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• Proprietary nature of intravascular medical device coatings limits safety testing
  Rashi I Mehta, Ansaar T Rai, James W Simpkins and Rupal I Mehta
  Published on: 15 November 2019
• The Device Specific Nature of Polymer Coating Emboli: An Optimal Approach For Future Investigations Related to Polymer Embolism
  Amitabh M Chopra, Yin C Hu and Juan P Cruz
  Published on: 15 November 2019

• Published on: 15 November 2019

  Proprietary nature of intravascular medical device coatings limits safety testing

  • Rashi I Mehta, Neuroradiologist West Virginia University Department of Neuroradiology
  • Other Contributors:
    • Ansaar T Rai, Interventional Neuroradiologist
    • James W Simpkins, Director, Center for Basic and Translational Stroke Research
    • Rupal I Mehta, Neuropathologist

  Proprietary nature of intravascular medical device coatings limits safety testing

  Dear Dr. Albuquerque:

  We are glad that our work has generated interest and discussion in the field [1]. Four years have elapsed since a need for updated device coating testing was officially announced [2], however complexities on the matter and persistent knowledge gaps limit safety studies of devices currently on the market for clinical intravascular use [3,4]. Standardized in vitro particulate generation testing is needed. However, available literature shows that preclinical device testing is not fully predictive of clinical response. Therefore, in vitro and animal studies cannot replace investigation in humans. Currently, lack of consensus on the following prevent meaningful testing in humans: I) optimal clinical testing methods; ii) definitions of permissible risk; iii) adverse cellular, organ, and temporal-specific effects of distinct coating biomaterials; and iv) effects of pre-existing comorbid conditions. Nevertheless, in vitro testing that does not incorporate clinical data has limited utility for safety guidance. Likewise, in vivo studies that do not incorporate biomaterial factors are incomplete. Thus, the proprietary nature of intravascular device coatings remains a significant limitation to clinical device testing and safety assurances. Growing data [2-6] suggest that it may be time for this to be addressed.

  1. Chopra AM, Hu YC, Cruz JP. The Device Specific...

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  Proprietary nature of intravascular medical device coatings limits safety testing

  Dear Dr. Albuquerque:

  We are glad that our work has generated interest and discussion in the field [1]. Four years have elapsed since a need for updated device coating testing was officially announced [2], however complexities on the matter and persistent knowledge gaps limit safety studies of devices currently on the market for clinical intravascular use [3,4]. Standardized in vitro particulate generation testing is needed. However, available literature shows that preclinical device testing is not fully predictive of clinical response. Therefore, in vitro and animal studies cannot replace investigation in humans. Currently, lack of consensus on the following prevent meaningful testing in humans: I) optimal clinical testing methods; ii) definitions of permissible risk; iii) adverse cellular, organ, and temporal-specific effects of distinct coating biomaterials; and iv) effects of pre-existing comorbid conditions. Nevertheless, in vitro testing that does not incorporate clinical data has limited utility for safety guidance. Likewise, in vivo studies that do not incorporate biomaterial factors are incomplete. Thus, the proprietary nature of intravascular device coatings remains a significant limitation to clinical device testing and safety assurances. Growing data [2-6] suggest that it may be time for this to be addressed.

  1. Chopra AM, Hu YC, Cruz JP. The Device Specific Nature of Polymer Coating Emboli: An Optimal Approach For Future Investigations Related to Polymer Embolism. Journal of Neurointerventional Surgery.
  2. U.S. Food and Drug Administration Lubricious Coating Separation From Intravascular Medical Devices FDA Safety Communication. Silver Spring MD: FDA; 2015. Available at: https://wayback.archive-it.org/7993/20161022044037/http://www.fda.gov/Me.... Accessed September 11, 2019.
  3. Mehta RI, Rai AT, Vos JA, et al. Intrathrombus polymer coating deposition: a pilot study of 91 patients undergoing endovascular therapy for acute large vessel stroke. Part I: Histologic frequency. Journal of NeuroInterventional Surgery Published Online First: 18 May 2019. doi: 10.1136/neurintsurg-2018-014684
  4. Mehta RI , Mehta RI. Hydrophilic polymer embolism: implications for manufacturing, regulation, and postmarketsurveillance of coated intravascular medical devices. J Patient Saf 2018 [Epub ahead of print 19 Mar 2019].doi:10.1097/PTS.0000000000000473
  5. Mehta RI , Mehta RI , Solis OE , et al. Hydrophilic polymer emboli: an under-recognized iatrogenic cause of ischemia and infarct. Mod Pathol 2010;23:921–30.doi:10.1038/modpathol.2010.74
  6. Mehta RI , Mehta RI. Hydrophilic polymer embolism: an update for physicians. Am J Med 2017;130:e287–90.doi:10.1016/j.amjmed.2017.01.032

  Sincerely,
  Rashi I. Mehta, MD
  West Virginia University
  Department of Neuroradiology

  Ansaar T. Rai, MD
  West Virginia University
  Department of Neuroradiology

  James W. Simpkins, PhD
  West Virginia University
  Department of Physiology and Pharmacology
  Center for Basic and Translational Stroke Research
  Rockefeller Neuroscience Institute

  Rupal I. Mehta, MD
  University of Rochester
  Center for Translational Neuromedicine

  Acknowledgments: RIM (Rashi I Mehta) is supported by a grant from the National Institute of General Medical Sciences of the National Institutes of Health (5U54GM104942-03). RIM (Rupal I Mehta) is supported by a grant from the National Institute of Neurological Disorders and Stroke (K08NS089830).

  Competing interests: ATR serves as a consultant for Stryker Corporation.

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  Conflict of Interest:
  ATR serves as a consultant for Stryker Corporation.

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• Published on: 15 November 2019

  The Device Specific Nature of Polymer Coating Emboli: An Optimal Approach For Future Investigations Related to Polymer Embolism

  • Amitabh M Chopra, Chemical Engineer / Medical Researcher Self Employed
  • Other Contributors:
    • Yin C Hu, Department of Neurosurgery
    • Juan P Cruz, Department of Radiology

  An increasing number of reports highlight polymer coating embolism as an iatrogenic complication of intravascular medical devices [1-3]. Autopsies, histologic evaluations of thrombectomy specimens, samples of captured debris, resected or biopsied tissues, are available methods used to study polymer emboli post investigative catherizations or interventional procedures. Reported data highlight the prevalence of this phenomenon and/or its clinicopathologic impacts, however, fall short of identifying higher-risk polymer emboli interventional devices. Consequently, an optimal approach for future investigations related to polymer coating embolism is required.

  Mehta et. al investigate the histologic frequency of polymer emboli among patients who underwent endovascular thrombectomy for treatment of acute ischemic stroke due to large vessel occlusion by retrospectively evaluating thrombectomy specimens [2]. In this study, the reported frequency of polymer emboli includes the use of various devices and techniques among selected cases. However, literature highlights polymer coating embolism is device specific and dependent on coating integrity measured by particulates released [4]. Thus, the use of alternate devices with higher or lower particulate release for a given procedure may result in a large variation in incidence rates from reported results. Also, as mentioned by the authors, subsequent statistical correlations unless appropriately powered provide limited informatio...

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  An increasing number of reports highlight polymer coating embolism as an iatrogenic complication of intravascular medical devices [1-3]. Autopsies, histologic evaluations of thrombectomy specimens, samples of captured debris, resected or biopsied tissues, are available methods used to study polymer emboli post investigative catherizations or interventional procedures. Reported data highlight the prevalence of this phenomenon and/or its clinicopathologic impacts, however, fall short of identifying higher-risk polymer emboli interventional devices. Consequently, an optimal approach for future investigations related to polymer coating embolism is required.

  Mehta et. al investigate the histologic frequency of polymer emboli among patients who underwent endovascular thrombectomy for treatment of acute ischemic stroke due to large vessel occlusion by retrospectively evaluating thrombectomy specimens [2]. In this study, the reported frequency of polymer emboli includes the use of various devices and techniques among selected cases. However, literature highlights polymer coating embolism is device specific and dependent on coating integrity measured by particulates released [4]. Thus, the use of alternate devices with higher or lower particulate release for a given procedure may result in a large variation in incidence rates from reported results. Also, as mentioned by the authors, subsequent statistical correlations unless appropriately powered provide limited information on higher-risk or culprit devices. Consequently, in addition to providing limited value, use of histologic evaluations of thrombi (or autopsies) to exclusively evaluate incidence rates may be time-consuming and have a high resource burden. Notably, this may not be the intent of the authors of this study who elude to an article series.

  Few studies related to polymer coating embolism have included controls over procedures and specific devices used. For example, histologic evaluations of captured debris within cerebral protection devices during a mitral valve repair procedure highlighted polymer coating type material in 12 of 14 cases [5]. The source of polymer emboli was speculated to be from the mitral valve repair catheter and/or adjunct devices. In another study, intracranial polymer emboli incidence rates were determined for a branded hydrophilic coated guide sheath used for carotid and iliac stenting procedures respectively in Yucatan miniswine [6]. Since the experimental stents and stent delivery systems lacked any coating, impacts of polymer emboli were isolated to the coated guide sheaths, guide catheters and guidewires used during the procedures. These studies with controls over procedures and devices may be leveraged to understand an incidence rate from a specific set of interventional devices repetitively used during a given procedure. Notably however, even this approach is unable to provide device specific information or identify higher-risk interventional devices as the origin of emboli are difficult to determine.

  Device type, coating composition-device substrate material combinations, coating application processes, coating thickness and degree of coating coverage are variables that impact polymer coating integrity on a device [4,7]. Particulate generation testing – the determination of a count, shape and size of particulates released from a device when used in an in-vitro vessel model – is the industry standard for evaluating polymer coating integrity from an intravascular device [8]. An intuitive correlation exists between particulates released in-vitro and the polymer emboli incidence rates [4]. Thus, particulate generation testing may be used to compare particulates released and understand relative incidence rates among intravascular devices. In-vitro particulate testing is an effective and efficient approach to determining higher-risk particulate release devices and may assist in identifying culprit interventional devices.

  Based on the aforementioned study methodologies and outcomes, the following approach may be outlined for future investigations related to polymer coating embolism: a) Autopsy based studies that typically lack device information or controls over prior procedures should be limited to determining clinicopathologic impacts of polymer emboli. For these studies, estimating a particulate burden to correlate impacts with the quantity of polymer emboli for each area of assessment is relevant; b) Histologic evaluations of thrombi, captured debris, resected or biopsied tissues are also effective in determining localized disease processes. These methods may be used to determine incidence rates for a procedure if devices are consistently repeated for selected cases. For these studies (and postmortem investigations) combining incidence rates with particulate test data from devices will assist in categorizing embolic risk and determine higher risk devices; c) When clinical presentations preclude the consistent use of devices for a procedure, animal studies may be used to determine incidence rates. Extrapolating clinical impacts from healthy animals maybe acceptable, however, investigations that include relevant disease conditions are preferred; d) In-vitro particulate generation testing may be the optimal method to rank embolic risk and determine higher risk polymer emboli devices.

  Inclusion and exclusion criteria for polymer emboli related investigations are essential for meaningful results. Patient history should be carefully evaluated as prior procedures may impact incidence rates. For this reason, patients with a history of multiple interventional procedures should be excluded from studies that attempt to determine polymer emboli frequencies. This patient subset may be included for studies determining potential impacts from polymer emboli for a worst-case scenario assessment. All investigations should include device specific information such as type, dimensions (e.g. length, diameter), brand, coating types (e.g. hydrophilic and/or hydrophobic) and coated dimensions. Other important parameters include patient baseline characteristics, procedural length, device in-dwell time (if available) and procedural outcomes.

  Comparing particulate data among devices or reporting the magnitude of embolic burden may require assumptions to characterize total particulate volume. For the aforementioned studies, use of an efficient light obscuration methodology for particulate assessments that provides an equivalent circular diameter for particle areas may be used [9]. Combined with a uniform 1-micron height representing the typical lamellar nature of polymer particulates [3], a cylindrical volume calculation for each particle may be optimal. Summation of particle volumes may provide a total particulate burden per device or affected area of inspection.

  The FDA continues to work with stakeholders to create tools which permit the standardization of particulate test methods and enable comparisons among devices [10]. Till these standards become available, investigations should include assumptions used to generate particulate data. In the future, an accumulation of procedural and device particulate data with associated incidence rates and clinicopathologic impacts may provide actionable input for regulators for setting device particulate limits. Given the sparse literature on this subject, more studies with controls over procedural parameters and devices used are required. Procedures with devices exposed to larger frictional forces (e.g. chronic total occlusions, aortic repair, or atherectomy), or aqueous environments for longer durations (e.g. percutaneous mechanical circulatory support) should be prioritized for future studies.

  Acknowledgements, Funding Sources, Disclosures & Author Contributions
  Acknowledgements: None. No persons other than the listed authors have made contributions to this manuscript.
  Funding Sources: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
  Disclosures: None. Authors declare no current relationship with industry and no conflicts of interest.
  Author Contributions: All authors have contributed to this manuscript.

  References:
  1. Chopra AM, Mehta M, Bismuth J, et al. Polymer coating embolism from intravascular medical devices - a clinical literature review. Cardiovasc Pathol 2017;30:45-54.
  2. Mehta RI, Rai AT, Vos JA, Solis OE, Mehta RI. Intrathrombus polymer coating deposition: a pilot study of 91 patients undergoing endovascular therapy for acute large vessel stroke. Part I: Histologic frequency. J Neurointerv Surg. Epub ahead of print 18 May 2019. doi: 10.1136/neurintsurg-2018-014684.
  3. Hickey TB, Honig A, Ostry AJ, et al. Iatrogenic embolization following cardiac intervention: postmortem analysis of 110 cases. Cardiovasc Pathol 2019;40:12-18.
  4. Babcock DE, Hergenrother RW, Craig DA, Kolodgie FD, Virmani R. In Vivo Distribution of Particulate Matter from Coated Angioplasty Balloon Catheters. Biomaterials 2013;34(13):3196-205.
  5. Frerker C, Schlüter M, Sanchez OD, et al. Cerebral Protection During MitraClip Implantation: Initial Experience at 2 Centers. JACC Cardiovasc Interv. 2016;9(2):171-9.
  6. Stanley JR, Tzafriri AR, Regan K, et al. Particulates from Hydrophilic-Coated Guiding Sheaths Embolize to the Brain. EuroIntervention 2016;11(12):1435-41.
  7. Work JW. Technical white paper: considerations for hydrophilic surface coatings on medical devices [internet]. Biocoat, Inc. Horsham, PA, USA. 2016. Available from www.biocoat.com. Accessed 22 Apr 2016.
  8. Center for Devices and Radiological Health Recognized Consensus Standards. Recognition number 3-99: AAMI TIR42:2010 Evaluation of Particulates Associated with Vascular Medical Devices (cardiovascular) [Internet]. 2010. Available from: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/detail.cf.... Accessed Jan. 13, 2019.
  9. AAMI TIR42:2010. Evaluation of Particulates Associated with Vascular Medical Devices. Arlington, VA: Association for the Advancement of Medical Instrumentation, 2010.
  10. ASTM WK60510. New Test Method for Simulated Use Testing of Neurointerventional Device in Tortuous Vasculature. West Conshohocken, PA: American Society for Testing and Materials International, 2018.

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  Conflict of Interest:
  None declared.

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