New And Precise Summary

New And Precise Summary

In vivo distribution of particulate matter from coated angioplasty balloon catheters

David E. Babcock a,*, Robert W. Hergenrother a, David A. Craig b, Frank D. Kolodgie c, Renu Virmani c a SurModics Inc., Eden Prairie, MN, USA b SynecorLabs LLC, Durham, NC, USA cCVPath Institute Inc., Gaithersburg, MD, USA

a r t i c l e i n f o

Article history: Received 5 December 2012 Accepted 5 January 2013 Available online 31 January 2013

Keywords: Surface modification Hydrogel Particulates Animal model Friction Hydrophilicity

a b s t r a c t

Most catheter-based vascular medical devices today have hydrophilic lubricious coatings. This study was designed to perform a territory-based downstream analysis of end organs subsequent to angioplasty with coated balloon catheters to better understand the potential in vivo physiological consequence of coating wear materials. Coronary angioplasty was performed on swine using balloon catheters modified with two polyvinylpyrrolidone (PVP)-based coatings of similar lubricity, but different levels of particu- lates (5-fold) when tested in a tortuous path model. Myocardial tissues examined 28 days post- angioplasty revealed no visible particulates in the animals treated with the lower particulate catheters while 3 of 40 sections from higher particulate catheters contained amorphous foreign material, and 1 of 40 sections from tissue treated with uncoated catheters had amorphous foreign material. Non-target organs and downstream muscle revealed no particulates for any of the treatments. Histological analy- sis showed that the overall number of vessels with embolic foreign material was low and evidence of myocyte necrosis was rare with either of the coatings investigated in this study.

! 2013 Elsevier Ltd. All rights reserved.

1. Introduction

The use of percutaneous, catheter-based vascular devices to treat the symptoms of cardiovascular disease has become the standard of care. Many of these interventional cardiovascular devices incorporate a hydrophilic lubricious coating in order to ease movement through the vasculature. Lubricious coatings have been used for over 20 years [1,2] and the benefits are well established: (1) lower frictional force between the device and the vessel reduces tissue damage [2] and prevents vasospasm [3]; (2) improved maneuverability aids navigation of complex lesions and facilitates access to tortuous vascular sites leading to expansion of the patient population that can benefit from these treatments; and (3) reduces thrombogenicity [1,4]. In addition, reduced friction between the therapy catheters and support catheters leads to improved out- comes, reduced procedure time, and, ultimately, reduced cost [5].

The most commonly used lubricious coatings in medical devices consist of chemically crosslinked water-soluble polymers, such as polyvinylpyrrolidone (PVP) or polyacrylamide. When exposed to aqueous environments, these coatings form a hydrogel. Hydrogel

coatings can decrease the frictional force exerted between devices 10 to 100-fold [6]. The enhanced lubricity derives in large part from the hydrated nature of the gel: In the swollen state, the hydrogel can be up to 90% or more water. When a swollen hydrogel is compressed, some of this water is released [7] and acts as a lubricant. The prop- erties of a hydrogel that impart lubricity e the ability to imbibe and exude water e also make hydrogels prone to mechanical failure [8]. Any hydrogel-based coating, if subjected to a sufficient amount of mechanical stress, has the potential to fracture and abrade from the medical device surface.

In the past few years, regulatory agencies have increased scrutiny of coated medical devices as possible sources of foreign particulate matter to the vasculature [9]. While there are two U.S. FDA guidance documents for the testing of percutaneous transluminal coronary angioplasty (PTCA) balloon catheters [10,11], an ASTM method [12] and an AAMI technical information report [13] for collection and analysis of particulate matter obtained from medical devices, there are no specifications regarding the levels of particulate matter gen- erated by coated medical devices. Factors that can affect device performance and resulting particulate matter generation include device materials and design, clinical technique and procedure, and device coatings.

Particulate matter in the vasculature, if large enough and in sufficient quantities, can cause occlusion of blood vessels that can

* Corresponding author. E-mail address: dbabcock@surmodics.com (D.E. Babcock).

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lead to tissue hypoxia and, ultimately, necrosis [14]. Microspheres made from various materials such as polyvinyl alcohol, chitosan, trisacryl gelatin, albumin, starch, poly(D,L lactide/glycolide), and polystyrene have been considered for use in therapeutic emboli- zation to treat hemorrhage or tumors [15]. For these applications, the effective size range of microspheres is typically from 100 to 600 mm. In the field of interventional cardiology, there are numerous reports of adverse clinical events related to athero- sclerotic debris arising from sources such as acute plaque rupture or erosion [16e21]. These events often result in downstream microvascular obstruction, thrombosis, stroke, and/or myocardial scarring. Cotton fiber emboli that may originate from sterile drapes, airborne dust, or gauze are common during angiographic pro- cedures and such emboli are usually asymptomatic [22]. A few case studies have reported clinical observation of foreign body emboli

related to polymer coated endovascular devices [23e25]. Mehta et al. [26] described nine cases of iatrogenic embolization of hy- drophilic polymer in patients who underwent multiple vascular interventions with hydrophilic-coated devices. However, there are no definitive preclinical references that characterize hydrogel wear particulates from coated medical devices and accompanying potential for adverse effects.

Our objective in this work was to gain a better understanding of the effects of hydrogel particulates if they are introduced to the vasculature during the use of devices containing lubricious, photo- crosslinked hydrophilic coatings. The ability to optimize lubricity while lowering particulate generation has been an ongoing industry challenge. Recent advances in coating formulations have led to the development of a submicron coating, which is designed to match the lubricity performance of traditional hydrophilic

Fig. 1. (A) Stained myocardial sections showing embolic foreign material from the apical right ventricle viewed 3 days after injection of a single swine with a coating particulate suspension. (B) Stained PVP coating coupon controls. (C) Confocal Raman spectral analysis of non-birefringent, amorphous basophilic embolic foreign material found in myocardial tissue section. Spectral match with hydrogel coating reference confirms identified foreign material is coating particulate (PVP).

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coatings while significantly reducing particulate generation. In this study, two coatings were investigated: one coating with an approximate dry thickness of 2 mm (hereafter referred to as “micron coating”) and a coating with an approximate dry thickness of 0.5 mm (hereafter referred to as “submicron coating”). We hypothesized that the submicron coating would generate fewer particulates than the micron coating. The primary endpoint of this study was histopathological evaluation of the 28-day time point of distal bed muscular tissues (primarily myocardium or specific skeletal muscle) known to be downstream of areas in which intra- arterial deployment of coated PTCA balloon catheters and/or injection of particulate suspensions occurred.

2. Materials and methods

2.1. Accessory devices

Cordis VISTA BRITE TIP” guiding catheters (5 and 6 French, JR4) and Hi-Torque Floppy II guide wires with MICROGLIDE coating (Abbott Vascular, 0.01400 , 190 cm) were obtained from SynecorLabs. Hemostasis valve Y-connectors (#80395) were from Qosina.

2.2. Lubricious coating formulations

Coating solutions were prepared by combining various polymers with benzophenone-based photo-reactive ionic crosslinkers in mixtures of isopropyl alcohol and water. Both the micron and submicron coatings (SurModics, Inc.) con- tained photo-reactive polyvinylpyrrolidone (PVP) and the submicron coating also contained polyacrylamide polymers that incorporated pendant benzophenone groups [27]. The micron coating also contained unmodified pharmaceutical grade PVP (Kollidon” 90 e BASF) and was applied in one thin layer with an approximate dry thickness of 2 mm. The submicron coating did not contain unmodified PVP, and was applied as two very thin layers with a total approximate dry thickness of 0.5 mm. Approximate coating thickness was determined by cryo-sectioning coated substrates and viewing the cross-section of the coating by scanning electron microscopy.

2.3. Preparation of coated plastic rods and PTCA balloon catheters

Surrogate catheter substrates made from extruded Pebax” plastic rods (1 mm O.D., 60 cm long, shore hardness 72D e Optinova-MLE, Inc.) were used to generate particulate suspensions for intra-arterial injections. Coatings were applied to 20 cm of one end using standard dip-coating methods described previously [28]. Briefly, the rods were wiped clean with isopropyl alcohol and allowed to air dry. The rod ends were dipped and withdrawn from coating solutions at velocities ranging from 0.3 to 0.9 cm/s and hung on racks to air dry. Dry coated rods were suspended midway between opposing UV flood-lamps and rotated during the cure to ensure even surface illumination. The curing step initiates the formation of covalent bonds between benzophenone moieties and any available abstractable hydrogen within the coating or on the substrate [6]. The coated rods were packaged and then ster- ilized with ethylene oxide gas (EtO). Coatings were also applied in a similar manner to the distal 23 cm of PTCA catheter shaft and balloon assemblies (3! 20 mm balloon size e Creggana-Tactx Medical, Inc.). The catheters were coated while the balloons were fully inflated. The balloons were coated to maximize the amount of coating on the catheters in order to increase the potential for generating particulates during the angioplasty procedures. After coatings were complete, the balloons were deflated, pleated, folded, and repackaged prior to sterilization with EtO.

2.4. Lubricity and durability testing

The lubricity of PTCA catheter shafts was tested by vertical pinch using a DL1000 friction tester (OakRiver Technology Corporation). All samples were hydrated in phosphate-buffered saline (PBS, pH 7.4) for “1 min before testing. The catheter assembly was fixtured so that the distal coated shaft would slide up and down between two silicone rubber gripper pads that were positioned just above a beaker filled with PBS. The force of the silicone rubber gripper pads was set to 750 g. A load cell measured the force needed to withdraw the sample as it traveled (10 cm at 0.5 cm/s) through the pads. Samples were cycled 15 times. The average coefficient of friction for each cycle was calculated by dividing the load cell force by the pinch force of the gripper pads.

2.5. PTCA balloon catheter simulated-use tracking and particulate collection

Benchtop particulate suspensions were generated by tracking coated PTCA balloon catheters through a coronary model as specified in the ASTM F2394-07 method [29]. This model is a two-dimensional simulation of a human coronary vessel without simulated lesions. The model was flushed with ISOTON” II diluent

(Beckman Coulter) prior to use. A 6 Fr guide catheter was tracked through the model up to the point where the highly tortuous path begins. A coated PTCA balloon catheter was hydrated for 1 min in diluent and then tracked over a guide wire until the balloon exited the model into a mock vessel made of silicone rubber tubing. The balloon was inflated to 15 atm, held for 30 s, deflated, and retracted through the model. The guide catheter was flushed twice with 20 ml volumes of diluent, once after catheter insertion and again after retraction. Finally, the mock vessel was flushed with 10 ml and all flush solutions were pooled in pre-cleaned 60 ml glass vials. Samples were allowed to degas by standing for 1 min before analysis by light obscuration (LO).

2.6. Particulate analysis by light obscuration

A HACH HIAC 9703þ instrument equipped with an HRLD400 sensor and PharmSpec 3.0 software was used for measuring particulate counts and sizes. The instrument was used in Run Counter mode, with n¼ 4 sample aliquots of 5 ml each analyzed per suspension. The first run was discarded, as per United States Phar- macopeial Convention Standard 788 Particulate Matter in Injections (USP <788>) [30], and particulate counts were averaged for the subsequent three runs and reported cumulatively (“10 mm, “25 mm, “50 mm, and “100 mm).

2.7. Coating particulate suspensions for intra-arterial injections

Particulate suspensions for intra-arterial administration were prepared imme- diately prior to injection. A hemostasis valve was attached to a 6 Fr guide catheter that had been shortened to 30 cm length. The guide catheter was inserted into the sterilized model fixture that had been flushed with normal saline. Sterile, coated Pebax” rods were hydrated for 1 min in normal saline and inserted into the guide catheter until the distal portion exited the model. The guide catheter was flushed with 7.5 ml of normal saline and the particulates were collected in a sterile, pre- cleaned glass vial. The test rod was removed and the model was flushed with another 7.5 ml that was collected and pooled with the first. This process was repeated with three additional rods and the four flush samples were pooled (a total of 60 ml). Particulate suspensions were inverted several times before withdrawing a sample for injection to ensure any larger particulates had not settled out. A sample of each particulate suspension was reserved and analyzed by LO to determine the number and size distribution of particulates.

2.8. Animal care and preparation

Thirteen healthy non-atherosclerotic domestic Yorkshire crossbred swine (juveniles, 30e50 kg) were used. Study protocols were in compliance with the National Research Councils “Guide for the Care and Use of Laboratory Animals” (8th Edition, 2011) and were approved by the testing facility’s Institutional Animal Care and Use Committee. All animals received dual anti-platelet therapy comprising

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clopidogrel (150 mg p.o., QD) and aspirin (325 mg p.o., QD) starting one day prior to the surgical procedures. Percutaneous catheter delivery was through arteriotomy of the femoral artery and using a 7 Fr introducer sheath. Heparin was administered as needed to maintain a target ACT “250 s.

2.9. Intra-arterial injections of particulate suspensions

A single animal received multiple catheter-based intra-arterial injections of coating particulate suspensions. Translucent particulate matter was clearly visible when suspensions were held up to light. For each injection the guide catheter was first positioned in the target vasculature, and 5 ml of particulate suspension was injected over a period of approximately 30 s. Immediately following injection, each catheter was flushed with approximately 10 ml of normal saline to ensure the entire suspension had been delivered to the target vasculature. An angiogram was per- formed to assess vessel patency and then the guide catheter was flushed repeatedly with a minimum of 40 ml total of normal saline before positioning it for the next injection. The micron coating suspensionwas injected into the right coronary artery (RCA) and the left internal iliac artery. The submicron coating suspension was injected into the left anterior descending (LAD) coronary artery and the right in- ternal iliac artery. No particulate suspension was injected into the left circumflex (LCx) coronary artery.

2.10. Balloon angioplasty

Twelve animals underwent percutaneous transluminal balloon angioplasty using both coated and uncoated balloon catheters. Under fluoroscopic guidance, a 6 Fr guide catheter was inserted through the sheath and advanced through vascula- ture to a pre-selected location. PTCA balloon catheters with the same coating (or uncoated) were deployed in the LAD, LCx, and RCA and the peripheral left internal iliac artery (a total of four catheters in each animal with n¼ 4 animals for each catheter type). Coronary and peripheral vasculature were selected that allowed a target deployment ratio of the balloon to the vessel size resulting in an

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Fig. 3. Particulates generated by PTCA balloon catheters tracked through ASTM F2394-07 tortuous path model with balloon expansion in a silicone rubber mock vessel (mean total counts per catheter% SD, each group n¼ 7 catheters tested except for the micron coating, n¼ 6). (A) “10 mm and “25 mm particulate counts per catheter, (B) “50 mm and “100 mm particulate counts per catheter.

Table 1 Distribution of myocardial findings described on a per section analysis based on 40 myocardial sections examined per angioplasty catheter treatment. Does not include the direct particulate injection animal.

Finding Uncoated Micron coating Submicron coating

Myocardial scarring 0 1 0 Birefringent foreign material 1 1 0 Amorphous foreign material 1 3 0

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approximately 10e20% overstretch. The guide wire was inserted and positioned in the distal bed of the target artery. The PTCA balloon catheter was then inserted through the guiding catheter over the guide wire. The balloon was inflated at the site, held for 30 s, and deflated by pulling negative pressure. After removal, each balloon plus a small length of the PTCA catheter shaft (approximately 10e20 cm) was cut from the device and saved for coating wear analysis. The extent of coating wear was later determined by staining the coatings on the catheters with Congo red. A final angiogram was performed to assess vessel patency. New guide wires and guide catheters were used for each animal.

2.11. Survival period treatment and tissue collection

For the remainder of the 28-day survival period, animals received aspirin (81 mg, p.o., QD) and clopidogrel (75 mg, p.o., QD). Animals were sedated and administered 10,000 units of heparin by intravenous injection prior to euthanasia. At necropsy, the gross appearance of organs was assessed. All tissues collected were fixed in 10% neutral buffered formalin. Whole hearts were excised, flushed gently with saline, and perfusion fixed. Representative samples of downstream muscle (gastrocnemius, gluteal), coronary band of the hoof, and non-target organs (lung, liver, kidney and spleen) were collected, fixed, and submitted for histopathology evaluation.

2.12. Histopathology assessment of 28-day tissues

The presence of emboli within hearts was evaluated by sectioning the right and left ventricles with parallel cuts at 1e1.5 cm apart to the posterior atrioventricular sulcus. Myocardial sections were sampled circumferentially in the distribution of the major coronary arteries, including the anterior, lateral, posterior, and septal wall at two levels (mid and apical). In addition, the right ventricle was sampled at themid

and apical levels. Myocardial samples were dehydrated in a graded series of alcohols and xylene. After embedding in paraffin, histologic sections were prepared on a ro- tary microtome at four to five microns and stained with hematoxylin and eosin (H&E) and Congo red [31]. Histologic sections were examined to identify and quantify any embolic particulates as well as any associated regions of ischemic necrosis/inflammation. In addition to the hearts, samples of gastrocnemius (calf muscles) and gluteal muscle were sampled at three equidistant regions along the main axis (proximal, middle, and distal); the rear coronary corium (coronary band), lung, liver, right and left kidney, and spleen were similarly embedded in paraffin, sectioned, and stained with H&E. Sections were examined for the presence of necrosis, scarring, thromboembolus, and other relevant pathology.

2.13. Confocal Raman microscopy

The chemical composition of foreign embolic material was determined by Raman spectroscopic analysis of unstained, deparaffinized tissue sections (without cover slips) using a confocal Raman microscope (WITec Instruments).

3. Results

3.1. Detection and identification of particulate matter in vivo

In a pilot study, to confirm the ability to detect hydrogel par- ticulates in vivo, more than 10,000 hydrogel coating particulates “10 mm per dose were suspended in normal saline and injected directly into the right coronary artery and the right renal artery of a single swine. No immediate angiographic evidence of arterial occlusion was observed. The procedure was uneventful, and the animal appeared clinically normal throughout the study. Embolic foreign material was observed during histological examination performed on myocardial samples collected at necropsy three days post-injection. No foreign materials were detected in the renal tissue sections. Hematoxylin and eosin (H&E), Masson’s trichrome, and Congo red histopathological staining techniques were useful in making a tentative identification of the foreign material in the myocardium as coating derived (Fig.1A). Sections cut fromparaffin- embedded hydrogel coating coupons lacked birefringence in polarized light and appeared dark blue on H&E, light blue on Masson’s trichrome, and light red on Congo red staining (Fig. 1B). Distal emboli in the myocardium were consistent with these characteristics and were observed in 8 intramyocardial vessels to- tal. Unstained myocardial sections adjacent to stained distal emboli were further analyzed by confocal Raman spectroscopy. Using this approach we confirmed the foreign material as coating derived particulate (Fig. 1C). Having demonstrated that we could locate and identify coating particulates using histochemical and analytical methods, we then evaluated the physiological effects of particu- lates that may be introduced to the vasculature from coated PTCA catheters in a 28-day swine model.

Fig. 4. Myocardial scarring found in a section from the APRV viewed 28 days after balloon angioplasty with catheters coated with the micron coating. H&E stained.

Fig. 5. Representative myocardial tissue section showing a fragment of birefringent foreign material viewed 28 days after balloon angioplasty. (A) Congo red stained, and (B) same section acquired under polarized light showing birefringence.

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3.2. Benchtop characterization of lubricious coatings

PTCA balloon catheters were modified with two different lubricious polymer coatings based on photo-derivatized PVP, one

with a thin single layer (“micron coating”) and the other with two very thin layers (“submicron coating”). The coating formulations were designed to have similar lubricity but varied particulate generation during tracking through a bench model fixture.

Fig. 6. Confocal Raman spectral analysis of foreign material found in myocardial tissue sections. The birefringent foreign material and the amorphous basophilic foreign material that were analyzed are shown in Figs. 5A and 7C, respectively.

Fig. 7. Representative myocardial tissue sections showing two amorphous basophilic foreign particulates viewed 28 days after balloon angioplasty with catheters coated with the micron coating. (A) H&E stained, (B) adjacent section stained with Congo red was negative due to the lack of foreign material, (C) H&E stained, and (D) adjacent section stained positive with Congo red.

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Although both coatings resulted in similarly low coefficients of friction when evaluated by the vertical pinch test (Fig. 2), the submicron coating generated an approximate 5-fold lower number of particulates “10 mm per catheter than the micron coating (Fig. 3A). The submicron coating also generated fewer large-size particulates “50 mm (Fig. 3B). Greater than 90% of the total par- ticulates generated from both coatings, however, were between 10 and 25 mm in diameter. The uncoated catheters produced on average of about 6,000 particulates “10 mm per catheter (Fig. 3A).

3.3. Assessment of the disposition of particulate matter from coated PTCA balloon catheters in vivo

Microscopic assessment of hearts 28 days post-angioplasty us- ing balloon catheters with micron or submicron coating showed rare foreign emboli and scarring (Table 1). There was no evidence of infarction, however, a small focal scar was observed in a single

section from the apical posterior right ventricle (APRV) of an animal in a region distal to a micron coated PTCA balloon catheter treat- ment site (Fig. 4). Unrelated birefringent foreign material (Fig. 5) was also seen in two sections in myocardial beds distal to arteries that underwent angioplasty with micron coated or uncoated bal- loon catheters. In this case the birefringent material shown in Fig. 5A stained positive for Congo red. In an attempt to further identify the material, the slide was destained and the particulate was analyzed by Raman spectroscopy. The spot spectrum of the birefringent material did not match the micron coating reference spectrum affirming that the foreign material was not derived from PVP coating (Fig. 6) and when compared against a library of Raman spectra, the results showed a strong match to n-benzoylglycine (hippuric acid) indicating the particulate may be biological and not device derived.

Amorphous foreign material (Fig. 7), similar to that observed for the pilot study, was seen in four myocardial sections (one section

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Fig. 8. Particulate counts of intra-arterial micron and submicron coating particulate doses (one dose equals 5 ml of coating particulate suspension). (A) “10 mm and “25 mm particulate counts per dose, (B) “50 mm and “100 mm particulate counts per dose.

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distal to an uncoated PTCA balloon catheter site and three distal to micron coated catheter sites). The foreign material was localized to the lumen and/or peri-adventitial space of small intramyocardial vessels and generally surrounded by chronic inflammatory cells, including giant cells. The material found in the uncoated catheter treated animal may have come from other devices and/or compo- nents that were used during angioplasty procedures. In at least two sections, visible staining of amorphous basophilic foreign material on H&E was negative on Congo red, presumably due to lack of foreign material in deeper sections (Figs. 7A and B, and 9A and B). Conversely in two sections, Congo red staining of foreign material was found where the adjacent H&E showed only focal inflamma- tory infiltrates and giant cells in the absence of visible foreign material. In all cases examined, Raman spectroscopic analysis confirmed that the material was PVP (Fig. 6).

Regardless of whether the coronary arteries were treated by coated or uncoated PTCA balloon catheters, multiple foci of chronic inflammatory cells in the absence of foreign material were also present and in addition to eosinophils and/or giant cells with or without necrotic myocytes. To determine if foreign material was deeper within the tissue, additional serial sectioning (w60 to 70 microns deep) was performed on three hearts where coronaries underwent balloon angioplasty with micron coated, submicron coated, or uncoated catheters. These sections also failed to show embolic foreign material, with the exception of a single mid- posterior right-ventricular section downstream from a micron coated catheter site, which showed embolic amorphous basophilic material on both H&E and the adjacent Congo red stain. All downstream skeletal muscle (gluteal, gastrocnemius), coronary band, and non-target organs (lungs, liver, spleen, kidneys) were within normal limits and negative for embolic material.

The single animal that received particulate injections (Fig. 8), up to 25,000 particulates “10 mm per dose, in coronary arteries and the left and right internal iliac arteries, showed embolic amorphous basophilic material viewed 28 days after injection (Fig. 9A) con- sistent with the coating in only a single intramyocardial vessel from the APRV region. This region is distal to the RCA, whichwas injected with the micron coating particulate dose. Rare fragments of bire- fringent foreign material (Fig. 9C and D), inconsistent with the coating material, were found in single sections from both the apical septal (AS) and APRV regions. The Raman spectrum of the bire- fringent foreign material in the AS region (not shown) was deter- mined to match the spectrum of the birefringent material present in the myocardial tissue shown in Fig. 5.

3.4. Assessment of coating wear

PTCA balloon catheters that were subjected to the simulated- use test or deployed in the swine were stained by Congo red to assess the extent of coating wear (Fig.10). The coatings on catheters subjected to simulated-use testing, especially the micron coated devices, showed markedly greater coating wear than the catheters that were deployed in the swine.

4. Discussion

In this study, we investigated the in vivo effects of hydrogel wear particulates originating from coated angioplasty balloon catheters. We tested two coatings that were similar in overall composition but differed in thickness. Both coatings were durable and provided excellent lubricity with coefficients of friction <0.020.

Fig. 9. Myocardial sections viewed 28 days after intra-arterial injections with particulate suspensions. (A) Embolic amorphous basophilic foreign material with a few surrounding inflammatory cells. (B) Congo red staining is negative, although no foreign material is seen in the adjacent section. (C) Birefringent foreign material with surrounding inflammation including giant cells. (D) Polarized light shows birefringence.

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Simulated-use testing results and the incidence of myocardial findings confirmed our hypothesis that the thinner submicron coatings generate fewer particulates than the micron coatings. PTCA balloon catheters coated with the micron coating (approx- imate dry thickness of 2 mm) generated an average of 73,000 par- ticulates “10 mm per catheter when tracked through a model specified in the ASTM F2394-07 standard guide for measuring the securement of balloon expandable vascular stents mounted on delivery systems. In this histopathological study, myocardial terri- tories distal to each of themajor coronary arteries were assessed for embolic foreign material, thrombus, infarct, and scarring. Approx- imately 10 transmural sections per heart were sampled at mid and apical levels involving the full circumference of the left ventricle with two samples from the right ventricle at each level. Coating particulates, or amorphous foreign material, were found in 3 of 40 myocardial sections from animals treated with catheters that were coated with the micron coating formulation. The submicron coated catheters (approximate dry thickness of 0.5 mm) generated almost 5-fold less particulates on the benchtop than the micron coated catheters, an average of 15,000 particulates “10 mm per catheter, and no coating particulates were found in the myocardium. Although hydrogel particulates were found in the myocardium downstream ofmicron coated catheter treatment sites, we consider the incidence to be low and the effects to be minimal.

When known quantities of particulates were injected as a bolus into subselected coronary arteries, there was no immediate angiographic evidence of occlusion, and upon examination of myocardial tissue 28 days after injection, we identified only a single intramyocardial arteriole with amorphous basophilic foreign material. Hydrogel coating particulates are pliable and, given that capillary walls are extremely flexible [14], particulates larger than the diameter of capillaries (approximately 5e10 mm) may still be able to compress and transverse the capillary bed. Although the particulate counts were as high as 25,180 particulates “10 mm per injected dose (micron coating), 93% of those particulates were less than 25 mm in diameter.

The apparent discrepancy between the small number of myo- cardial sections that contained particulates and the large number of particulates measured in simulated-use testing might be

explained by the much higher abrasive forces subjected to PTCA balloon catheters in the simulated-use models than those expe- rienced during actual angioplasty. To explore this concept further, the wear patterns of catheter coatings were identified by Congo red staining after the devices were subjected to simulated-use or deployed in swine, which demonstrated greater wear on coatings of catheters exposed to simulated-use testing. In this regard, the simulated-use model is constructed of hard, hydrophobic mate- rials (Teflon” and Lexan” polycarbonate) and does not optimally mimic the elasticity and hydrophilic nature of the coronary and peripheral vasculature. Moreover, the pathway of the model con- tains tight corners that can act like sharp edges to the surface of the catheter. Consequently, it is highly likely that the actual number of particulates generated in the angioplasty procedure in the swine was significantly less than the number measured in more stringent simulated-use testing.

5. Conclusions

In this study, we examined the quantity of particulates gen- erated from PTCA balloon catheters by comparing two modified lubricious polymeric hydrogel coatings applied at different thick- nesses. In vivo 28-day catheterization studies in swine were also performed where target tissues (myocardium and downstream muscle) and non-target (lung, spleen, liver, and kidney) were examined histologically after intra-arterial injection of hydrogel coating particulate suspensions or arterial inflation of hydrophilic- coated PTCA balloon catheters. The results of our study demon- strate that the submicron coating is as lubricious as the micron coating but generates far fewer particulates than the micron coat- ing on the same substrate in a simulated-use model. Notably, we found that hydrogel coating particulates appear only rarely in the tissue downstream of the treatment site regardless of the number of particulates generated by the coating. The result that no visible coating particulates were found in the tissue of animals that were treated with PTCA balloon catheters with the submicron coating, combined with the substantial reduction in particulate generation, suggests that the thinner submicron coating offers a low- particulate advantage over the micron coating.

Fig. 10. Representative hydrophilic-coated PTCA balloon catheter shafts stained with Congo red to assess coating wear. The two parallel white lines in all images are artifacts due to reflection of light.

D.E. Babcock et al. / Biomaterials 34 (2013) 3196e32053204

 

 

Acknowledgments

The authors thank Tony Anderson (SurModics) for Raman spectroscopy analysis; Mike Militello and Anchor Sarslow (SurModics) for simulated-use testing and friction testing; Brad Hubbard (SynecorLabs) for advice on study design; Robert Varuska and Thomas Hoffman (SynecorLabs) for conducting surgical and angioplasty procedures; and Nathan Lockwood, ShannonWadman, and Joseph Tokos (SurModics) for editorial assistance.

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D.E. Babcock et al. / Biomaterials 34 (2013) 3196e3205 3205

 

  • In vivo distribution of particulate matter from coated angioplasty balloon catheters
    • 1. Introduction
    • 2. Materials and methods
      • 2.1. Accessory devices
      • 2.2. Lubricious coating formulations
      • 2.3. Preparation of coated plastic rods and PTCA balloon catheters
      • 2.4. Lubricity and durability testing
      • 2.5. PTCA balloon catheter simulated-use tracking and particulate collection
      • 2.6. Particulate analysis by light obscuration
      • 2.7. Coating particulate suspensions for intra-arterial injections
      • 2.8. Animal care and preparation
      • 2.9. Intra-arterial injections of particulate suspensions
      • 2.10. Balloon angioplasty
      • 2.11. Survival period treatment and tissue collection
      • 2.12. Histopathology assessment of 28-day tissues
      • 2.13. Confocal Raman microscopy
    • 3. Results
      • 3.1. Detection and identification of particulate matter in vivo
      • 3.2. Benchtop characterization of lubricious coatings
      • 3.3. Assessment of the disposition of particulate matter from coated PTCA balloon catheters in vivo
      • 3.4. Assessment of coating wear
    • 4. Discussion
    • 5. Conclusions
    • Acknowledgments
    • References
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