Diffusible contrast-enhanced micro-CT improves visualization of stented vessels.

In this report, we showcase diffusible iodine-based contrast-enhanced computed tomography (DICE-CT) as a method for improving soft tissue visualization and reducing beam hardening artifact within a stented vessel. This technique is commonly used in our pathology lab to image soft tissue specimens with dense metal implants and to ensure reliable morphological analysis through clear delineation of tissue structures. For this report, a porcine right coronary artery with an implanted metal stent was scanned using both conventional and DICE-CT methods. Upon reconstruction, DICE-CT produced less beam hardening artifact in comparison to traditional micro-CT; furthermore, DICE-CT produced results with morphometric similarity to histology. Accordingly, these differences illustrated the clear advantage of using DICE-CT over conventional micro-CT when imaging soft tissue specimens with dense metal implants.

Histologic features of thrombosis events with a centrifugal left ventricular assist device.

BACKGROUND: Histology of thrombosis events in left ventricular assist devices (LVADs) may point to differences between the etiology of either ingested or de novo thrombus formation within LVADs. Materials ingested by the pump would have features suggestive of lifting and folding, whereas thrombi formed de novo would have uniform, parallel layers. This study tested this hypothesis in a cohort of explanted HeartWare Ventricular assist devices (HVADs) (Medtronic, Miami Lakes, Florida). METHODS: Histology of thrombi from 59 explanted HVAD pumps were classified as presumed ingested, presumed de novo, or undeterminable on the basis of pre-defined criteria. The apparent size and location of the thrombotic materials were noted. RESULTS: Histologically, all thrombotic materials were either presumed to be ingested (73%; 95 of 130 total histology cassettes examined) or of undeterminable origin (27%; 35 of 130 histology cassettes). Undetermined origin commonly was due to a lack of sufficient material for analysis. The larger materials (>800 mm3) tended to be in the inflow region. The most common finding was smaller thrombotic materials (<150 mm3) within the pump (64%; 38 of 59 HVADs); when these smaller materials were ingested by the pump, they were most often found within the smaller flow pathways within the pump. CONCLUSIONS: Our study suggests that the thrombi within HVAD pumps are commonly ingested materials rather than de novo thrombus formation within the pump. Further research to understand the source of this ingested material and the consideration to mitigate this complication should be considered.

Microscopic Assessment of Healing and Effectiveness of a Foam-Based Peripheral Occlusion Device.

The IMPEDE Embolization Plug is a catheter-delivered vascular occlusion device that utilizes a porous shape memory polymer foam as a scaffold for thrombus formation and distal coils to anchor the device within the vessel. In this study, we investigated the biological response of porcine arteries to the IMPEDE device by assessing the extent of healing and overall effectiveness in occluding the vessel at 30, 60, and 90 days. Compared to control devices (Amplatzer Vascular Plug and Nester Embolization Coils), the host response to IMPEDE showed increased cellular infiltration (accommodated by the foam scaffold), which led to advanced healing of the initial thrombus to mature collagenous connective tissue (confirmed by transmission electron microscopy (TEM)). Over time, the host response to the IMPEDE device included degradation of the foam by multinucleated giant cells, which promoted fibrin and polymer degradation and advanced the healing response. Device effectiveness, in terms of vessel occlusion, was evaluated histologically by assessing the degree of recanalization. Although instances of recanalization were often observed at all time points for both control and test articles, the mature connective tissue within the foam scaffold of the IMPEDE devices improved percent vessel occlusion; when recanalization was observed in IMPEDE-treated vessels, channels were exclusively peri-device rather than intradevice, as often observed in the controls, and the vessels mostly remained >75% occluded. Although total vessel occlusion provides the optimal ischemic effect, in cardiovascular pathology, there is a progressive ischemic effect on the downstream vasculature as a vessel narrows. As such, we expect a sustained ischemic therapeutic effect to be observed in vessels greater than 75% occluded. Overall, the current study suggests the IMPEDE device presents advantages over controls by promoting an enhanced degree of healing within the foam scaffold, which decreases the likelihood of intradevice recanalization and ultimately may lead to a sustained ischemic therapeutic effect.

Micro-CT and histopathology methods to assess host response of aneurysms treated with shape memory polymer foam-coated coils versus bare metal coil occlusion devices.

Recent studies utilizing shape memory polymer foams to coat embolizing coils have shown potential benefits over current aneurysm treatments. In the current study utilizing a rabbit-elastase aneurysm model, the performance of test article (foam-coated coil [FCC]) and control (bare platinum coils [BPCs]) devices were compared at 30, 90, and 180 days using micro-CT and histological assessments. The host response was measured by identifying the cells regionally present within the aneurysm, and assessing the degree of residual debris and connective tissue. The 3D reconstructions of aneurysms provided context for histologic findings, and aided in the overall aneurysm assessment. At all time points, >75% of the cells categorized in each aneurysm were associated with a bioactive yet biocompatible host response (vs. the remainder of cells that were associated with acute inflammation). The extracellular matrix exhibited a transition from residual fibrin at 30 days to a greater degree of connective tissue at 90 and 180 days. Although the control BPC-treated aneurysms exhibited a greater degree of connective tissue at the earliest time point examined (30 days), by 180 days, the FCC-treated aneurysms had more connective tissue and less debris overall than the control aneurysms. When considering cell types and extracellular matrix composition, the overall host response scores were significantly better in FCC-treated aneurysms at the later time point. Based on the results of these metrics, the FCC device may lead to an advanced tissue remodeling response over BPC occlusion devices.

Introduction to Currently Applied Device Pathology.

Pathologic evaluation is crucial to the study of medical devices and integral to the Food and Drug Administration and other regulatory entities' assessment of device safety and efficacy. While pathologic analysis is tailored to the type of device, it generally involves at a minimum gross and microscopic evaluation of the medical device and associated tissues. Due to the complex nature of some implanted devices and specific questions posed by sponsors, pathologic evaluation inherently presents many challenges in accurately assessing medical device safety and efficacy. This laboratory's experience in numerous collaborative projects involving veterinary pathologists, biomedical engineers, physicians, and other scientists has led to a set of interrelated assessments to determine pathologic end points as a means to address these challenges and achieve study outcomes. Thorough device evaluation is often accomplished by utilizing traditional paraffin histology, plastic embedding and microground sections, and advanced imaging modalities. Combining these advanced techniques provides an integrative, comprehensive approach to medical device pathology and enhances medical device safety and efficacy assessment.

Method for preclinical pathology evaluation and analysis of cardiovascular implantable electronic device implant sites.

Cardiovascular implantable electronic devices (CIEDs) typically incorporate leads that directly contact the endocardium. Post-explant pathology evaluation of formalin-fixed CIED lead implant sites and downstream organs (i.e., lungs) can provide useful safety data to the US Food and Drug Administration; however, current regulatory guidelines do not mandate how the safety data are collected. In this paper, we outline a protocol for preclinical pathology evaluation of leads associated with CIEDs, which includes formalin fixation of the heart and lungs, gross evaluation, and qualitative and quantitative histologic evaluation. We recommend fixation of the whole heart with leads in situ alongside intratracheal formalin infusion; this enables rapid and effective preservation of target tissues and increases histologic quality to allow for accurate qualitative and quantitative pathology evaluation. Overall, we believe that our approach to pathology evaluation of leads may maximize information acquired from preclinical studies, leading to more accurate safety assessments. SUMMARY: This article introduces an established method for pathology evaluation and analysis of cardiac leads recommended for companies and researchers that seek approval from a regulatory body.

Comparison of shape memory polymer foam versus bare metal coil treatments in an in vivo porcine sidewall aneurysm model.

The endovascular delivery of platinum alloy bare metal coils has been widely adapted to treat intracranial aneurysms. Despite the widespread clinical use of this technique, numerous suboptimal outcomes are possible. These may include chronic inflammation, low volume filling, coil compaction, and recanalization, all of which can lead to aneurysm recurrence, need for retreatment, and/or potential rupture. This study evaluates a treatment alternative in which polyurethane shape memory polymer (SMP) foam is used as an embolic aneurysm filler. The performance of this treatment method was compared to that of bare metal coils in a head-to-head in vivo study utilizing a porcine vein pouch aneurysm model. After 90 and 180 days post-treatment, gross and histological observations were used to assess aneurysm healing. At 90 days, the foam-treated aneurysms were at an advanced stage of healing compared to the coil-treated aneurysms and showed no signs of chronic inflammation. At 180 days, the foam-treated aneurysms exhibited an 89-93% reduction in cross-sectional area; whereas coiled aneurysms displayed an 18-34% area reduction. The superior healing in the foam-treated aneurysms at earlier stages suggests that SMP foam may be a viable alternative to current treatment methods. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1892-1905, 2017.

Design and verification of a shape memory polymer peripheral occlusion device.

Shape memory polymer foams have been previously investigated for their safety and efficacy in treating a porcine aneurysm model. Their biocompatibility, rapid thrombus formation, and ability for endovascular catheter-based delivery to a variety of vascular beds makes these foams ideal candidates for use in numerous embolic applications, particularly within the peripheral vasculature. This study sought to investigate the material properties, safety, and efficacy of a shape memory polymer peripheral embolization device in vitro. The material characteristics of the device were analyzed to show tunability of the glass transition temperature (Tg) and the expansion rate of the polymer to ensure adequate time to deliver the device through a catheter prior to excessive foam expansion. Mechanical analysis and flow migration studies were performed to ensure minimal risk of vessel perforation and undesired thromboembolism upon device deployment. The efficacy of the device was verified by performing blood flow studies that established affinity for thrombus formation and blood penetration throughout the foam and by delivery of the device in an ultrasound phantom that demonstrated flow stagnation and diversion of flow to collateral pathways.

A Method for Creating Artificial Thrombi In Vitro Using a Rotating Mechanical Surface.

Thromboembolism is a common concern in ventricular assist device (VAD) therapy. Precise VAD response to pass-through thromboembolism needs to be studied in a controlled in vitro setting where specific pump parameters (i.e., power consumption, flow rates, impeller RPM) can be monitored while various types of thrombi are introduced. In this article, we describe a method for creating standardized fibrin thrombi that could be introduced into a mock circulatory loop for testing VAD response to thromboembolism. Donor equine blood collected using a sodium citrate was allowed to clot by adding calcium chloride (CaCl2) while a rotating component applied shear forces to the blood. This rotating force was applied at various speeds and at various distances into the blood. Resulting clots showed similar microscopic features to thrombi taken from explanted clinical VADs. Higher RPM of the rotating component and smaller clearances between the rotating component and the blood created clots that closely resembled ante-explant clots found within VADs in vivo. This method is an effective way to create artificial fibrin clots for use in in vitro experiments to test thromboembolism in VADs.

A brief review of ventricular assist devices and a recommended protocol for pathology evaluations.

UNLABELLED: Heart failure is a leading cause of death in human populations, and as people live longer, it is becoming an increasingly prominent problem. Because of the insufficient numbers of donor hearts, physicians and engineers are turning to mechanical circulatory support in the form of ventricular assist devices (VADs). Their clinical performance and increasing availability of various types, sizes, and functions are increasing VAD recognition. However, for any implantable medical device, especially one that is life supporting, performance and safety must be evaluated both pre- and postmarket. It has been demonstrated that specific pathology analysis can provide unique and important information to augment the evaluation of performance and safety. To help ensure the safety and efficacy of a device, we propose that regulatory agencies include pathology analysis by experienced, independent pathologists with relevant expertise as an integral component of device submissions. We believe that this analysis should include both gross and microscopic components and, when warranted, supplementary data obtained through radiography, electron microscopy, or both. The pathology data acquired through these analyses should be correlated with clinical data to yield a more thorough data set for submission to the governing regulatory body. Submitting this coordinated analysis of data will demonstrate to regulatory agencies (United States Food and Drug Administration, Therapeutic Goods Administration, Brazilian Health Surveillance Agency, etc.) that the device manufacturer shares their objective: making medical devices as safe and effective as possible. SUMMARY: This review of ventricular assist devices introduces a recommended protocol for pathology evaluations of devices from organizations or researchers seeking approval by a governing regulatory agency.