Annals of Biomedical Engineering, Vol. 42, No. 12, December 2014 (Ó 2014) pp. 2416–2424 DOI: 10.1007/s10439-014-1088-3

Design and Validation of a Novel Ferromagnetic Bare Metal Stent Capable of Capturing and Retaining Endothelial Cells SUSHEIL UTHAMARAJ,1 BRANDON J. TEFFT,2 MARTIN KLABUSAY,3 OTA HLINOMAZ,4 GURPREET S. SANDHU,2,5 and DAN DRAGOMIR-DAESCU1,5 1

Division of Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; 2Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; 3Integrated Center of Cellular Therapy and Regenerative Medicine, ICRC, St. Anne’s University Hospital, Pekarska 53, 65691 Brno, Czech Republic; 4Department of Cardioangiology, ICRC, St. Anne’s University Hospital, Pekarska 53, 65691 Brno, Czech Republic; and 5Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA (Received 16 May 2014; accepted 4 August 2014; published online 20 August 2014) Associate Editor Andreas Anayiotos oversaw the review of this article.

improve patient outcomes. Incomplete or delayed endothelialization requires administration of extended anti-platelet therapy to prevent thrombosis; however such therapies increase bleeding risk and may be contraindicated in certain patient populations.10 Consequently, there is significant clinical need to develop strategies for rapid and complete endothelialization of implanted cardiovascular devices in order to mitigate thrombogenic risk without the need for long-term antiplatelet therapy.38 Vascular stents are lifesaving cardiovascular devices, but they are typically fabricated from thrombogenic materials such as stainless steel, cobalt chromium, and platinum chromium. For this reason, anti-platelet therapy is administered to prevent thrombus formation on the stent. Bare metal stents (BMS) heal rapidly and usually do not require long-term anti-platelet therapy beyond approximately 6 weeks [The American College of Cardiology (ACC) and American Heart Association (AHA) guidelines recommend up to 12 months for all stents], but they are prone to late-stage restenosis due to incomplete healing. Drug eluting stents (DES) are less prone to late-stage restenosis, but they require long-term anti-platelet therapy and are prone to late-stage thrombosis due to delayed healing.2,28 The ideal stent will heal rapidly to achieve blood compatibility without the need for anti-platelet therapy and will heal completely to mitigate late-stage restenosis. Coating stents with blood compatible materials such as gold or various biopolymers has been shown to improve thrombo-resistance in the initial stages of healing;9 however, optimal blood compatibility can only be achieved by a monolayer of endothelial cells.40

Abstract—Rapid healing of vascular stents is important for avoiding complications associated with stent thrombosis, restenosis, and bleeding related to antiplatelet drugs. Magnetic forces can be used to capture iron-labeled endothelial cells immediately following stent implantation, thereby promoting healing. This strategy requires the development of a magnetic stent that is biocompatible and functional. We designed a stent from the weakly ferromagnetic 2205 stainless steel using finite element analysis. The final design exhibited a principal strain below the fracture limit of 30% during crimping and expansion. Ten stents were fabricated and validated experimentally for fracture resistance. Another 10 stents magnetized with a neodymium magnet showed a magnetic field in the range of 100–750 mG. The retained magnetism was sufficiently strong to capture magnetically-labeled endothelial cells on the stent surfaces during in vitro studies. Magnetically-labeled endothelial cell capture was also verified in vivo after 7 days following coronary implantation in 4 pigs using histological analysis. Images of the stented blood vessels showed uniform endothelium formation on the stent surfaces. In conclusion, we have designed a ferromagnetic bare metal stent from 2205 stainless steel that is functional, biocompatible, and able to capture and retain magnetically-labeled endothelial cells in order to promote rapid stent healing. Keywords—Magnetic stent, Stent healing, Endothelialization, Finite element analysis, Restenosis, Thrombosis.

INTRODUCTION Endothelialization of implanted cardiovascular devices has the potential to reduce morbidity and Address correspondence to Dan Dragomir-Daescu, Division of Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Electronic mail: [email protected]

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Ó 2014 Biomedical Engineering Society

Magnetic Stent Design, Cell Capture and Animal Studies

Several strategies have been explored for endothelializing vascular stents. Seeding stents with endothelial cells prior to implantation is not feasible with traditional balloon-deployed stents, but may be possible with self-expanding nitinol stents.1,14,15 Post implantation capture of circulating endothelial progenitor cells (EPC) by utilizing antibodies or ligands offers the advantage of self-seeding of an off-the-shelf stent; however, limited numbers of circulating stem cells and non-specific cell capture remain major hurdles.7,8,39 A very promising strategy is to deliver endothelial cells to the stent following implantation. This strategy requires a means to rapidly capture cells during a brief blood flow occlusion period and then subsequently retain them on the surface following restoration of blood flow. We have developed a strategy that utilizes magnetic forces to rapidly capture endothelial cells to the surface of a stent immediately following implantation.30 A critical component of this strategy is a functional and biocompatible stent with sufficient magnetic properties to capture and retain magnetically-labeled endothelial cells. The purpose of this study was to develop a mechanically functional and magnetizable bare metal stent that can be used to treat coronary heart disease (CHD) with only a short duration of anti-platelet therapy. The stent design was accomplished by using computer aided design (CAD) and finite element analysis (FEA). Design validation was accomplished by fabricating stents and inspecting them for mechanical failure following mechanical crimping and expansion. The stents were also tested for their ability to capture magnetically-labeled endothelial cells using both in vitro and large animal implantation studies.

METHODS Material Identification and Stent Design Commercially available stents are constructed from non-magnetic materials (e.g., 316L stainless steel, cobalt chromium alloy, and platinum chromium alloy), so fabrication of a magnetic stent required novel material selection and design. Stents must exhibit a variety of characteristics including flexibility, low yield stress, radio-opacity, thrombo-resistance, inflammation resistance, corrosion resistance, minimal MRI footprint, and radial-strength.13,19,41 Identifying a magnetic material that satisfied these criteria was especially challenging since most magnetic materials are brittle and/or non-biocompatible. Nevertheless, even a weakly magnetic material has the potential to capture magnetically-labeled cells and thereby achieve blood compatibility.32,37

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We surveyed candidate materials and identified a duplex stainless steel known as 2205 stainless steel (2205 SS) (UNS S31803/S32205) that not only has similar corrosion and mechanical properties to those of 316L stainless steel but also has weak ferromagnetic properties. This material was used in subsequent design, fabrication, and testing. Design and Verification Using FEA We used SolidWorks 2009 (Dassault Syste`mes, Providence, RI, USA) to generate a CAD model of the stent design (Fig. 1). We designed the stent to have a total length of 10–18 mm and to open a 3 mm diameter vessel, which are typical parameters for human coronary applications. The stent structure consisted of Z-shaped elements connected together with peak-topeak cross-members to allow for the bending flexibility necessary for the stent to reach the implantation site for deployment.36 It is critically important for a stent to withstand large plastic deformation without fracture and to exhibit minimal recoil. This is because the stent must crimp onto a balloon, expand with the balloon, and radially support the vessel without excessive distortion after balloon removal. The plastic strains are determined by the material’s stress–strain behavior and also largely dependent upon the geometry of the struts.27 To assess effective strains in the stent, the strut crosssection was designed as a square and the edge length of the cross-section was varied. Fabricating a prototype stent is expensive and FEA is an invaluable tool for quickly studying various iterations of stent designs for mechanical properties and stress–strain behavior during the crimping and relaxation followed by expansion and final relaxation. This process was modeled using FEA to incorporate nonlinear material behavior and large deformation. To build the FEA model, a CAD parasolid file was imported into the finite element software package Abaqus 6.9-EF (Dassault Syste`mes, Providence, RI, USA). The resulting three-dimensional solid was meshed using 20 node brick elements with reduced integration (C3D20R). Reduced integration elements were used because of their superior convergence and computational efficiency. In addition to using an 8point integration scheme instead of a 27-point integration scheme, 20-node brick elements with reduced integration are more tolerant to shape distortions.4,5 Virtual topology was used to combine different faces of the geometry to enable the sweep meshing technique. Three stent strut rings were modeled and the complete finite element model contained a total of 103,350 elements with 569,123 nodes.

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FIGURE 1. Stent geometry used to manufacture stents from 2205 stainless steel tubes.

FIGURE 2. Flow chart depicting the finite element simulation of a 2205 stainless steel stent undergoing the crimping and expansion process (outer crimping cylinder not shown for clarity).

An outer rigid cylinder, which acts as the crimping tool, was modeled to be slightly larger than the outside diameter of the undeformed stent. An inner rigid cylinder, which acts as the expansion balloon, was modeled to have an initial diameter of 1 mm. The crimping cylinder’s inner surface and the stent’s outer surface were established as one contact pair while the stent’s inner surface and the expansion cylinder’s outer surface were established as another contact pair. The entire elasto-plastic stress–strain behavior of 2205 SS with an initial Young’s modulus of 200 GPa and a Poisson’s ratio of 0.265 was used to model the stent material.21 Boundary conditions for the stent domain were applied to allow radial crimping and expansion, but a boundary condition of Uz = Uh = 0 was applied to a single node of the stent to avoid rigid body motion (the coordinate system is shown in Fig. 2). Frictionless rigid contact was defined between the crimping cylinder’s inner surface and the stent’s outer surface during the crimping stage as well as between the stent’s inner surface and the expansion cylinder’s outer surface during the expansion stage. The first step in the FEA simulation was crimping whereby the crimping cylinder was radially contracted in cylindrical coordinates to a diameter of 1 mm to simulate the plastic deformation of the stent onto a balloon. Following crimping, the next step was to

remove the crimping cylinder so as to allow the stent to relax to its equilibrium configuration. The next step in the FEA simulation was expansion whereby the expansion cylinder was radially expanded in cylindrical coordinates to a diameter of 3 mm to simulate the plastic deformation of the stent to the deployment size. Following expansion, the final step was to remove the expansion cylinder so as to allow the stent to recoil to its equilibrium configuration. A schematic of the entire crimping and expansion FEA process is shown in Fig. 2. The simulation was carried out using 12 cores (AMD Opteron 8384, 2700 MHz) with 256 GB of RAM. The stress–strain behavior of the candidate stent designs was analyzed and the design including the size of the cross sectional dimension was iteratively improved by a trial and error method until suitable mechanical behavior was achieved. Stent Fabrication and Mechanical Testing Based on the FEA simulation results, the stent design was finalized and modeled in SolidWorks as a flat pattern for laser cutting. Stents were manufactured by laser cutting and electro-polishing at LaserageÒ, Inc. (Waukegan, IL, USA) in the undeformed state. The stents were acid pickled to further improve the

Magnetic Stent Design, Cell Capture and Animal Studies

surface quality, passivate the surface, and remove organic debris.42 The stents were then mechanically tested by crimping onto a clinical tri-fold balloon catheter using a handheld crimping tool (Blockwise Engineering, LLC., Tempe, AZ, USA) and then expanded to 3 mm using a clinical inflation device (n = 10 stents). The crimped and expanded stents were then inspected by microscopy for signs of fracture or uneven expansion. Magnetization of Stents The stents were magnetized using a neodymium rare earth magnet at 2 different orientations since the orientation of the field lines passing through the stent determined how the dipoles were aligned within the stent material. When the stent was magnetized with field lines passing diametrically, the achieved magnetic field of the stent was also aligned diametrically. When the stent was magnetized with field lines passing axially, the magnetic field of the stent was also aligned axially. The stents were then carefully removed from the magnet such that the field lines continued to pass through the stents in the same direction to prevent misalignment of the dipoles (n = 10 stents). The magnetized stents were inspected for retained magnetism above background with a Spin TJ magnetometer (Micro Magnetics, Fall River, MA, USA) at 8 bent segments and 16 straight segments for each stent and compared to a non-magnetized control stent. In Vitro Cell Capture Studies In vitro studies were used to determine the effectiveness of cell capture to the magnetic stents. Endothelial outgrowth cells (EOC) were derived from porcine peripheral blood as described previously.11,31 EOC represent a late outgrowth EPC population. In contrast to early outgrowth EPC, late outgrowth EPC are highly proliferative, and feature the ability to directly form tubes and intact vascular vessels. The EOC were labeled with superparamagnetic iron oxide nanoparticles (SPION) by incubation at a concentration of 200 lg per mL of cell culture media for 16 h. EOC naturally endocytosed the SPION and stored them in cytoplasmic endosomes as described previously.32,41 SPION were synthesized as a 10 nm diameter magnetite (Fe3O4) core surrounded by a 50 nm thick poly(lactic-co-glycolic acid) (PLGA) shell as described previously.20 The cells were also stained with a fluorescent dye (CM-DiI, Molecular Probes, Eugene, OR, USA) for imaging. The stents were magnetized at different orientations and exposed to an aqueous suspension of SPION-labeled EOC. Cell capture to the stent surface was imaged using a fluorescence microscope (Zeiss Axioplan, Jena, Germany).

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In Vivo Cell Capture and Retention Studies All animal studies were approved by the Institutional Animal Care and Utilization Committee (IACUC) at Mayo Clinic. Peripheral blood was drawn from Yorkshire pigs weighing approximately 50 kg 3 weeks prior to stent implantation and used to derive autologous EOC as described previously.11,31 Pigs were anesthetized and 1 magnetized 2205 SS stent and 1 non-magnetized control 2205 SS stent were implanted into the right coronary artery (RCA) using standard cardiac catheterization techniques (n = 4 pigs). Approximately 2 9 106 autologous EOC labeled with SPION and CM-DiI were delivered to the RCA during 2 min of blood flow occlusion using an over the wire balloon catheter inflated proximally to the stents. Blood flow was restored after an additional 2 min of occlusion time. After 7 days of implantation, the pigs were sacrificed and the stented arteries were carefully harvested and fixed in 10% formalin buffer. The samples were embedded in plastic, cross-sectioned, and analyzed histologically using H&E stain, Movat’s pentachrome stain, and Prussian blue to stain iron.

RESULTS Design Verification Using FEA FEA simulation of early candidate stent designs undergoing the crimping and expansion process resulted in principal strains in excess of the 30% ultimate strain of 2205 SS, indicating that fracture was likely to occur. The design was improved iteratively by adding material to the bend regions to more evenly distribute the strain at those locations. The FEA simulation of the final stent design with the strut cross section dimensions of 90 lm 9 90 lm resulted in maximum principal strain of 20% for the stent’s flex members, indicating fracture was unlikely with the calculated safety factor of 1.5. This was due in part to the evenly distributed strain across the strut thickness as revealed in sectional views (Fig. 3). Furthermore, the simulation showed that the stent recoiled approximately 4% after the expansion step, which is within acceptable limits. Finally, the stress distribution of the stent’s flex members always remained within the ultimate strength limit of 869 MPa as reported by the CarpenterÒ steel data sheet (Fig. 3). The FEA simulation usually completed within 62 h with total CPU time of 381 h using 12 cores. Mechanical Testing From a total of 80 manufactured stents, 10 were used for mechanical validation. The stents underwent

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FIGURE 4. 2205 stainless steel stent shown (a) crimped onto a balloon and (b) expanded on the balloon to the designed diameter. Scale is 1/2 mm per division.

FIGURE 3. Finite element analysis contour plots of (a) maximum principal strain and (b) von Mises stress of a 2205 stainless steel stent after crimping and expansion.

the process of mechanical crimping and expansion without any macroscopic fracture (Fig. 4). The stents were examined microscopically and no fractures were observed. Crimping and expansion led to very uniform strut patterns and minimal recoil. Comparisons between the mechanically tested stents and their FEA simulations demonstrated suitable qualitative agreement in terms of final strut geometry and dimensions.26 Magnetic Properties The magnetized stents demonstrated varied levels of magnetism retained at different regions as measured by a magnetometer. Axially magnetized stents retained higher average magnetic field at the bent segments (429.3 ± 93.5 mG) and lower magnetism at the straight segments (196.3 ± 28.7 mG). Diametrically magnetized stents generally retained a more uniform

FIGURE 5. Magnetism measurement stations on the stent. Table also shows uniform magnetism in bent and straight segments for diametrically magnetized stent and higher magnetism in bent segments for axially magnetized stent.

average magnetic field as shown by measurements of 293.3 ± 82.5 mG at the bent segments and 298.7 ± 51.0 mG at the straight segments (Fig. 5). Non-magnetized stents showed considerably lower magnetic field with a maximum of about 10 mG both at the straight segments and the bent segments when compared to magnetized stents. The maximum retained magnetism was approximately 750 mG in the magnetized stents. Stronger retained magnetism could not be achieved by longer exposure time or by magnetization with a 3 T MRI, a 5 T capacitive inductor, or an electromagnet. The acquired magnetism was

Magnetic Stent Design, Cell Capture and Animal Studies

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retained indefinitely, but could be diminished upon plastic deformation or mild mechanical shock. In Vitro Cell Capture Studies EOC labeled with SPION showed significantly enhanced attraction to magnetized stents when compared to non-magnetized stents. Cells that came to within a few hundred microns of a magnetic stent’s surface were observed to track towards the stent. Axially magnetized stents generally demonstrated high cell capture to the bent segments and low cell capture to the straight segments. Diametrically magnetized stents generally demonstrated moderate cell capture to both bent segments and straight segments (Fig. 6). These observations are consistent with the retained magnetism measurements described previously and demonstrate that 2205 SS stents can retain sufficient magnetism to capture magnetically-labeled cells in an aqueous suspension. In Vivo Cell Capture and Retention Studies Histological analysis of the explanted stented coronary arteries revealed iron staining near the struts of the magnetized stents (Fig. 7), but no such staining was observed near the struts of the non-magnetized stents. This indicated that magnetized 2205 SS stents possessed sufficient magnetism to capture and retain magnetically-labeled endothelial cells after 7 days of exposure to blood shear stress in the coronary circulation of a large animal model. Furthermore, the ironstained cells were observed to contribute to the formation of a neointima over the stent struts (Fig. 7).

DISCUSSION In this study, we used the weakly ferromagnetic material 2205 SS to develop a mechanically functional stent that could be implanted to support a coronary artery without excessive injury or inflammation. Furthermore, we have shown the 2205 SS stents can be easily magnetized using a rare earth magnet and the retained magnetic field is sufficiently strong to capture and retain magnetically-labeled cells. The design and development of a functional, biocompatible, and ferromagnetic stent was critical because magnetic capture of cells or drugs can potentially mitigate complications related to long term anti-platelet therapy as well as late-stage thrombosis and restenosis in a clinically viable manner. The stent developed in this study was of sufficient quality for short-term porcine implantation and may be suitable for long-term implantation and

FIGURE 6. Fluorescence microscopy images showing cell capture in (a) a non-magnetized stent, (b) a diametrically magnetized stent, and (c) an axially magnetized stent. In the images, the fluorescently labeled cells appear white and the stents appear black.

clinical trials in the future; however, this will require more rigorous design validation. Magnetic stents have been studied previously for drug delivery and healing applications; however, it is unclear if these stents are suitable for cell capture and rapid endothelialization. For example, Palmaz-Schatz stents were developed to retain magnetism for 2 years to induce vessel healing.12,13,23 Our group as well as other groups have generated prototype magnetic stents by coating commercial stents with nickel.31,35 However, nickel is not biocompatible and is often allergenic

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FIGURE 7. Histological cross section of a stented coronary artery from 7 day pig implantation studies showing iron particles stained blue near the strut of a magnetized stent.

and therefore cannot be used clinically. In addition, 304 stainless steel stents are commercially available and demonstrate paramagnetic properties.6,33,34 Cell capture to these stents has been demonstrated in an external magnetic field, but the lack of ferromagnetic properties potentially limits cell retention upon removal of the external magnetic field. Given the limitations of currently available magnetic stents, we designed a ferromagnetic stent capable of rapidly capturing cells to its surface as well as retaining those cells following restoration of blood flow.18,37 While previous stent designs were used as a guide, 2205 SS has a much lower ultimate strain (30%) when compared to 316L stainless steel (70%). Therefore, it was necessary to create a novel design to ensure the yield strain of 2205 SS would never exceed the 30% material limit during the crimping and expansion process. Strut thickness of a BMS is important for preventing strut failure under tensile stress.27 Therefore, this parameter was carefully studied to ensure a mechanically competent design. Our stent’s strut thickness was approximately 90 lm following acid pickling and surface treatments, thus making our stent comparable to the thinnest commercially available BMS.16,29 FEA simulations suggested design modifications in which material was added at the bent segments of the stent struts to help evenly distribute the strain and ensure the yield strain was not exceeded during crimping and expansion. Once the FEA model predicted a mechanically competent design, stents were fabricated and successfully crimped and expanded without observed failure. The duplex microstructure of 2205 SS makes the material weakly ferromagnetic. The characteristics of the retained magnetism of the stent depend upon the orientation of the stent relative to the magnetic field

lines during magnetization. Axially magnetized 2205 SS stents showed preferential cell capture at the bent segments while diametrically magnetized 2205 SS stents showed more uniform cell capture to both the bent segments and the straight segments. Porcine model implantation studies proved that 2205 SS stents can quickly capture and subsequently retain cells upon exposure to coronary blood flow conditions. The porcine animal model used for our in vivo studies healed very quickly; therefore, we did not observe any noticeable difference in healing of control stents as compared to magnetized stents. However, we did observe iron staining from captured and retained iron labeled endothelial cells near the struts of magnetized stents. The material identified in this study for stent manufacturing is weakly ferromagnetic and a novel material with stronger ferromagnetic properties may improve cell capture and subsequent healing. Additionally, our in vivo experiments were limited by the small number of animals used due to the pilot nature of the study. Stents to be used in future long-term implantation studies—both pre-clinical and clinical trials—will require a more rigorously validated design in regard to mechanical integrity, fatigue resistance, chemical/corrosion resistance, and biocompatibility. In the present study, we focused on validation of FEA and mechanical integrity of the stent design during crimping and expansion which is the first stage of failure and also important for all implantation studies. As a part of our continuing work, we are conducting biocompatibility and chemical/corrosion resistance testing of the 2205 SS material. A stent subjected to long-term implantation requires a design that can withstand 108 fatigue cycles. Future work will include stent life cycle testing using fatigue resistance by accelerated simulated physiological loading.25 Rapid and complete endothelialization of a coronary stent is important for facilitating healing and achieving desirable clinical outcomes, but approaches proposed to date have been limited by hurdles including: (1) the need for prolonged seeding time, (2) the lack of an optimal delivery device, and (3) poor adhesion of endothelial cells. Our current approach of targeted attraction of magnetically-labeled endothelial cells shows great promise for achieving rapid and complete endothelialization of stents and the strategy is made more feasible by the successful development of a functional, biocompatible, and ferromagnetic stent.

CONCLUSION We have shown an engineering approach to design and fabricate a functional, biocompatible, and ferro-

Magnetic Stent Design, Cell Capture and Animal Studies

magnetic stent capable of retaining magnetism, capturing endothelial cells, and retaining those cells while implanted in the coronary circulation. Although our research is focused on endothelial cell capture and retention, magnetic 2205 SS stents can be used for other applications including capture of drug loaded nanoparticles,3,6,17,24,35 induction of local hyperthermia,22 and inhibition of restenosis.23 2205 SS may also be useful for functionalizing a variety of other implantable medical devices for local drug and cell delivery applications.

ACKNOWLEDGEMENTS The authors thank Tyra Witt, Cheri Mueske, Brant Newman and Dr. Peter J. Psaltis, MBBS, Ph.D. for their valuable contributions to this study. The authors also thank Drs. Maria Kempe, Ph.D., Shu Q. Liu, Ph.D., Adriele Prina-Mello, Ph.D., and Tre´ R. Welch, Ph.D. for their suggestions in writing this manuscript. This study was financially supported by European Regional Development Fund—FNUSA-ICRC (No. CZ.1.05/1.100/ 02.0123), American Heart Association Scientist Development Grant (AHA #06-35185N) and The Grainger Innovation Fund—The Grainger Foundation.

DISCLOSURES The authors have no relevant disclosures.

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Design and validation of a novel ferromagnetic bare metal stent capable of capturing and retaining endothelial cells.

Rapid healing of vascular stents is important for avoiding complications associated with stent thrombosis, restenosis, and bleeding related to antipla...
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