Analysis: Intravascular Devices with a Higher Risk of Polymer Emboli: The Need for Particulate Generation Testing

Abstract

Hydrophilic polymer coatings on intravascular devices lower friction between the device and vasculature, thereby reducing trauma during interventional procedures. Polymer coating embolism—the detachment and downstream embolism of polymer particles—has been reported as an iatrogenic complication of coated interventional devices affecting the vasculature and various organs. The Food and Drug Administration (FDA) acknowledges this complication and continues to work with stakeholders to close gaps in performance testing and standards related to polymer coating integrity. Recent innovations within interventional technologies have led to development of new hydrophilic-coated devices with expanded indications for use. The 2018 FDA draft guidance for intravascular guidewires expands the application of particulate generation testing to most devices and recommends labeling changes to increase industry awareness. This article highlights current procedural trends where the phenomenon of polymer coating embolism may be more prevalent. It describes the mechanisms of polymer separation, reported clinical sequelae, and risk factors for relevant indications. These procedural trends and associated risk factors articulate the need for particulate testing and support the FDA’s draft guidance recommendations for performance testing of applied coatings. If standardized, particulate assessments may allow characterization and comparisons of coating integrity among devices from various manufacturers, and are an important foundation for setting particulate limits. As hydrophilic coatings enable endovascular treatment for a range of patient populations, setting particulate limits or finding alternative solutions without compromise to device function may be essential. Particulate testing is relevant to physicians, regulators, and manufacturers for the purposes of product development and quality improvement of interventional devices.

Hydrophilic polymer coatings are an important addition in the evolution of intravascular devices. These polymers lower the coefficient of friction between the device and vasculature, reduce patient discomfort, and often enable endovascular treatment.^1,2 Polymer coating embolism—the detachment and downstream embolism of polymer particles—has been reported as an iatrogenic complication of coated interventional devices, affecting the heart, lung, brain, and dermal vasculature and contributing to patient morbidity.³ A Food and Drug Administration (FDA) safety communication acknowledges this complication and highlights more than 500 manufacturing defect reports, 11 recalls, and nine mortalities related to polymer separation from intravascular devices, likely representing an underestimate of actual occurrences.⁴ Recently, complex and high-risk interventions have supported the development of new hydrophilic-coated devices with expanded indications for use. The agency’s 2018 draft guidance for interventional guidewires expands the application of coating performance tests, such as particulate generation testing, for most devices and proposes labeling changes to increase industry awareness. ⁵

This article highlights devices with indications where the phenomenon of polymer embolism may be more prevalent. It describes the mechanisms of polymer coating separation, reported clinical sequelae, and risk factors for relevant indications, and presents the need for particulate testing for product development and quality improvement of interventional devices.

Mechanisms of Polymer Coating Separation

Mechanical abrasion and time-dependent chemical degradation are mechanisms by which hydrophilic polymers detach from an interventional device. Mechanical abrasion is a result of device interaction with the vasculature (e.g., atherosclerotic debris) or other devices used to access or treat a lesion. Mechanical abrasion causes incremental strain on chemical bonds within the bulk polymer structure and between the polymer and device substrate. Upon reaching a bond-energy threshold, the chemical bonds break, resulting in coating separation (scraping or peeling) from the device. Figure 1 highlights a schematic of coating separation due to mechanical abrasion.

Figure 1.

Schematic of hydrophilic coating separation from an interventional device due to mechanical abrasion. Hydrophilic polymer top coat (black wavy lines) bonded with device metallic surface (gray) via chemical bonds (red ovals). Bonds within the bulk polymer structure are identified by intersections of overlapping black wavy lines. Highlighted scraping and peeling of hydrophilic coating (short wavy and curved lines) due to mechanical abrasion between device and atherosclerotic plaque (yellow-orange area) within arterial wall. Polymer emboli highlighted by migration of smaller polymer particles (blue arrows) away from device. Blue area indicates water absorption and swelling of hydrophilic polymer.

In time-dependent chemical degradation, bonds within the bulk polymer structure and subsequently between the polymer and device substrate weaken upon contact with saline or pulsatile blood over long durations. Avulsions of hydrophilic polymer in aqueous solutions are reported within 60 minutes, with shedding observed in as few as 15 minutes.⁶, Figure 2 is a representative schematic of time-dependent chemical degradation of hydrophilic coating. Notably, in both mechanisms, the chemical bonds binding the bulk polymer or polymer and device substrate break, resulting in separation of coating from the device.⁷

Figure 2.

Schematic of time-dependent chemical degradation and shedding of hydrophilic coating from an interventional device.

Polymer Coating Emboli Clinical Sequelae

Once within the bloodstream, trace amounts of polymer particles (25–1,300 μm) embolize to distal parts of the vasculature and occlude small- and medium-sized vessels in the heart, lungs, brain, and skin.³ In the heart, the presence of polymer coating emboli has been mostly affiliated with ischemia and infarct.³ In the brain, polymer particles have been associated with round enhancing lesions, surrounding edema, and, in some cases, accompanied by neurologic decline.³ Subcutaneous polymer emboli occluding dermal vessels has resulted in lower extremity skin lesions (petechiae and purpuric patches).³ Polymer emboli are often surrounded by an inflammatory response (i.e., presence of neutrophils and histocytes, formation of giant cells or granulomas). This response is reported to be most intense in the lungs and noted to mimic granulomatosis with polyangiitis.³

High-Risk Polymer Emboli Device Indications and Risk Factors

Percutaneous Mechanical Circulatory Support Devices for Cardiogenic Shock

Percutaneous mechanical circulatory support (pMCS) devices augment blood flow and reduce the heart’s workload by providing circulatory support. Select pMCS devices, introducer sheaths, and arterial and venous cannulae are hydrophilic coated to facilitate device placement or function. For pMCS devices recently indicated for cardiogenic shock with dwell times up to six days,⁸ the risk of hydrophilic coating separation arises from continuous exposure of catheters, sheaths, and/or cannulae to pulsatile blood. Whereas most temporary pMCS catheters (and adjunct devices) are used between 30 and 100 minutes for high-risk percutaneous coronary interventions^9,10 and may present a risk of polymer shedding, the average duration of support for cardiogenic shock is greater than 24 hours.¹¹ With recent innovations of left and right ventricular support devices and sparse data for or against their use in cardiogenic shock, concomitant use of pMCS devices have been explored for select patient profiles (e.g., right ventricular dysfunction or left ventricular distension when on venous-arterial extracorporeal membrane oxygenation).¹² This increases the risk of polymer emboli, as multiple hydrophilic-coated devices, sheaths, or cannulae may be inserted from a number of access sites at the same time. Potentially affected areas include the dermal, peripheral, and cerebral vasculature.³

Catheters and Guidewires for Chronic Total Occlusions

Hydrophilic-coated guidewires, guide catheters, support catheters, and microcatheters enable guidewire access and treatment of chronic total occlusion (CTO) lesions. The J-CTO (Multicenter CTO Registry in Japan) score—a difficulty-grading and time-assessment tool used to determine guidewire crossing within 30 minutes—highlighted 57.8% and 90% failure to cross within 30 minutes for CTOs graded as difficult and very difficult, respectively.¹³ Other CTO grading time-efficiency tools, such as CT-RECTOR (Computed Tomography Registry of Chronic Total Occlusion Revascularization) and KCCT (Korean Multicenter CTO CT Registry) scores, report similar results.^14,15 Among these tools, multiple occlusions, blunt stump, presence of calcification, bending of 45° or more, proximal side branch involvement, and occlusion length of 20 mm or more were variables affiliated with guidewire crossing greater than 30 minutes.^13–15 For difficult CTO cases, a retrograde approach may be adopted, further increasing procedural times (>2 hours)¹⁶ and requiring excessive manipulation with coaxial or triaxial catheterization techniques. These clinical, anatomical, and procedural factors increase the risk of coating separation and subsequent embolism into severely diseased coronary blood vessels.³

Percutaneous Interventional Devices for Structural Heart Diseases

More recently, minimally invasive options have been explored for symptomatic severe aortic stenosis, mitral regurgitation, tricuspid valve regurgitation, degenerative mitral stenosis, and other structural heart conditions. ¹⁷ Percutaneous interventions for structural heart procedures often use larger-diameter hydrophilic-coated sheaths and delivery systems (14–24 Fr) to access and navigate the tortuous femoral, iliac, and aortic anatomy. Larger-diameter sheaths and delivery systems used for transcatheter aortic valve replacement (TAVR), mitral valve repair, and left atrial appendage occlusion (among other procedures) have increased polymer-coated surface areas. Mechanical abrasion during insertion (at the femoral access site) and navigation through tortuous anatomy may result in peeling and scraping of larger amounts of coating and a higher probability of polymer emboli occluding dermal, peripheral, and neurovascular blood vessels.³

Atherectomy Devices for Calcific Lesions

Atherectomy devices are indicated for the removal of calcific and atherosclerotic plaque from diseased vasculature. Hydrophilic coatings are used to facilitate easier device movement through tortuous anatomy. The risk of polymer emboli from these devices is increased by the requirement for multiple passes through vessels lined with hardened protrusions of calcified atheroma. ¹⁸ Instructions for use of most atherectomy devices recommend slow back and forth movements or a pecking motion.¹⁸ The repetitive interaction of mechanically vibrating catheter shafts with calcific debris or adjunct devices (e.g., guide catheters) during these movements results in mechanical abrasion. Given a maximum run time for most atherectomy devices (~5 min), the use of a second device may be required, further increasing the risk of polymer emboli entering the distal coronary or peripheral vasculature.

Discussion

Current technology highlights particulate generation testing as the performance standard for evaluating coating integrity of intravascular devices.¹⁹ Particulate testing determines the number, size, and shape of polymer particles shed from a device when used in a clinically simulated environment and is an FDA-recognized consensus standard for coating integrity for select interventional devices.²⁰ The 2018 updated draft guidance for intravascular guidewires expands the application of particulate testing to most devices (including guides and catheters).⁵ For the above-stated indications, where the risk of polymer embolism may be higher, particulate testing can assist in determining the embolic potential from a device. An animal study by Babcock et al.²¹ reported a strong correlation between particulates released in vitro and polymer emboli incidence rates. Data correlating the presence of polymer emboli with clinical sequelae are limited; however, occlusions of small- and medium-sized blood vessels are commonly reported.³ Thus, mitigating particulates or reducing clinical exposure of particulates may be optimal approaches to resolving this potential complication.

Balancing the amount of coating with the devices indication for use may be a possible mitigation strategy.²²Subsequent particulate assessments and animal studies may allow characterization, comparisons, and safety evaluations of device coating integrity—essential steps for setting particulate limits. Standardization of particulate test equipment (e.g., vessel models, solutions), test methods, and evaluation parameters will be required for comparisons among various manufacturers. If standardized, the addition of particulate release information on device labeling may be a beneficial awareness tool for comparisons as new devices become available for use.

Hydrophilic coatings enable endovascular treatment for patients at a higher risk for surgery.²³ The introduction of the intra-aortic balloon pump and subsequent pMCS devices permit higher-risk percutaneous interventions.^9,10 Transcatheter structural heart procedures treat patients that cannot be treated surgically, often due to age, frailty, anatomic risks, or comorbidities.¹⁷ Consequently, finding solutions for this iatrogenic complication without compromise to device indication for use may be essential. Current coating technologies highlight the potential of using lower-particulate solutions without impacting device function. Research on specialty coatings highlight the availability of lower-particulate solutions that focus on improved adhesion methods between the hydrophilic polymer and device substrate with use of novel bonding agents or cross-linkers (e.g., metal oxides, metalloid ions, photoactivated cross-linkers).^24–27

With the advent of high-risk interventions, pMCS devices are often used in conjunction with CTO and/or atherectomy devices, further increasing the risk of polymer emboli. Structural heart procedures, such as TAVR, are a fast-growing subset of percutaneous interventions with innovative transcatheter approaches being developed to treat a wider range of patient conditions. Table 1 summarizes polymer emboli risk factors for the aforementioned devices and indications. These clinical, anatomical, and procedural risk factors may be used to determine other high-risk devices—devices that may be exposed to higher frictional forces within the vasculature (e.g., endovascular aortic repair) or those required for longer-duration procedures (e.g., arteriovenous fistula thrombectomy, central venous catheters). The adoption of particulate testing with appropriate simulated use models may assist in categorizing devices based on embolic risk.

Table 1.

Polymer Coating Emboli Risk Factors

	pMCS Devices	CTO Guidewires and Catheters	Transcatheter Structural Heart Devices	Atherectomy Devices
Traverses long and tortuous vasculature	+	+	+	+
Large bore device	++		++
Requires excessive manipulation		++		+
Hard luminal plaque		++		++
High frequency vibrations				++
Long dwell time	++	+

Abbreviations: pMCS – percutaneous mechanical circulatory support; CTO – chronic total occlusion. Symbols:

⁺moderate risk factor;

⁺⁺high risk factor.

Among limited device-specific studies on polymer coating embolism, an 85.7% incidence rate was reported for a transcatheter mitral valve repair system.²⁸ A 71% rate was highlighted for a polymer-jacketed, hydrophilic-coated guidewire during coronary thrombectomy procedures.²⁹ Also, an animal study reported 63% polymer emboli from a hydrophilic guide sheath used during carotid stenting procedures.⁶ Further device-specific studies with correlations to particulate test data are required to better understand incidence rates and potential clinical impacts from the aforementioned high-risk interventional devices.

Conclusion

Particulate testing can assist in identifying hydrophilic-coated devices with a higher embolic potential. The highlighted procedural trends and associated risk factors articulate the need for particulate testing and support the FDA draft guidance recommendations for testing of applied coatings. If standardized, this performance test may allow characterization and comparisons of coating integrity among various manufacturers—an important foundation for setting particulate limits. The addition of particulate release information on device labeling may be an important awareness tool for physicians. The use of lower-particulate coating solutions is beneficial for interventional devices with a higher risk of polymer emboli. Hydrophilic polymer coatings on intravascular devices enable endovascular treatment for a wide range of patient populations. Consequently, finding solutions for this iatrogenic complication without compromise to device function may be essential.