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Research Letters |

Changes to Polymer Surface of Drug-Eluting Stents During Balloon Expansion FREE

Scott J. Denardo, MD; Paul L. Carpinone, BS; David M. Vock, MS; Christopher D. Batich, PhD; Carl J. Pepine, MD
[+] Author Affiliations

Author Affiliations: Division of Cardiovascular Medicine, Duke University Medical Center, Durham, North Carolina (scott.denardo@duke.edu).


JAMA. 2012;307(20):2148-2150. doi:10.1001/jama.2012.4111.
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Published online

To the Editor: Drug-eluting stents (DES) have advanced percutaneous treatment of coronary artery disease by reducing restenosis. However, DES have not eliminated restenosis, can serve as a nidus for thrombosis, and are associated with microvascular and endothelial dysfunction.1,2 We hypothesized that the polymer surface of DES may be damaged during delivery balloon expansion and that microparticles may detach, which could contribute to these limitations.

We used optical microscopy to systematically image the polymer surface of the 4 US Food and Drug Administration–approved DES following expansion using the accompanying delivery balloon. The manufacturers (DES trade name in parentheses) are Abbott Laboratories (Xience V), Boston Scientific (Taxus Liberté), Cordis (Cypher), and Medtronic (Endeavor). They are deidentified as DES A, B, C, and D. A total of 5 stents were tested from each manufacturer in a vacuum filtration system containing a filtered test medium. Each stent came directly from its original package, premounted on its delivery balloon by the manufacturer, and not directly handled in any way. Although each stent was expanded unconstrained, the tests were otherwise conducted under a range of conditions that mimic regulatory submission requirements and the variability seen in clinical practice and to ensure that conclusions on the effect of manufacturer held averaging over a full range of deployment conditions. The 5 conditions (applied to 1 DES from each manufacturer) were delivery balloon maximum pressure of 9.0 atm, 14.0 atm, or 22.0 atm in deionized water at 25°C; and 14.0 atm in deionized water or plasma at 37°C. For control, a bare-metal stent was expanded using the same technique to a maximum inflation pressure of 14.0 atm in deionized water at room temperature.

Prior to expansion, the abluminal surface of each stent was imaged. Following expansion, all abluminal and adluminal surfaces were imaged. Additionally, all water and plasma solutions were filtered, and the filter and balloon surfaces imaged to identify any microparticles. The definitions of types of damage to polymer are: delamination, complete separation of polymer from stent surface; ridging, dislocation without detachment but with accumulation of polymer to form an elevated mass on the stent surface; webbing, distortion of the polymer such that material is stretched across and partially obstructs an open cell in between stent struts; peeling, partial but incomplete delamination of the polymer, which protrudes into the vessel lumen; and cracking, fine transection through entire polymer thickness.

Dispersive Raman spectroscopy was used for definitive identification of microparticles. Kruskal-Wallis tests were performed to determine if the proportion of the total surface area that was damaged differed by manufacturer. Analyses were performed using SAS version 9.2 and statistical significance was defined by a P value of less than .05 using 2-sided tests.

Prior to balloon expansion, the abluminal polymer surface of DES D showed cracks; abluminal surfaces of all other DES appeared homogeneous. Following balloon expansion, the abluminal and adluminal polymer surfaces of all DES were damaged, affecting 4.6% to 100% of the surface area imaged (Figure and Table). In the Figure, the proportion of the surface area affected by each form of damage relative to the total surface area imaged was determined using quantitative image analysis. For webbing, the area of the 2 bases forming each individual web was used for the calculation.

Place holder to copy figure label and caption
Figure. Representative Damage to the Polymers on the Adluminal Surface of Each Drug-Eluting Stent Following Balloon Expansion
Graphic Jump Location

Each stent shown was 3.0 mm in diameter and 16 to 18 mm in length. The adluminal and abluminal polymer surface of the drug-eluting stents were systematically imaged following balloon expansion using optical microscopy (Olympus BX 60; Olympus America Inc). Magnification was 50 to 500 × . Each polymer surface was imaged at 16 locations (8 adluminal, 8 abluminal), spanning the length of the drug-eluting stents. The locations were predefined in a spiral configuration. For quantitative measurements, the magnification was 100 × . Values in each bin interval are greater than the lower limit of the interval and less than or equal to the upper limit.

Table Graphic Jump LocationTable. Proportion of Polymer Surface Damaged, Microparticles Shed, and Microparticles Adherent to Delivery Balloona

No significant differences were observed between various expansion conditions for each particular DES; therefore results were pooled across conditions. Surface damage ranged from deformation (ridging, cracking, peeling, or webbing) to complete delamination with visually confirmed separation of polymer. The dimensions of damage and of detached microparticles ranged from 2 to 350 μm. Microparticles from all but DES B were confirmed to be polymer. The extent of damage differed by manufacturer (P < .001 for adluminal and P = .002 for abluminal damage).

In this preliminary study, balloon expansion damaged the polymer surface of DES and microparticles detached. The median proportion of total surface damage was associated with polymer type and involved both adluminal and abluminal surfaces.

Polymer damage during balloon expansion of DES has been reported by 2 research groups,3,4 but is disputed by others.5 Additionally, case reports of embolization of polymer fragments from other intravascular devices have been described and correlated with subsequent adverse clinical events.6 However, there have been no published reports pertaining to DES.

Polymer damage and detached microparticles could theoretically contribute to DES-associated complications, including thrombosis, restenosis, and microvascular and endothelial dysfunction. Confirmation of our results would be useful, and further studies should determine physiological and clinical consequences of polymer damage and microparticle detachment. Additionally, the role of other components of DES (eg, drug and stent superstructure) require investigation. Data from this study may be used to calculate sample size for future biomaterial and engineering studies focusing on polymers and microparticles.

Author Contributions: Dr Denardo had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Denardo, Carpinone, Batich.

Acquisition of data: Denardo, Carpinone.

Analysis and interpretation of data: Denardo, Carpinone, Vock, Batich, Pepine.

Drafting of the manuscript: Denardo, Carpinone, Batich, Pepine.

Critical revision of the manuscript for important intellectual content: Denardo, Carpinone, Vock, Pepine.

Statistical analysis: Denardo, Vock.

Obtained funding: Denardo, Pepine.

Administrative, technical, or material support: Denardo, Carpinone, Batich, Pepine.

Study supervision: Denardo, Batich, Pepine.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Denardo reported serving on a speakers bureau for Merck. Dr Batich reported serving as a consultant to Xhale Inc, Materials Consultants Inc, and Akzono Inc; providing expert testimony for Materials Consultants Inc; having grants pending with the National Institutes of Health; receiving royalties from Xhale, QuickMed Inc, and Akzano Inc; and owning stock or stock options in Xhale and Akzano Inc. Drs Carpinone and Pepine and Mr Vock did not report any disclosures.

Funding/Support: This research was supported by the University of Florida Gatorade Fund (<$10 000). Drs Batich and Pepine received support from National Institute of Health Clinical and Translational Science Award UL1 RR029890 to the University of Florida.

Role of the Sponsor: The funding sources had no involvement in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Additional Contributions: We acknowledge James E. Tcheng, MD, and Harry R. Phillips III, MD (Division of Cardiovascular Medicine, Duke University Medical Center, Durham, North Carolina) for their critical review of the data and contribution to the development of this research letter. Neither received compensation for their effort.

Malenka DJ, Kaplan AV, Lucas FL, Sharp SM, Skinner JS. Outcomes following coronary stenting in the era of bare-metal vs the era of drug-eluting stents.  JAMA. 2008;299(24):2868-2876
PubMed   |  Link to Article
van den Heuvel M, Sorop O, van Beusekom HM, van der Giessen WJ. Endothelial dysfunction after drug eluting stent implantation.  Minerva Cardioangiol. 2009;57(5):629-643
PubMed
Otsuka Y, Chronos NA, Apkarian RP, Robinson KA. Scanning electron microscopic analysis of defects in polymer coatings of three commercially available stents: comparison of BiodivYsio, Taxus and Cypher stents.  J Invasive Cardiol. 2007;19(2):71-76
PubMed
Basalus MW, Ankone MJ, van Houwelingen GK, de Man FH, von Birgelen C. Coating irregularities of durable polymer-based drug-eluting stents as assessed by scanning electron microscopy.  EuroIntervention. 2009;5(1):157-165
PubMed   |  Link to Article
Boden M, Richard R, Schwarz MC, Kangas S, Huibregtse B, Barry JJ. In vitro and in vivo evaluation of the safety and stability of the TAXUS Paclitaxel-Eluting Coronary Stent.  J Mater Sci Mater Med. 2009;20(7):1553-1562
PubMed   |  Link to Article
Mehta RI, Mehta RI, Solis OE,  et al.  Hydrophilic polymer emboli: an under-recognized iatrogenic cause of ischemia and infarct.  Mod Pathol. 2010;23(7):921-930
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure. Representative Damage to the Polymers on the Adluminal Surface of Each Drug-Eluting Stent Following Balloon Expansion
Graphic Jump Location

Each stent shown was 3.0 mm in diameter and 16 to 18 mm in length. The adluminal and abluminal polymer surface of the drug-eluting stents were systematically imaged following balloon expansion using optical microscopy (Olympus BX 60; Olympus America Inc). Magnification was 50 to 500 × . Each polymer surface was imaged at 16 locations (8 adluminal, 8 abluminal), spanning the length of the drug-eluting stents. The locations were predefined in a spiral configuration. For quantitative measurements, the magnification was 100 × . Values in each bin interval are greater than the lower limit of the interval and less than or equal to the upper limit.

Tables

Table Graphic Jump LocationTable. Proportion of Polymer Surface Damaged, Microparticles Shed, and Microparticles Adherent to Delivery Balloona

References

Malenka DJ, Kaplan AV, Lucas FL, Sharp SM, Skinner JS. Outcomes following coronary stenting in the era of bare-metal vs the era of drug-eluting stents.  JAMA. 2008;299(24):2868-2876
PubMed   |  Link to Article
van den Heuvel M, Sorop O, van Beusekom HM, van der Giessen WJ. Endothelial dysfunction after drug eluting stent implantation.  Minerva Cardioangiol. 2009;57(5):629-643
PubMed
Otsuka Y, Chronos NA, Apkarian RP, Robinson KA. Scanning electron microscopic analysis of defects in polymer coatings of three commercially available stents: comparison of BiodivYsio, Taxus and Cypher stents.  J Invasive Cardiol. 2007;19(2):71-76
PubMed
Basalus MW, Ankone MJ, van Houwelingen GK, de Man FH, von Birgelen C. Coating irregularities of durable polymer-based drug-eluting stents as assessed by scanning electron microscopy.  EuroIntervention. 2009;5(1):157-165
PubMed   |  Link to Article
Boden M, Richard R, Schwarz MC, Kangas S, Huibregtse B, Barry JJ. In vitro and in vivo evaluation of the safety and stability of the TAXUS Paclitaxel-Eluting Coronary Stent.  J Mater Sci Mater Med. 2009;20(7):1553-1562
PubMed   |  Link to Article
Mehta RI, Mehta RI, Solis OE,  et al.  Hydrophilic polymer emboli: an under-recognized iatrogenic cause of ischemia and infarct.  Mod Pathol. 2010;23(7):921-930
PubMed   |  Link to Article
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