An evaluation of current research and medical applications
Mentor: Dr. John Karanian
Director of FDA Center for Cardiovascular and Interventional Therapeutics
Mr. Charles Ashcraft
Glenelg High School
This project investigated current stent implantation techniques with a focus on the development of safer and more effective treatments. By researching every aspect of work currently being completed in the field, from new stent devices to more detailed, less invasive scanning technology, it is possible to better grasp the research in its entirety and what can be done to improve a device that is implanted in over one million Americans annually. Focusing also on the regulation and control of current medical devices, this study aimed to provide insight into the one of the medical community’s most controversial devices, both heralded as a revolution in minimally invasive cardiac therapy and criticized as a misused, dangerous, and potentially life-threatening device. Additionally, highlighting the specific design of stents themselves, quantitative analysis of stent function within a biological environment has been crucial to understanding the affects of arterial change (torsion, compression, bending, etc) on stent effectiveness and safety, an important element in predicting the device’s long term performance. Computer simulation and reanimation continues to be a deciding factor in the modeling of vascular pathways, through which experimental designs can be tested without the need for animal trials, a pre-clinical stage that routinely undergoes change as animal models do not always provide the most accurate representations of projected biological conditions within human patients. Further research is needed to continue the development of new intra-vascular devices, and could provide additional insight into the relationships present between the biological and mechanical aspects of cardiovascular and interventional therapeutics.
Table of Contents
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A Stent can be defined as any device inserted into a biological pathway to keep it open or clear it of blockages.1 Used in a wide-array of treatments today, from supporting the esophagus after the removal of a cancerous lining to correcting aneurysms and atherosclerosis within arterial vessels, stents provide an invaluable service to patients, allowing a countless number of recipients every year to continue leading healthy, active lifestyles. Found in either a bare metal or drug-eluting state, stents continuously evolve and change, from both a mechanical and pharmaceutical standpoint. Made primarily of stainless steel, bare metal stents are also found with compositions of nitinol, TiN, and TiO2.2 Drug eluting stents on the other hand, while comprised of the same materials, include common anti-inflammatory agents, immunosuppressant’s (inhibits neointimal tissue growth), mitotic inhibitors, and anti-platelet formulations (Sirolimus, Paclitaxel, etc). In response to the rejection of metal stents by the body and the resulting scarring that occurs, new biodegradable stents made of carbon and polymer frameworks have exhibited promising results and depict the future of interventional medicine, as they do not undergo rejection and match the surrounding organic enviorment.3
Another aspect of stent implantation involves quantitative analysis of stent implant sites and arterial shifts that occur with natural body movement. Given that stents are specifically designed for specific ranges of motion through geometric configuration, understanding the role of an implant sites affect through torsion, bending, axial strain (linear movement), and compression is crucial in designing stents that can serve as multi-purpose treatments, a device needed in order to halt the excessive mal-application of stent grafts that occurs in today’s surgical setting, where , for example, stents meant specifically for the carotid artery have instead been applied to the femoral artery. This shift drastically alters the operating parameters of the stent’s implant site, therefore changing the conditions under which the stent has been developed to operate within.4
Testing new stent designs in today’s field of research involves complex approval procedures, with pre-clinical trials, commonly consisting of animal studies, as the backbone of development. Current research into testing substitutes for common porcine or rodent studies could allow a greater degree accuracy to be attained, increasing the validity of a project and/or pre-clinical study. By using cell cultures or genetically modified test subjects, simulated environments may further display those parameters present in human patients, a goal that would not only quicken device approval, but would also reduce cost and increase resource potential of regulatory and research agencies.5 Additionally, building upon the resource potentials of modern medical centers, it remains crucial to continually evaluate new technological devices, as it is important not only to provide the best possible information to a physician or scientist, but also to identify those devices which represent the greatest benefit to a practice or research institution. Overall, aiming to identify patterns in data and new medical applications, this project highlighted current research and emphasized the various sectors involved in the development of more effective and safe stent treatments.
This project consisted of a multifaceted approach to interventional therapeutics, harnessing multiple tools in the investigation and research of current applications and pre-clinical trials. As seen in a project completed on quantitative mapping of vascular geometry, the computer program cvSim® has been used to analyze computed tomography angiography images in order to identify vascular deformations occurring through a wide range of motion. After doing so, vascular path lines may then be drawn in order to identify changes in torsion, compression, bending, and axial strain.4 This information was then analyzed to reveal that changes in motion do indeed affect vascular geometry, with each new position creating a unique mix of alterations.
Moving on, the use of advanced scanning equipment continues to provide invaluable assistance in the development and testing of new stent designs. Including intravascular ultrasound, CT, and magnetic resonance imaging (all with the addition of fluoroscopy), scanning techniques continue to evolve in the search for the most detailed and reliable data. Another aspect of the technology involved in interventional therapeutics takes the form of guidance devices, which may be the next step in further simplifying the process of treating arterial disease and other ailments. With such innovations as EM tracking making medical procedures far safer given their ability to guide physicians around obstacles, such as blood vessels, arteries, and other vital areas, they represent another key component of stent design and application.6 Overall, by applying such technology in order to better understand the relationships present between interventional procedures and the biological environments within which they operate, new treatments may reach development both more quickly and safely, giving more patients the opportunity to receive the best treatment possible.
Stents today represent a wide array of solutions available for treating both cardiovascular and other pathway based ailments. Unfortunately though, they continue to be misused with side affects including restinosis (re-narrowing of the arteries) and total stent failure. Beginning first with the treatment of restinosis, it is evident that approximately 20 - 25% of all drug-eluting stent procedures result in restinosis, as compared with 35 - 40% in bare metal operations.7 Although this improvement seems positive in terms of short-term recovery, it does not express the fact that when compared to bare metal stents, drug-eluting stents exhibit a lower long term survival rate, as seen in a New England study in which the survival rates of patients with sirolimus eluting stents remained at 93.3%, in comparison to bare metal stents with a 94.6% survival rating. Additional complications, such as diabetes, also magnified this difference, expanding it to 87.8% and 95.6% respectively.7 Albeit, although this study later reflected that no significant differences between bare metal and drug eluting stents existed, another study completed by the Columbia University Medical Center somewhat contradicted its findings, as although it agreed that cumulative death rates were equitable, it was found that stent thrombosis after 1 year was more common in drug-eluting stents than in traditional bare metal treatments.9 Citing another article studying the effects of drug-eluting stents (DES) on neointimal thickness, it was clearly stated that “DES have limitations such as stent thrombosis because of local and long-term endothelial dysfunction and inflammation” 10. Given this information, research must continue on the development of less biologically hazardous compounds, with an emphasis on the encouragement of long term re-endothelialization needed in the prevention of stent thrombosis, a primary contributor to stent failure.
In addition to clinical solutions to stent malfunction based upon specific drug elution, the effect of stent material and composition on performance is another key factor in evaluating overall safety and effectiveness. Evaluating the effects of varying materials on endothelial cell growth, a study completed by a group of Taiwanese doctors compared metallic sheets of stainless steel, nitinol, and the stainless steel coated with both TiN and TiO2 for differences in cell culture growth.10 Concluding that all the metal formulations tested in the study exhibited anti-endothelialization properties due to the production of nitric acid, a sign of endothelial dysfunction, it can be projected that research must continue on the development of new polymer and carbon based stents that do not exhibit the rejection properties found in modern metal stent designs. As seen in a study completed in Beijing, China, new bio-degradeble polymer-coated DES significantly reduce early in-stent neointimal formation (3 months), after which complications involving both drug-induced inflammatory response on the arterial surface and variations in drug concentration (drug delivery) forced neointimal proliferation to normal non-polymer levels. This study represents an important step in the development of organic-based stents and depicts the promise polymer based coatings and new compositions could hold in reducing in-stent thrombosis.3
Representing another aspect of stent development, pre-clinical trials and the analyzation of data depict a growing problem in the design and approval of new devices. Just recently, as seen in a study completed at the FDA’s center for interventional therapeutics, quantitative mapping of vascular pathways has become an important step in understanding the effects of body position on changes in the parameters of individual pathways, including torsion, bending, compression, and axial strain. Finding that arterial conditions change rapidly with the modification of position, this study concluded that deformations could be leading to stent fracture and/or failure.4 Further research and continued exploration of the biomechanical relationships present between stents and vascular pathways will be important in understanding what is occurring, allowing new treatments to better suit the environment in which they will be operating. Continuing on, as stated in this study, animal models need to be continually improved in order to insure statistical validity and relevancy in terms of human application. Further options should also be pursued to assist in not only speeding up pre-clinical trials, but also in assuring that the most affective and economic means our used in the approval process.
The continued use of stents in the medical field today carries not only the possibility of success in improving the lives of patients, but also that of danger, especially with the continued appearance of in-stent restinosis and thrombosis. By effectively understanding the field of research as a whole, and applying modern technology in the pursuit of safer, more effective treatments, the threat of stent failure, whether it be a result of a specific stent-based drug, a certain material, or geometric configuration, may be reduced, improving the livelihoods of the millions who suffer from pathway based ailments every year.
I would like to especially thank Dr. John Karanian, Director of the FDA’s center for cardiovascular and interventional therapeutics, for giving me the immense opportunity to experience the most advanced stent research program currently being completed in the field of medicine. His guidance has inspired not only my personal interest in interventional therapeutics, but also has filled me with extensive knowledge of the field and its many components. I also would like to thank Mr. Charles Ashcraft, Director of the Glenelg Gifted and talented research program, for his invaluable help in the development of this research project, and much needed guidance that has led to such a successful school year. Finally, I would like to thank my father, Dr. John Baker, for making this project possible and his continued support throughout the school year.
- What is a Stent? (n.d.). Retrieved May 27, 2010, from
- Yeh, H.-I., Lu, S.-K., Tian, T.-Y., Hong, R.-C., Lee, W.-H., & Tsai, C.-H.
(n.d.). Comparison of endothelial cells grown on different stent materials.
- Peng, H.-Y., Chen, M., Zheng, B., Wang, X.-G., & Huo, Y. (n.d.). Long term
Effects of Novel Biodegradeble, Polymer-Coated, Sirolimus-Eluting Stents on
Neointimal Formation in a Porcine Coronary Model.
- Karanian, J. W., Lopez, O., Rad, D., McDowell, B., Kreitz, M., Esparza, J., . .
. Pritchard, W. F. (n.d.). Quantitative Mapping of Vascular Geometry for
- Leigh Perkins, L. E. (n.d.). Preclinical Models of restinosis and their
application in the evaluation of DRus-Eluting Stent systems.
- Karanian, J. W., PhD., Jaoudeh, N. A., MD., Glossop, N., PhD., Cleary, K., PhD.,
Chiesa, O. A., DVM, PhD., Dreher, M., PhD., . . . Wood, B. J., MD. (n.d.).
Translational Technologies in EVAR: Multimodality Interventions.
- Hamilos, M. I., Papafaklis, M. I., Ligthart, J. M., Serruys, P. W., & Sianos, G.
(n.d.). Stent Fracture and Restinosis of a Paclitaxel-Eluting Stent.
- Spaulding, C., Daemen, J., Boersma, E., Cutlip, D. E., & Serruys, P. W. (n.d.).
A Pooled Analysis of Data Comparing Sirolimus-Eluting Stents with
- Stone, G. W., Moses, J. W., Ellis, S. G., Schofer, J., Dawkins, K. D., Morice,
M.-C., . . . Leon, M. B. (n.d.). Safety and Efficacy of Sirolimus and
Paclitaxel-Eluting Coronary Stents.
10. Miyauchi, K., Kasai, T., Yokayama, T., Aihara, K., Kurata, T., Kajimoto, K., . .
. Daida, H. (n.d.). Effectiveness of Statin-Eluting Stent on Early
Inflammatory Response and Neointimal Thickness in a Porcine Coronary Model.
11. Yeh, H.-I., Lu, S.-K., Tian, T.-Y., Hong, R.-C., Lee, W.-H., & Tsai, C.-H.
(n.d.). Comparison of endothelial cells grown on different stent materials.