requires the capability of producing high spatial resolution isodose curves. Quantification of the dose rate in water per unit air kerma strength was obtained using a high-resolution transmission commercial scanner (Agfa DuoScan T1200 with the capability of digitising up to 600 x 1200 pixels per inch using 36 bits per pixel, together with optical density measurements. The Monte Carlo calculations and experimental measurements compared well in the 0-50 Gy dose interval used in this study.     

A fibre optic scintillator dosemeter for absorbed dose measurements of low-energy X-ray-emitting brachytherapy sources

A newly developed dosemeter using a 0.5 mm diameter x 0.5 mm thick cylindrical plastic scintillator coupled to the end of a fibre optic cable is capable of measuring the absorbed dose rate in water around low-activity, low-energy X-ray emitters typically used in prostate brachytherapy. Recent tests of this dosemeter showed that it is possible to measure the dose rate as a function of distance in water from 2 to 30 mm of a (103)Pd source of air-kerma strength 3.4 U (1 U = 1 microGy m(2) h(-1)), or 97 MBq (2.6 mCi) apparent activity, with good signal-to-noise ratio. The signal-to-noise ratio is only dependent on the integration time and background subtraction. The detector volume is enclosed in optically opaque, nearly water-equivalent materials so that there is no polar response other than that due to the shape of the scintillator volume chosen, in this case cylindrical. The absorbed dose rate very close to commercial brachytherapy sources can be mapped in an automated water phantom, providing a 3-D dose distribution with sub-millimeter spatial resolution. The sensitive volume of the detector is 0.5 mm from the end of the optically opaque waterproof housing, enabling measurements at very close distances to sources. The sensitive detector electronics allow the measurement of very low dose rates, as exist at centimeter distances from these sources. The detector is also applicable to mapping dose distributions from more complex source geometries such as eye applicators for treating macular degeneration.     

Absorbed dose measurements of a handheld 50 kVP X-ray source in water with thermoluminescence dosemeters

Absorbed dose rate measurements of a 50 kV(p) handheld X-ray probe source in a water phantom are described. The X-ray generator is capable of currents of up to 40 microA, and is designed for cranial brachytherapy and intraoperative applications with applicators. The measurements were performed in a computer-controlled water phantom in which both the source and the detectors are mounted. Two different LiF thermoluminescence dosemeter (TLD) phosphors were employed for the measurements, MTS-N (LiF:Mg,Ti) and MCP-N (LiF:Mg,Cu,P). Two small ionisation chambers (0.02 and 0.0053 cm(3)) were also employed. The TLDs and chambers were positioned in watertight mounts made of water-equivalent plastic. The chambers were calibrated in terms of air-kerma rate, and conventional protocols were used to convert the measurements to absorbed dose rate. The TLDs were calibrated at National Institute of Standards and Technology (NIST) in terms of absorbed dose rate using a (60)Co teletherapy beam and narrow-spectrum X-ray beams. For the latter, absorbed dose was inferred from air-kerma rate using calculated air-kerma-to-dose conversion factors. The reference points of the various detectors were taken as the center of the TLD volumes and the entrance windows of the ionisation chambers. Measurements were made at distances of 3-45 mm from the detector reference point to the source center. In addition, energy dependence of response measurements of the TLDs used was made using NIST reference narrow spectrum X-ray beams. Measurement results showed reasonable agreement in absorbed dose rate determined from the energy dependence corrected TLD readings and from the ionisation chambers. Volume averaging effects of the TLDs at very close distances to the source were also evident.     

Evaluation of Coronary Stents in the Animal Model: A Review

Metallic vascular endoprotheses (stents) have been introduced clinically to help to retain or to restore a patent vascular lumen after balloon angioplasty and to improve long-term patency of vessels. Despite the widespread use of intracoronary stents, instent restenosis remains a major clinical problem. During the last years considerable research effort had been spent on the understanding of the pathophysiology of restenosis and developing strategies to prevent this major shortcoming of PTCA and stent implantation. The current review focuses in its first part on basic pathophysiological mechanisms, which are involved in the formation of restenosis after ballon angioplasty and stent implantation. In the second part different animal models are presented, which serve as experimental models for examining these processes and testing strategies for the prevention of restenosis. Advantages and disadvantages of each model will be discussed, which are important when transferring results from animal models to clinical practice.     

Smooth contact strategies with emphasis on the modeling of balloon angioplasty with stenting

Critical to the simulation of balloon angioplasty is the modeling of the contact between the artery wall and the medical devices. In standard approaches, the 3D contact surfaces are described by means of C⁰‐continuous facet‐based techniques, which may lead to numerical problems. This work introduces a novel contact algorithm where the target surfaces are described by polynomial expressions with C²‐continuity. On the basis of uniform cubic B‐splines, two different parametrization techniques are presented and compared, while the related implementation of the algorithm into a finite element analysis program is described. Two numerical examples are selected to demonstrate the special merits of the proposed contact formulation. The first example is a benchmark contact problem selected to point out the special features of the proposed strategies. The second example is concerned with the simulation of balloon angioplasty and stenting, where the contact between the balloon, the stent and the artery wall is numerically modeled. A patient‐specific 3D model of a stenotic femoral artery serves as a basis. The study concludes by identifying the changes in the mechanical environment of the artery in terms of contact forces and strains by considering two different stent designs. Copyright © 2008 John Wiley & Sons, Ltd.     

Exploitation of nano alumina for the chromatographic separation of clinical grade 188Re from 188W: a renaissance of the 188W/188Re generator technology

The (188)W/(188)Re generator using an acidic alumina column for chromatographic separation of (188)Re has remained the most popular procedure world over. The capacity of bulk alumina for taking up tungstate ions is limited (～50 mg W/g) necessitating the use of very high specific activity (188)W (185-370 GBq/g), which can be produced only in very few high flux reactors available in the world. In this context, the use of high-capacity sorbents would not only mitigate the requirement of high specific activity (188)W but also facilitate easy access to (188)Re. A solid state mechanochemical approach to synthesize nanocrystalline γ-Al(2)O(3) possessing very high W-sorption capacity (500 mg W/g) was developed. The structural and other investigations of the material were carried out using X-ray diffraction (XRD), transmission electron microscopy (TEM), Brunauer Emmett Teller (BET) surface area analysis, thermogravimetric-differential thermal analysis (TG-DTA), and dynamic light scattering (DLS) techniques. The synthesized material had an average crystallite size of ～5 nm and surface area of 252 ± 10 m(2)/g. Sorption characteristics such as distribution ratios (K(d)), capacity, breakthrough profile, and elution behavior were investigated to ensure quantitative uptake of (188)W and selective elution of (188)Re. A 11.1 GBq (300 mCi) (188)W/(188)Re generator was developed using nanocrystalline γ-Al(2)O(3), and its performance was evaluated for a period of 6 months. The overall yield of (188)Re was >80%, with >99.999% radionuclidic purity and >99% radiochemical purity. The eluted (188)Re possessed appreciably high radioactive concentration and was compatible for the preparation of (188)Re labeled radiopharmaceuticals.