Vascular closure devices (VCDs) are a diverse class of cardiovascular devices intended to achieve hemostasis following arteriotomy in the common femoral artery for diagnostic and therapeutic interventional procedures. While the preclinical evaluation of VCDs parallel that of many other cardiovascular devices, there are device-specific nuances and model-specific technical considerations in assessing in vivo performance and handling, determining safety, and satisfying regulatory requirements. Despite the multi-decade use and continued development of novel VCD technologies, there is a paucity of published literature on their preclinical evaluation. This review intends to help mitigate this gap through a discussion of conventional animal models, their attributes and limitations, and standards in the in vivo assessment of performance and safety of VCDs.

BACKGROUND:During the transition from dual antiplatelet therapy (DAPT) to single antiplatelet therapy (SAPT), previous studies have raised concerns about a rebound effect. We compared platelet and inflammatory cell adhesion on different types of stents in the setting of clopidogrel presence and withdrawal. METHODS:In Experiment 1, three pigs were administered with DAPT, that is, clopidogrel and acetylsalicylic acid (ASA), for 7 days. Each animal underwent an extracorporeal carotid arteriovenous shunt model implanted with fluoropolymer-coated everolimus-eluting stent (FP-EES), biodegradable-polymer sirolimus-eluting stent (BP-SES), and biodegradable-polymer everolimus-eluting stents (BP-EES). In Experiment 2, two pigs were administered DAPT, clopidogrel was then withdrawn at day 7, and SAPT with ASA was continued for next 21 days. Then flow-loop experiments with the drawn blood from each time point were performed for FP-EES, BioLinx-polymer zotarolimus-eluting stents (BL-ZES), and BP-EES. The rebound effect was defined as the statistical increase of inflammation and platelet adhesion assessed with immunohistochemistry on the stent-strut level basis from baseline to day-14 or 28. RESULTS:Both experiments showed platelet adhesion value was highest in BP-EES, while the least in FP-EES during DAPT therapy. There was no increase in platelet or inflammatory cell adhesion above baseline values (i.e., no therapy) due to the cessation of clopidogrel on the stent-strut level. Monocyte adhesion was the least for FP-EES with the same trend observed for neutrophil adhesion. CONCLUSIONS:No evidence of rebound effect was seen after the transition from DAPT to SAPT. FP-EES demonstrated the most favorable antithrombotic and anti-inflammatory profile regardless of the different experimental designs.

In 2020, the European Commission up-classified metal cobalt as Class 1B Carcinogen (presumed to have carcinogenic potential) based primarily on data from rodent inhalation carcinogenicity studies. This up-classification requires an assessment under the Medical Device Regulations of cobalt cancer risk from medical devices. We performed a systematic review and meta-analysis to evaluate site-specific cancer risks with cobalt exposure from either total joint replacement (TJR) or occupational exposure (OC). Results were stratified by exposure type (OC or TJR), exposure level (metal-on-metal (MoM) or non-MoM), follow-up duration (latency period: <5, 5-10 or >10 years), and cancer incidence or mortality (detection bias assessment). From 30 studies (653,104 subjects, average 14.5 years follow-up), the association between TJR/OC and cancer risk was null for 22 of 27 cancer sites, negative for 3 sites, and positive for prostate cancer and myeloma. Significant heterogeneity and large estimate ranges were observed for many cancer sites. No significant increase in estimates was observed by exposure level or follow-up duration. The current evidence, including weak associations, heterogeneity across studies and no increased association with exposure level or follow-up duration, is insufficient to conclude that there exists an increased risk for people exposed to cobalt in TJR/OC of developing site-specific cancers.

BACKGROUND:The relative thrombogenicity and albumin adsorption and retention of different durable polymers used in coronary stents has not been tested.AIMS:This study sought to compare the thromboresistance and albumin binding capacity of different durable polymer drug-eluting stents (DES) using dedicated preclinical and in vitro models.METHODS:In an ex vivo swine arteriovenous shunt model, a fluoropolymer everolimus-eluting stent (FP-EES) (n=14) was compared with two durable polymer DES, the BioLinx polymer-coated zotarolimus-eluting stent (BL-ZES) (n=9) and a CarboSil elastomer polymer-coated ridaforolimus-eluting stent (EP-RES) (n=6), and bare metal stents (BMS) (n=10). Stents underwent immunostaining using a cocktail of antiplatelet antibodies and a marker for inflammation and were then evaluated by confocal microscopy (CM). Albumin retention was assessed using a flow loop model with labelled human serum albumin (FP-EES [n=8], BL-ZES [n=4], EP-RES [n=4], and BMS [n=7]), and scanned by CM.RESULTS:The area of platelet adherence (normalised to total stent surface area) was lower in the order FP-EES (9.8%), BL-ZES (32.7%), EP-RES (87.6%) and BMS (202.0%), and inflammatory cell density was least for FP-EES <BL-ZES <EP-RES <BMS. Although nearly full coverage by albumin binding was shown for all durable polymer DES, FP-EES showed significantly greater intensity of albumin as compared to BL-ZES, EP-RES and BMS (FP-EES 79.0%; BL-ZES 13.2%; EP-RES 6.1%; BMS 1.5%).CONCLUSIONS:These results suggest that thromboresistance and albumin retention vary by polymer type and that these differences might result in different suitability for short-term dual antiplatelet therapy.

In 2017, the European Union (EU) Committee for Risk Assessment (RAC) recommended the classification of metallic cobalt (Co) as Category 1B with respect to its carcinogenic and reproductive hazard potential and Category 2 for mutagenicity but did not evaluate the relevance of these classifications for patients exposed to Co-containing alloys (CoCA) used in medical devices. CoCA are inherently different materials from Co metal from a toxicological perspective and thus require a separate assessment. CoCA are biocompatible materials with a unique combination of properties including strength, durability, and a long history of safe use that make them uniquely suited for use in a wide-range of medical devices. Assessments were performed on relevant preclinical and clinical carcinogenicity and reproductive toxicity data for Co and CoCA to meet the requirements under the EU Medical Device Regulation triggered by the ECHA re-classification (adopted in October 2019 under the 14th Adaptation to Technical Progress to CLP) and to address their relevance to patient safety. The objective of this review is to present an integrated overview of these assessments, a benefit-risk assessment and an examination of potential alternative materials. The data support the conclusion that the exposure to CoCA in medical devices via clinically relevant routes does not represent a hazard for carcinogenicity or reproductive toxicity. Additionally, the risk for the adverse effects that are known to occur with elevated Co concentrations (e.g., cardiomyopathy) are very low for CoCA implant devices (infrequent reports often reflecting a unique catastrophic failure event out of millions of patients) and negligible for CoCA non-implant devices (not measurable/no case reports). In conclusion, the favorable benefit-risk profile also in relation to possible alternatives presented herein strongly support continued use of CoCA in medical devices.

Cobalt (Co) is an essential element with human exposure occurring from the diet, supplement ingestion, occupational sources, and medical devices. The European Chemical Agency (ECHA) recently voted to classify Co metal as a Reproductive Hazard Category 1B; presumed human reproductive toxicant due to adverse testicular effects in male rodents. A weight of evidence evaluation of the preclinical reproductive and developmental toxicity studies and available clinical data was performed to critically evaluate the relevance of this proposed classification for Co in medical devices. Reproductive responses to Co are limited to the male testes and sperm function following high systemic exposure in rodents, only at Co concentrations/doses that result in overt toxicity (i.e., above the maximum tolerable dose (MTD)). The potential mechanisms of Co reproductive/developmental toxicity, including its indirect mode of action in the testes and relevance to humans, are discussed. The available preclinical and clincial evidence suggests that it would be more appropriate to classify Co as a Reproductive Hazard Category 2 compound: suspected human reproductive toxicant and, in the case of Co-containing medical devices, it should not be considered a reproductive hazard.

Cobalt (Co) alloys have been used for over seven decades in a wide range of medical devices, including, but not limited to, hip and knee implants, surgical tools, and vascular stents, due to their favorable biocompatibility, durability, and mechanical properties. A recent regulatory hazard classification review by the European Chemicals Agency (ECHA) resulted in the classification of metallic Co as a Class 1B Carcinogen (presumed to have carcinogenic potential for humans), primarily based on inhalation rodent carcinogenicity studies with pure metallic Co. The ECHA review did not specifically consider the carcinogenicity hazard potential of forms or routes of Co that are relevant for medical devices. The purpose of this review is to present a comprehensive assessment of the available in vivo preclinical data on the carcinogenic hazard potential of exposure to Cocontaining alloys (CoCA) in medical devices by relevant routes. In vivo data were reviewed from 33 preclinical studies that examined the impact of Co exposure on local and systemic tumor incidence in rats, mice, guinea pigs, and hamsters. Across these studies, there was no significant increase of local or systemic tumors in studies relevant for medical devices. Taken together, the relevant in vivo data led to the conclusion that CoCA in medical devices are not a carcinogenic hazard in available in vivo models. While specific patient and implant factors cannot be fully replicated using in vivo models, the available in vivo preclinical data support that CoCA in medical devices are unlikely a carcinogenic hazard to patients.

Background Recent clinical studies have suggested the feasibility of 1-month dual antiplatelet therapy (DAPT) for patients receiving drug-eluting stent (DES). Although our previous ex-vivo swine arteriovenous (AV) shunt studies under low dose heparin treatment suggested superior thromboresistance of fluoropolymer-coated everolimus-eluting stent (FP-EES) when compared to other polymer-based DESs, the relative thromboresistance of different DESs under single antiplatelet therapy (SAPT) has never been examined. This study aimed to evaluate platelet adhesion under SAPT in competitive DESs in the in vitro flow loop model and ex vivo swine AV shunt model. Methods The thrombogenicity of FP-EES, BioLinx polymer zotarolimus-eluting stent (BL-ZES), and biodegradable polymer everolimus-eluting stent (BP-EES) was assessed acutely using the swine AV shunt model under aspirin or clopidogrel SAPT. Stents were immunostained using antibodies against platelets and inflammatory markers and evaluated by confocal microscopy. Also, the adhesion of platelet and albumin on the three DESs was assessed by an in-vitro flow loop model using human platelets under aspirin SAPT and fluorescent albumin, respectively. Results In the shunt model, FP-EES showed significantly less platelet and inflammatory cell adhesion than BL-ZES and BP-EES. In the flow loop model, FP-EES showed significantly less platelet coverage and more albumin adsorption than BL-ZES and BP-EES. Conclusions These results suggest FP-EES may have particular advantage for short-term DAPT compared to other DESs.

The integration of the Absorb bioresorbable vascular scaffold (BVS) into the arterial wall has never been tested in an in vivo model of atherosclerosis. This study aimed to compare the long-term (up to 4 years) vascular healing responses of BVS to an everolimus-eluting metallic stent in the familial hypercholesterolemic swine model of atherosclerosis. The multimodality imaging and histology approaches indicate that the resorption and vascular integration profile of BVS is not affected by the presence of atherosclerosis. BVS demonstrated comparable long-term vascular healing and anti-restenotic efficacy to everolimus-eluting metallic stent but resulted in lower late lumen loss at 4 years.

AIMS Durable fluoropolymer-coated everolimus-eluting stents (FP-EES) have shown lower rates of stent thrombosis (ST) versus bare metal stents (BMS) and first-generation bioabsorbable polymer (BP) DES. The aim of the study was to evaluate the specific role of the FP in thromboresistance. METHODS AND RESULTS A total of 57 stents were assessed in three separate ex vivo swine arteriovenous shunt model experiments (first shunt experiment, custom-made fluoropolymer-coated BMS [FP-only] vs. BMS [n=8 each]; second shunt experiment, FP-EES vs. abluminally coated biodegradable polymer sirolimus-eluting stents [BP-SES] vs. BMS [n=8 each]; and third shunt experiment, FP-EES vs. polymer-free Biolimus A9-coated stents [PF-BCS] vs. BMS [n=6 each]). After one hour of circulation, stents were bisected, and each half was dual-immunostained using a platelet cocktail and a marker for inflammation. Antibody staining was visualised by confocal microscopy. In addition, stents were evaluated by scanning electron microscopy. FP-only stents showed significantly lower platelet adherence compared with BMS (% fluorescence-positive area: FP-only=1.8%, BMS=5.6%, p=0.047) with similar inflammatory cell density. FP-EES also demonstrated the lowest platelet adherence compared with BP-SES (p=0.056), PF-BCS (p=0.013) and BMS (p=0.003) with the significantly lowest inflammatory cell density. CONCLUSIONS Fluoropolymer coating imparts greater thromboresistance relative to BMS and to polymer-free DES designs, which reflects an unique phenomenon known as fluoropassivation, representing one proposed mechanism for clinically observed low ST rates in FP-EES.

Recent clinical studies suggest that 1-month dual antiplatelet therapy is feasible for patients receiving Xience everolimus-eluting stents, but whether this applies to other current drug-eluting stents (DES) remains uncertain. Under low-dose heparin treatment, ex vivo porcine arteriovenous shunt

Atherosclerosis places a significant burden on humankind; it is the leading cause of mortality globally, and for those living with atherosclerosis, it can significantly impact quality of life. Fortunately, treatment advances have effectively reduced the morbidity and mortality related to atherosclerosis, with one such modality being percutaneous intervention (PCI) to open occluded arteries. Over the 40-year history of PCI, preclinical models have played a critical role in demonstrating proof of concept, characterizing the in vivo behavior (pharmacokinetics, degradation) and providing a reasonable assurance of biologic safety of interventional devices before entering into clinical trials. Further, preclinical models may provide insight into the potential efficacy of these devices with the appropriate study design and end points. While several species have been used in the evaluation of interventional devices, the porcine model has been the principal model used in the evaluation of safety of devices for both coronary and endovascular treatments. This article reviews the fundamentals of permanent stents, transient scaffolds, and drug-coated balloons and the models, objectives, and methods used in their preclinical evaluation.

Atherosclerosis places a significant burden on humankind; it is the leading cause of mortality globally, and for those living with atherosclerosis, it can significantly impact quality of life. Fortunately, treatment advances have effectively reduced the morbidity and mortality related to atherosclerosis, with one such modality being percutaneous intervention (PCI) to open occluded arteries. Over the 40-year history of PCI, preclinical models have played a critical role in demonstrating proof of concept, characterizing the in vivo behavior (pharmacokinetics, degradation) and providing a reasonable assurance of biologic safety of interventional devices before entering into clinical trials. Further, preclinical models may provide insight into the potential efficacy of these devices with the appropriate study design and end points. While several species have been used in the evaluation of interventional devices, the porcine model has been the principal model used in the evaluation of safety of devices for both coronary and endovascular treatments. This article reviews the fundamentals of permanent stents, transient scaffolds, and drug-coated balloons and the models, objectives, and methods used in their preclinical evaluation.

Several meta-analyses have demonstrated that stent thrombosis is significantly lower in Xience everolimus-eluting stents (Xience-EES) as compared to bare metal stents (BMS) and biodegradable polymer stent drug-eluting stents. Likewise, ex-vivo porcine arteriovenous shunt studies also support

The ABSORB bioresorbable vascular scaffold (BVSs) has set the stage for the new bioresorbable era as the lead technology of its kind, demonstrating through novel endpoints that the potential advantages of this technology appear to be significant. This chapter details the design and performance features of the ABSORB BVSs. The ABSORB BVSs is coated with everolimus, a semisynthetic antiproliferative macrolide, in poly d,l-lactide in a 1:1 drug:polymer ratio. Development of a bioresorbable vascular scaffold and delivery system to meet the clinical and regulatory needs requires a broad cross-functional product development team. The performance profile of ABSORB BVSs is described by three phases that span its lifecycle: revascularization, restoration, and resorption. The ABSORB BVSs currently has Conformité Européenne (CE) approval and regulatory approval in multiple geographies including the United States, Japan, Korea, Taiwan, India, Brazil, Canada, and Australia and is seeking approval in China.

The polymers poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) and poly(n-butyl methacrylate) (PBMA) are employed in manufacturing the XIENCE family of coronary stents. PBMA serves as a primer and adheres to both the stent and the drug coating. PVDF-HFP is employed in the drug matrix layer to hold the drug everolimus on the stent and control its release. Chemical stability of the polymers of XIENCE stents in the in-vivo environment was evaluated by pyrolysis-gas chromatography with mass spectrometry (Py-GC/MS) detection. For this evaluation, XIENCE stents explanted from porcine coronary arteries and from human coronary artery specimens at autopsy after 2-4 and 5-7 years of implantation, respectively, were compared to freshly manufactured XIENCE stents (controls). The comparison of pyrograms of explanted stent samples and controls showed identical fragmentation fingerprints of polymers, indicating that PVDF-HFP and PBMA maintained their chemical integrity after multiple years of XIENCE coronary stent implantation. The findings of the present study demonstrate the chemical stability of PVDF-HFP and PBMA polymers of the XIENCE family of coronary stents in the in-vivo environment, and constitute a further proof of the suitability of PVDF-HFP as a drug carrier for the drug eluting stent applications. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1721-1729, 2018.

Throughout the 30-year history of vascular stents, from their initial conception to current drug-eluting and bioresorbable technologies, animal models have played an instrumental role in the development of vascular stents. From rodents to rabbits, dogs, sheep, and swine, a variety of animal models for the evaluation of vascular stents exist, each being balanced with a unique set of advantages and shortcomings. With the appropriate selection of species and anatomy, animal models can be used to provide insight into the pathophysiology of vessel healing and restenosis, to confirm the feasibility of new endovascular technologies, to assess the potential efficacy of a stent at improving specific clinical outcomes, and to establish reasonable safety of a stent for a specified clinical use. This review provides an overview of the predominant animal models used for evaluating vascular stents and the translation of these models to the clinical setting.