Antithrombogenic Coatings Research Articles

Comparison of the hemocompatibility of neurovascular flow diverters with anti-thrombogenic coatings

Despite the continual progress in technology, thromboembolic complications still occur following endovascular treatment of cerebral aneurysms and remain the primary contributor to morbidity and mortality. Thus, coating the surfaces of blood-contacting flow diverters may reduce thrombus-related complications in clinical use. In this study, the hemocompatibility of different commercially available flow diverters Pipeline Flex Embolization Device with Shield Technology (Medtronic), the p64 MW HPC (Phenox), and the DERIVO 2heal (Acandis) was investigated using an in vitro blood circulation model. The DERIVO 2 flow diverter was included in this study as an uncoated device. The markers of coagulation (thrombin-antithrombin complex (TAT)), thrombocytes (β-thromboglobulin (β-TG)), inflammation (PMN elastase), and complement system (SC5b-9, C3a, and C5a) activation were detected by enzyme-linked immunosorbent assay (ELISA). In addition to blood cell counts and hemolysis, thrombogenicity was determined using scanning electron microscopy. Flow diverters with anti-thrombogenic coatings resulted in significantly lower activation of coagulation (TAT) and platelets (β-TG) and lower adhesion of platelets compared with the uncoated DERIVO 2 flow diverter. There were no significant differences between the coated flow diverters in terms of TAT and β-TG levels, as well as platelet adhesion. However, significantly lower activation of the complement system (SC5b-9 and C5a) was observed for the DERIVO 2heal flow diverter in comparison with the Pipeline Flex Shield and the p64 MW HPC flow diverters emphasizing the improved hemocompatibility of the fibrin/heparin-coated DERIVO 2heal flow diverter.

Stability and Thrombogenicity Analysis of Collagen/Carbon Nanotube Nanocomposite Coatings Using a Reversible Microfluidic Device

Currently, the development of stable and antithrombogenic coatings for cardiovascular implants is socially important. This is especially important for coatings exposed to high shear stress from flowing blood, such as those on ventricular assist devices. A method of layer-by-layer formation of nanocomposite coatings based on multi-walled carbon nanotubes (MWCNT) in a collagen matrix is proposed. A reversible microfluidic device with a wide range of flow shear stresses has been developed for hemodynamic experiments. The dependence of the resistance on the presence of a cross-linking agent for collagen chains in the composition of the coating was demonstrated. Optical profilometry determined that collagen/c-MWCNT and collagen/c-MWCNT/glutaraldehyde coatings obtained sufficiently high resistance to high shear stress flow. However, the collagen/c-MWCNT/glutaraldehyde coating was almost twice as resistant to a phosphate-buffered solution flow. A reversible microfluidic device made it possible to assess the level of thrombogenicity of the coatings by the level of blood albumin protein adhesion to the coatings. Raman spectroscopy demonstrated that the adhesion of albumin to collagen/c-MWCNT and collagen/c-MWCNT/glutaraldehyde coatings is 1.7 and 1.4 times lower than the adhesion of protein to a titanium surface, widely used for ventricular assist devices. Scanning electron microscopy and energy dispersive spectroscopy determined that blood protein was least detected on the collagen/c-MWCNT coating, which contained no cross-linking agent, including in comparison with the titanium surface. Thus, a reversible microfluidic device is suitable for preliminary testing of the resistance and thrombogenicity of various coatings and membranes, and nanocomposite coatings based on collagen and c-MWCNT are suitable candidates for the development of cardiovascular devices.

Extended Cellular Deposits on Gas Exchange Capillaries Are Not an Indicator of Clot Formation: Analysis of Different Membrane Oxygenators.

Antithrombogenic coatings of artificial surfaces within extracorporeal membrane oxygenation (ECMO) circuits improved its bio- and hemocompatibility. However, there is still a risk of thrombus formation in particular within the membrane oxygenator (MO). Since inflammatory cells are essential components within clots, the aim was to identify the extent of cellular accumulations on gas exchange capillaries from different ECMO systems. Thirty-four MOs (PLS, n = 27, Getinge; Hilite 7000 LT, n = 7, Fresenius Medical Care, Germany) were collected from adult patients. The extent of cellular deposits on gas exchange capillaries was classified using nuclear 4',6-diamidino-2-phenylindole staining and fluorescence microscopy. All Hilite oxygenators exhibited small cellular deposits. In contrast, the cellular distribution was heterogeneous on capillaries from PLS oxygenators: small deposits (34%), clusters (44%) and membrane-spanning cell structures (pseudomembranes) (22%). Overall, the median fluorescence intensity was significantly higher in the PLS group. Nevertheless, within 3 days before MO removal, there was no alteration in critical parameters ( d -dimer and fibrinogen levels, platelet counts, and pressure drop across the MO). In conclusion, despite the histological differences on the gas capillaries from different types of oxygenators, there was no further evidence of increased inflammation and coagulation parameters that indicate clot formation within oxygenators.

Fibrin formation and fractal organization at cationic, anionic, and zwitterionic polymer coated interfaces.

Biomaterial-associated thrombosis remains a persistent challenge whenever medical devices are inserted in blood vessels. The issue is principally addressed by the development of antithrombogenic coatings that prevent the formation of blood clots, e.g. by limiting adsorption of fibrin - the core protein network of a clot. Charged polymers (i.e. polyelectrolytes and zwitterionic polymers) show potential as coating materials for medical devices, and we here investigate these polymer coatings in the context of biomaterial-associated thrombosis. Our findings indicate that fibrin polymerization can yield a surface-dependent distribution of fractal-like branched structures and amorphous aggregates, with surface-induced fibrin formation dominating for anionic polymer interfaces and recruitment of bulk-formed fibrin dominating for cationic polymer interfaces. In addition, we identify coatings containing zwitterionic sulfobetaine groups as promising candidates for antithrombogenic biomaterials.

A Vascular Graft On‐a‐Chip Platform for Assessing the Thrombogenicity of Vascular Prosthesis and Coatings with Tuneable Flow and Surface Conditions

AbstractVascular grafts are essential for the management of cardiovascular disease. However, the lifesaving potential of these devices is undermined by thrombosis arising from material and flow interactions on the blood contacting surface. To combat this issue, antithrombogenic coatings have emerged as a promising strategy for modulating blood and graft interaction in vivo. Although an important determinant of graft performance, hemodynamics are frequently overlooked for in vitro testing of coatings and their translatability remains poorly understood. Herein, this limitation is addressed with a microscale graft on‐a‐chip platform incorporating vascular prosthesis and coatings with tuneable flow and surface conditions in vitro. As a proof of concept, the platform is used to test the thrombogenicity of a novel class of lubricant‐infused surface (LIS) and antibody lubricant‐infused (anti‐CD34 LIS) coated expanded polytetrafluoroethylene (ePTFE) vascular grafts in the presence of arterial wall shear stress with and without endothelial cells. The findings suggest LIS ePTFE is thromboresistant under flow with significantly reduced fibrin(ogen) deposition, thrombin activity, and blood cell adhesion compared to uncoated controls. It is moreover apparent that the microscale properties of the device are advantageous for the testing and translation of novel antithrombogenic coatings and blood‐contacting materials in general.

Investigation of heparin-loaded poly(ethylene glycol)-based hydrogels as anti-thrombogenic surface coatings for extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO), a critical life-sustaining tool, faces significant challenges for the maintenance of normal haemostasis due to the large volume of circulating blood continuously in contact with artificial surfaces, hyperoxia and excessive shear stresses of the extracorporeal circuit. From a biomaterials perspective, it has been hypothesised that drug eluting coatings composed of haemocompatible hydrogels loaded with an anticoagulant drug could potentially enhance the haemocompatibility of the circuit. Poly(ethylene glycol) (PEG) has been well established as a biocompatible and anti-fouling material with wide biomedical application. Unfractionated heparin is the most commonly used anticoagulant for ECMO. In the present study, the feasibility of using heparin-loaded PEG-based hydrogels as anti-thrombogenic surface coatings for ECMO was investigated. The hydrogels were synthesised by photopolymerisation using poly(ethylene glycol) diacrylate (PEGDA) as the crosslinking monomer and poly(ethylene glycol) methacrylate (PEGMA) as the hydrophilic monomer, with heparin loaded into the pre-gel solution. Factors which could affect the release of heparin were investigated, including the ratio of PEGDA/PEGMA, water content, loading level of heparin and the flow of fluid past the hydrogel. Our results showed that increased crosslinker content and decreased water content led to slower heparin release. The hydrogels with water contents of 60 wt% and 70 wt% could achieve a sustained heparin release by adjusting the ratio of PEGDA/PEGMA. The anticoagulation efficacy of the released heparin was evaluated by measuring the activated clotting time of whole blood. The hydrogels with desirable heparin release profiles were prepared onto poly(4-methyl-1-pentene) (PMP) films with the same chemical composition as the PMP ECMO membranes. The coatings showed sustained heparin release with a cumulative release of 70-80% after 7 days. Haemocompatibility tests demonstrated that PEG hydrogel coatings significantly reduced platelet adhesion and prolonged plasma recalcification time. These results suggest that heparin-loaded PEG hydrogels are potential anti-thrombogenic coatings for ECMO.

A rechargeable anti-thrombotic coating for blood-contacting devices

Despite the potential of anti-thrombogenic coatings, including heparinized surfaces, to improve the performance of blood-contacting devices, the inevitable deterioration of bioactivity remains an important factor in device failure and related thrombotic complications. As a consequence, the ability to restore the bioactivity of a surface coating after implantation of a blood-contacting device provides a potentially important strategy to enhance its clinical performance. Here, we report the regeneration of a multicomponent anti-thrombogenic coating through use of an evolved sortase A to mediate reversible transpeptidation. Both recombinant thrombomodulin and a chemoenzymatically synthesized ultra-low molecular weight heparin were repeatedly and selectively immobilized or removed in a sequential, alternating, or simultaneous manner. The generation of activated protein C (aPC) and inhibition of activated factor X (FXa) was consistent with the molecular composition of the surface. The fabrication of a rechargeable anti-thrombogenic surface was demonstrated on an expanded polytetrafluoroethylene (ePTFE) vascular graft with reconstitution of the surface bound coating 4 weeks after in vivo implantation in a rat model.

Anti-thrombogenic coatings for devices in neurointerventional surgery: Case report and review of the literature

Background:Stent-assisted coiling and extra-saccular flow diversion require dual anti-platelet therapy due to the thrombogenic properties of the implants. While both methods are widely accepted, thromboembolic complications and the detrimental effects of dual anti-platelet therapy remain a concern. Anti-thrombogenic surface coatings aim to solve both of these issues. Current developments are discussed within the framework of an actual clinical case.Case description:A 33-year-old male patient lost consciousness while doing sport and was administered 500 mg acetylsalicylic acid on site. Computed tomography revealed a massive subarachnoid haemorrhage, and digital subtraction angiography showed an aneurysm of the right middle cerebral artery. Stent-assisted coiling using a neck bridging device with a hydrophilic coating (pCONUS_HPC) was considered as an appropriate approach. Another 500 mg acetylsalicylic acid IV was given. After the single anti-platelet therapy was seen to be effective, a pCONUS_HPC was implanted, and the aneurysm sac subsequently fully occluded using coils. No thrombus formation was encountered. During the following days, 2 × 500 mg acetylsalicylic acid IV daily were required to maintain single anti-platelet therapy, monitored by frequent response testing. Follow-up digital subtraction angiography after 13 days confirmed the occlusion of the aneurysm and the patency of the middle cerebral artery.Conclusion: A variety of ways to reduce the thrombogenicity of neurovascular stents is discussed. Hydrophilic surface coatings are a valid concept to improve the haemocompatibility of neurovascular implants while avoiding the use of dual anti-platelet therapy. Phosphorylcholine and phenox hydrophilic polymer coating are currently the most promising candidates. This concept is supported by anecdotal experience. However, formalised registries and randomised trials are currently being established.

In vivo canine study of three different coatings applied to p64 flow-diverter stents: initial biocompatibility study

BackgroundFlow-diverter stents (FDSs) have revolutionised the treatment of intracranial aneurysms. However, associated dual antiplatelet treatment is mandatory. We investigated the biocompatibility of three proprietary antithrombogenic coatings applied to FDSs.MethodsAfter Institutional Animal Care and Use Committee approval, four domestic juvenile female dogs (weight 19.9 ± 0.9 kg, mean ± standard deviation) were commenced on three different oral antiplatelet regimes: no medication (n = 1), acetylsalicylic acid (n = 2), and acetylsalicylic acid and clopidogrel (n = 1). Four p64 FDSs were randomly implanted into the subclavian, common carotid, and external carotid arteries of each dog, including both uncoated p64 stents and p64 stents coated with three different antithrombogenic hydrophilic coating (HPC). Angiography and histological examinations were performed. Wilcoxon/Kruskal-Wallis and ANOVA were used with p value < 0.05 considered as significant.ResultsMinimal inflammatory cell infiltration and no device-associated granulomatous cell inflammation were observed. No significant difference in adventitial inflammation (p = 0.522) or neointimal/medial inflammation (p = 0.384) between coated and uncoated stents as well as between the different stent groups regarding endothelial cell loss, surface fibrin/platelet deposition, medial smooth muscle cell loss, or adventitial fibrosis were found. Acute self-limiting thrombus formed on 6/16 implants (37.5%), and all of the thrombi were noted on devices implanted in the common or external carotid artery irrespective of the surface coating. Two of 12 p64 HPC-coated stents (16.7%) and 1/4 uncoated p64 stents (25%) showed severe or complete stenosis at delayed angiography.ConclusionsIn these preliminary in vivo experiments, HPC-coated p64 FDSs appeared to be biocompatible, without acute inflammation.

Nanofibrous Heparin and Heparin-Mimicking Multilayers as Highly Effective Endothelialization and Antithrombogenic Coatings

Combining the advantages of the fibrous nanostructure of carbon nanotubes (CNTs) and the bioactivities of heparin/heparin-mimicking polyanions, functional nanofibrous heparin or heparin-mimicking multilayers were constructed on PVDF membrane with highly promoted endothelialization and antithrombogenic activities. Oxidized CNT (oCNT) was first functionalized with water-soluble chitosan (polycation), then enwrapped with heparin or a typical sulfonated heparin-mimicking polymers (poly(sodium 4-styrenesulfonate-co-sodium methacrylate)) to construct the multilayers. Then, the surface-deposited multilayers were constructed via electrostatic layer-by-layer assembly of the functionalized oCNTs. The scanning electron microscope and atom force microscope images confirmed that the coated multilayers exhibited nanofibrous and porous structure. The live/dead cell staining and cell viability assay results indicated that the coated nanofibrous multilayers had excellent compatibility with endothelial cells. The cell morphology observation further confirmed the promotion ability of surface endothelialization due to the coated heparin/heparin-mimicking multilayers. Further systematical evaluation on blood compatibility revealed that the surface heparin/heparin-mimicking multilayer-coated membranes also had significantly improved blood compatibility including restrained platelet adhesion and activation, prolonged blood clotting times, and inhibited activation of coagulation and complement factors. In summary, the proposed nanofibrous multilayers integrated endothelialization and antithrombogenic properties; meanwhile, the heparin-mimicking coating validated comparable performances as heparin coating. Herein, it is expected that the surface coating of nanofibrous multilayers, especially the facilely constructed heparin-mimicking coating, may have great application potential in biomedical fields.

Inner surface modification of the tube-like elements for medical applications

The objective of this work was to modify the inner surfaces of polymer tubes to improve their biocompatibility with blood cells. New materials that were designed to be placed in contact with blood during forced blood circulation were studied. The inner surfaces of these tubes were covered with anti-thrombogenic coatings. Materials based on silicon carbide, silicon oxide, and silicon nitride were deposited. Depending on the topography and the chemical nature of the inner vessel surface, a non-thrombogenic bio-surface, also called a neointima, was formed. Several expected applications of this work are discussed, including archetypal human blood vessels, the design of a nanostructural artificial substitute, optimising the surface using vacuum-coating techniques, characterising materials on multiple scales, and studying the blood-material interaction under dynamic conditions in an arterial flow environment. Several promising solutions for inhibiting the activation of the blood-clotting cascade via the use of appropriate surface architectures have been obtained. These solutions may be applied in advanced biocompatible cardiovascular implants.

Graphene coatings for enhanced hemo-compatibility of nitinol stents

In this study, we used graphene, a one-atom thick sheet of carbon atoms, to modify the surfaces of existing implant materials to enhance both bio- and hemo-compatibility. This novel effort meets all functional criteria for a biomedical implant coating as it is chemically inert, atomically smooth and highly durable, with the potential for greatly enhancing the effectiveness of such implants. Specifically, graphene coatings on nitinol, a widely used implant and stent material, showed that graphene coated nitinol (Gr–NiTi) supports excellent smooth muscle and endothelial cell growth leading to better cell proliferation. The authors further determined that the serum albumin adsorption on Gr–NiTi is greater than that of fibrinogen, which is an important and well understood criterion for promoting a lower thrombosis rate. These hemo- and biocompatible properties, along with high strength, chemical inertness and durability provide graphene with an edge over most antithrombogenic coatings for biomedical implants and devices.

Biocompatible polyurethane coating for use in pulsatile ventricular asist dvices

Aims: Because of its mechanical stability, poly(carbonate)urethane (PUR) is commonly used to make membranes used in pulsatile ventricular assist devices (VADs). However, long term implantation in which the material is in contact with blood is reduced due to high thrombogenicity. For better biocompatibility, anti-thrombogenic coatings are developed biologically and synthetically.

Development of antimicrobial and antithrombogenic coatings for inside and outside of medical catheters

Catheter-related infections are costly problems for hospitals around the world. Protection of the body against infection involves not only the immune system, but also the integrity of the external skin and internal mucosal surface. Catheters, introduced from the outside into the interior of the body, breach this important defense and lay the patient open to the risk of infection. It is believed that the surface characteristics of the polymers used in today's catheters are, to a large degree, responsible for this. In particular, the surface roughness, the hydrophobic nature of the surface and the ability of certain types of common bacteria to attach to and metabolize on the polymers are at fault. Interestingly, prior to the 1950s, when venous access required the use of rigid stainless steel needles, catheter infection was a minor problem. This has led us to develop various metal coatings (e.g. Ag, Pt, etc.) both for inside and outside of even the smallest catheter of 1 mm in diameter. Electroless deposition has been used for silver coating of both inside and outside of catheters, while hollow cathode magnetron and vacuum arc deposition have been used for outside coating. High-quality adherent metallic films have been deposited on Teflon, polyimide and latex substrates. Both biological and animal tests have shown the excellent antimicrobial and good mechanical durability of these films. The fabrication processes, results of thin film characterizations and investigations of antimicrobial effects are discussed. The biocompatibility of the chosen metals is also addressed.