Blood-contacting Medical Devices Research Articles

Platelet Adhesion and Activation in an ECMO Thrombosis-on-a-Chip Model.

Use of extracorporeal membrane oxygenation (ECMO) for cardiorespiratory failure remains complicated by blood clot formation (thrombosis), triggered by biomaterial surfaces and flow conditions. Thrombosis may result in ECMO circuit changes, cause red blood cell hemolysis, and thromboembolic events. Medical device thrombosis is potentiated by the interplay between biomaterial properties, hemodynamic flow conditions and patient pathology, however, the contribution and importance of these factors are poorly understood because many in vitro models lack the capability to customize material and flow conditions to investigate thrombosis under clinically relevant medical device conditions. Therefore, an ECMO thrombosis-on-a-chip model is developed that enables highly customizable biomaterial and flow combinations to evaluate ECMO thrombosis in real-time with low blood volume. It is observed that low flow rates, decelerating conditions, and flow stasis significantly increased platelet adhesion, correlating with clinical thrombus formation. For the first time, it is found that tubing material, polyvinyl chloride, caused increased platelet P-selectin activation compared to connector material, polycarbonate. This ECMO thrombosis-on-a-chip model can be used to guide ECMO operation, inform medical device design, investigate embolism, occlusion and platelet activation mechanisms, and develop anti-thrombotic biomaterials to ultimately reduce medical device thrombosis, anti-thrombotic drug use and therefore bleeding complications, leading to safer blood-contacting medical devices.

Transient Performance Analysis of Centrifugal Left Ventricular Assist Devices Coupled With Windkessel Model: Large Eddy Simulations Study on Continuous and Pulsatile Flow Operation.

Computational fluid dynamics (CFD) simulations are widely used to develop and analyze blood-contacting medical devices such as left ventricular assist devices (LVADs). This work presents an analysis of the transient behavior of two centrifugal LVADs with different designs: HeartWare VAD and HeartMate3. A scale-resolving methodology is followed through Large Eddy Simulations, which allows for the visualization of turbulent structures. The three-dimensional (3D) LVAD models are coupled to a zero-dimensional (0D) 2-element Windkessel model, which accounts for the vascular resistance and compliance of the arterial system downstream of the device. Furthermore, both continuous- and pulsatile-flow operation modes are analyzed. For the pulsatile conditions, the artificial pulse of HeartMate3 is imposed, leading to a larger variation of performance variables in HeartWare VAD than in HeartMate3. Moreover, CFD results of pulsatile-flow simulations are compared to those obtained by accessing the quasi-steady maps of the pumps. The quasi-steady approach is a predictive tool used to provide a preliminary approximation of the pulsatile evolution of flow rate, pressure head, and power, by only imposing a speed pulse and vascular parameters. This preliminary quasi-steady solution can be useful for deciding the characteristics of the pulsatile speed law before running a transient CFD simulation, as the former entails a significant reduction in computational cost in comparison to the latter.

Surface nanostructuring of Ti40Cu40Zr11Fe3Sn3Ag3 amorphous alloy by alkaline chemical treatment for potential use as a biocompatible material

Amorphous alloys show potential as implant materials due to their superior mechanical properties and good corrosion resistance. However, the presence of toxic elements in the alloy composition can pose challenges, as they can react with the surrounding tissue, leading to inflammation and cell death. To address this, Ti40Cu40Zr11Fe3Sn3Ag3 at% amorphous alloy is developed. This composition comprises of biocompatible elements (Ti, Zr, and Sn) and antimicrobial elements (Ag, Fe, and Cu), for potential use as implant materials. Chemical pseudo-dealloying using a solution of ammonium hydroxide and hydrogen peroxide is employed to selectively remove copper from the sample surface, which may induce toxicity by prolonged contact, and promote the formation of a patterned passivating Ti/Zr oxide-rich surface to enable possible antimicrobial effects. The surface of the samples was analyzed using atomic force microscopy, scanning electron microscopy, and X-ray photoelectron spectroscopy. The modified surfaces show titanium oxide-rich nanostructured topography with depleted amounts of copper from the surface. The kinetics of the selective removal of copper, and the influence of parameters such as electrolyte concentration, immersion time, and stirring velocity on the evolution of morphology were investigated. Our findings elucidate the mechanism of pseudo-dealloying using an ammonia-based solution and demonstrate its efficacy in enhancing the biocompatibility of the alloy. In detail, the pseudo-dealloyed samples exhibited hydrophilic interactions and demonstrated hemocompatibility, making them promising candidates for blood-contacting medical devices. This study underscores the significance of our approach in tailoring the surface properties of amorphous alloys for biomedical applications, paving the way for their utilization in implant materials with improved biocompatibility.

Comparison of Binary Alcohol/Water Solvent Systems to Blood for Extractions of Blood-Contacting Medical Devices

Comparison of Binary Alcohol/Water Solvent Systems to Blood for Extractions of Blood-Contacting Medical Devices

Bioinspired superhydrophobic surfaces with silver and nitric oxide-releasing capabilities to prevent device-associated infections and thrombosis

Bacteria-associated infections and thrombus formation are the two major complications plaguing the application of blood-contacting medical devices. Therefore, functionalized surfaces and drug delivery for passive and active antifouling strategies have been employed. Herein, we report the novel integration of bio-inspired superhydrophobicity with nitric oxide release to obtain a functional polymeric material with anti-thrombogenic and antimicrobial characteristics. The nitric oxide release acts as an antimicrobial agent and platelet inhibitor, while the superhydrophobic components prevent non-specific biofouling. Widely used medical-grade silicone rubber (SR) substrates that are known to be susceptible to biofilm and thrombus formation were dip-coated with fluorinated silicon dioxide (SiO2) and silver (Ag) nanoparticles (NPs) using an adhesive polymer as a binder. Thereafter, the resulting superhydrophobic (SH) SR substrates were impregnated with S-nitroso-N-acetylpenicillamine (SNAP, an NO donor) to obtain a superhydrophobic, Ag-bound, NO-releasing (SH-SiAgNO) surface. The SH-SiAgNO surfaces had the lowest amount of viable adhered E. coli (> 99.9 % reduction), S. aureus (> 99.8 % reduction), and platelets (> 96.1 % reduction) as compared to controls while demonstrating no cytotoxic effects on fibroblast cells. Thus, this innovative approach is the first to combine SNAP with an antifouling SH polymer surface that possesses the immense potential to minimize medical device-associated complications without using conventional systemic anticoagulation and antibiotic treatments.

Durable plasma-mediated zwitterionic grafting on polymeric surfaces for implantable medical devices

Adverse body reactions to blood-contacting medical devices endanger patient safety and impair device functionality, with events invariably linked to nonspecific protein adsorption due to suboptimal material biocompatibility. To improve the safety and durability of such devices, herein we propose a strategy for introducing stable zwitterionic grafts onto polymeric surfaces via plasma functionalization. The resulting zwitterion-grafted substrates exhibit long-lasting superhydrophilicity, enabling antifouling and anti-thrombogenic properties. We demonstrate the successful modification of the surface elemental composition, morphology, and hydrophilicity, while retaining the underlying mechanical properties of the polymeric substrate. Furthermore, we optimise the fabrication process to ensure long-lasting modifications at least three months after fabrication. This strategy decreases fibrinogen adsorption by approximately 9-fold, and thrombosis by almost 75% when applied to a commercial polyurethane. Moreover, this process is universally applicable to a wide range of polymeric materials, even those with stable chemistry such as polytetrafluoroethylene.

High-density zwitterionic polymer brushes exhibit robust lubrication properties and high antithrombotic efficacy in blood-contacting medical devices

High-performance catheters are essential for interventional surgeries, requiring reliable anti-adhesive and lubricated surfaces. This article develops a strategy for constructing high-density sulfobetaine zwitterionic polymer brushes on the surface of catheters, utilizing dopamine and sodium alginate as the primary intermediate layers, where dopamine provides mussel-protein-like adhesion to anchor the polymer brushes to the catheter surface. Hydroxyl-rich sodium alginate increases the number of grafting sites and improves the grafting mass by more than 4 times. The developed high-density zwitterionic polymer brushes achieve long-lasting and effective lubricity (μ<0.0078) and are implanted in rabbits for four hours without bio-adhesion and thrombosis in the absence of anticoagulants such as heparin. Experiments and molecular dynamics simulations demonstrate that graft mass plays a decisive role in the lubricity and anti-adhesion of polymer brushes, and it is proposed to predict the anti-adhesion of polymer brushes by their lubricity to avoid costly and time-consuming bioassays during the development of amphoteric polymer brushes. A quantitative influence of hydration in the anti-adhesion properties of amphiphilic polymer brushes is also revealed. Thus, this study provides a new approach to safe, long-lasting lubrication and anticoagulant surface modification for medical devices in contact with blood. Statement of significanceHigh friction and bioadhesion on medical device surfaces can pose a significant risk to patients. In response, we have developed a safer, simpler, and more application-specific surface modification strategy that addresses both the lubrication and anti-bioadhesion needs of medical device surfaces. We used dopamine and sodium alginate as intermediate layers to drastically increase the grafting density of the zwitterionic brushes and enabled the modified surfaces to have an extremely low coefficient of friction (μ = 0.0078) and to remain non-bioadhesive for 4 hours in vivo. Furthermore, we used molecular dynamics simulations to gain insight into the mechanisms behind the superior anti-adhesion properties of the high-density polymer brushes. Our work contributes to the development and application of surface-modified coatings.

Investigation of the role of von Willebrand factor in shear-induced platelet activation and functional alteration under high non-physiological shear stress.

von Willebrand factor (vWF) plays a crucial role in physiological hemostasis through platelet and subendothelial collagen adhesion. However, its role in shear-induced platelet activation and functional alteration under non-physiological conditions common to blood-contacting medical devices (BCMDs) is not well investigated. Fresh healthy human blood was treated with an anti-vWF antibody to block vWF-GPIbα interaction. Untreated blood was used as a control. They were exposed to three levels of non-physiological shear stress (NPSS) (75, 125, and 175 Pa) through a shearing device with an exposure time of 0.5 s to mimic typical shear conditions in BCMDs. Flow cytometric assays were used to measure the expression levels of PAC-1 and P-Selectin and platelet aggregates for platelet activation and the expression levels of GPIbα, GPIIb/IIIa, and GPVI for receptor shedding. Collagen/ristocetin-induced platelet aggregation capacity was characterized by aggregometry. The levels of platelet activation and aggregates increased with increasing NPSS in the untreated blood. More receptors were lost with increasing NPSS, resulting in a decreased capacity of collagen/ristocetin-induced platelet aggregation. In contrast, the increase in platelet activation and aggregates after exposure to NPSS, even at the highest level of NPSS, was significantly lower in treated blood. Nevertheless, there was no notable difference in receptor shedding, especially for GPIIb/IIIa and GPVI, between the two blood groups at the same level of NPSS. The block of vWF exacerbated the decreased capacity of collagen/ristocetin-induced platelet aggregation. High NPSS activates platelets mainly by enhancing the vWF-GPIbα interaction. Platelet activation and receptor shedding induced by high NPSS likely occur through different pathways.

Bivalirudin-hydrogel coatings of polyvinyl chloride on extracorporeal membrane oxygenation for anticoagulation.

Thromboembolic events associated with extracorporeal membrane oxygenation (ECMO) in clinical treatment are typical. Heparin coating has been widely employed as a surface modification strategy for ECMO tubes. However, its clinical application is often accompanied by unavoidable complications due to its mechanism of action. As a direct thrombin inhibitor with a single target, Bivalirudin (BV) has exhibited a lower incidence of adverse events and superior pharmacokinetic performance compared to heparin. A gelatin methacrylate hydrogel (GelMA) coating layer with BV was successfully synthesized on polyvinyl chloride, and the drug release ratio was close to complete release within 7 days. Simulated extracorporeal circulation experiments using roller pumps in vitro and jugular arteriovenous bypass experiments in rabbits demonstrated its outstanding anticoagulant efficacy. The systemic anticoagulant assay proved that BV hydrogel coating does not affect the coagulation level, and reduces the risk of complications such as systemic bleeding compared to intravenous injection. BV-Coating GelMA hydrogel tube has exhibited good biocompatibility and significantly improved anticoagulant performance, making it an optimal choice for surface materials used in blood-contacting medical devices.

Achieving superior anticoagulation of endothelial membrane mimetic coating by heparin grafting at zwitterionic biocompatible interfaces

Thrombosis and bleeding are common complications of blood-contacting medical device therapies. In this work, an endothelium membrane mimetic coating (PMPCC/Hep) has been created to address these challenges. The coating is fabricated by multi-point anchoring of a phosphorylcholine copolymer (poly-MPC-co-MSA, PMPCC) with carboxylic side chains and end-group grafting of unfractionated heparin (Hep) onto polydopamine precoated blood-contacting material surfaces. The PMPCC coating forms an ultrathin cell outer membrane mimetic layer to resist protein adsorption and platelet adhesion. The tiny defects/pores of the PMPCC layer provide entrances for heparin end-group to be inserted and grafted onto the sub-layer amino groups. The combination of the PMPCC cell membrane mimetic anti-fouling nature with the grafted heparin bioactivity further enhances the anticoagulation performance of the formed endothelium membrane mimetic PMPCC/Hep coating. Compared to conventional Hep coating, the PMPCC/Hep coating further decreases protein adsorption and platelet adhesion by 50 % and 90 %, respectively. More significantly, the PMPCC/Hep coating shows a superior anticoagulation activity, even significantly higher than that of an end-point-attached heparin coating. Furthermore, the blood coagulation function is well preserved in the PMPCC/Hep coating anticoagulation strategy. All the results support that the PMPCC/Hep coating strategy has great potential in developing more efficient and safer blood-contacting medical devices.

Visualizing a Nanoscale Lubricant Layer under Blood Flow.

Tethered-liquid perfluorocarbons (TLPs) are a class of liquid-infused surfaces with the ability to reduce blood clot formation (thrombosis) on blood-contacting medical devices. TLP comprises a tethered perfluorocarbon (TP) infused with a liquid perfluorocarbon (LP); this LP must be retained to maintain the antithrombotic properties of the layer. However, the stability of the LP layer remains in question, particularly for medical devices under blood flow. In this study, the lubricant thickness is spatially mapped and quantified in situ through confocal dual-wavelength reflection interference contrast microscopy. TLP coatings prepared on glass substrates are exposed to the flow of 37% glycerol/water mixtures (v/v) or whole blood at a shear strain rate of around 2900 s-1 to mimic physiological conditions (similar to flow conditions found in coronary arteries). Excess lubricant (>2 μm film thickness) is removed upon commencement of flow. For untreated glass, the lubricant is completely depleted after 1 min of shear flow. However, on optimized TLP surfaces, nanoscale films of lubricants (thickness between 100 nm and 2 μm) are retained over many tens of minutes of flow. The nanoscale films conform to the underlying structure of the TP layer and are sufficient to prevent the adhesion of red blood cells and platelets.

Fucoidan- and Ciprofloxacin-Doped Plasma-Activated Polymer Coatings on Biodegradable Zinc: Hemocompatibility and Drug Release.

Blood-contacting medical devices such as biodegradable metallic bone implant materials are expected to show excellent hemocompatibility both in vitro and in vivo. Different approaches are being studied and used to modify biomaterial surfaces for enhanced biocompatibility and hemocompatibility. However, the composition of degradable biomaterial must address several drawbacks at once. Iron-reinforced zinc material was used as a metallic substrate with improved mechanical properties when compared with those of pure zinc. Poly(lactic) acid (PLA) or polyethylenimine (PEI) was selected as a polymeric matrix for further doping with antibiotic ciprofloxacin (CPR) and marine-sourced polysaccharide fucoidan (FU), which are known for their antibacterial and potential anticoagulant properties, respectively. Radiofrequency air plasma was employed to induce metallic/polymer-coated surface activation before further modification with FU/CPR. Sample surface morphology and composition were studied and evaluated (contact angle measurements, AFM, SEM, and FT-IR) along with the hemolysis ratio and platelet adhesion test. Successful doping of the polymer layer by FU/CRP was confirmed. While PEI induced severe hemolysis over 12%, the PLA-coated samples exhibited even lower hemolysis (∼2%) than uncoated samples while the uncoated samples showed the lowest platelet adhesion. Moreover, gradual antibiotic release from PLA determined by the electrochemical methods using screen-printed carbon electrodes was observed after 24, 48, and 72 h, making the PLA-coated zinc-based material an attractive candidate for biodegradable material design.

Unravelling Surface Modification Strategies for Preventing Medical Device-Induced Thrombosis.

The use of biomaterials in implanted medical devices remains hampered by platelet adhesion and blood coagulation. Thrombus formation is a prevalent cause of failure of these blood-contacting devices. Although systemic anticoagulant can be used to support materials and devices with poor blood compatibility, its negative effects such as an increased chance of bleeding, make materials with superior hemocompatibility extremely attractive, especially for long-term applications. This review examines blood-surface interactions, the pathogenesis of clotting on blood-contacting medical devices, popular surface modification techniques, mechanisms of action of anticoagulant coatings, and discusses future directions in biomaterial research for preventing thrombosis. In addition, this paper comprehensively reviews several novel methods that either entirely prevent interaction between material surfaces and blood components or regulate the reaction of the coagulation cascade, thrombocytes, and leukocytes.

PB0443 Innovative Non-Isocyanate Polyurethane-Derived Hemocompatible Polymers for Blood-Contacting Medical Devices

PB0443 Innovative Non-Isocyanate Polyurethane-Derived Hemocompatible Polymers for Blood-Contacting Medical Devices

Tackling the Root Cause of Surface-Induced Coagulation: Inhibition of FXII Activation to Mitigate Coagulation Propagation and Prevent Clotting.

Factor XII (FXII) is a zymogen present in blood that tends to adsorb onto the surfaces of blood-contacting medical devices. Once adsorbed, it becomes activated, initiating a cascade of enzymatic reactions that lead to surface-induced coagulation. This process is characterized by multiple redundancies, making it extremely challenging to prevent clot formation and preserve the properties of the surface. In this study, a novel modulatory coating system based on C1-esterase inhibitor (C1INH) functionalized polymer brushes, which effectively regulates the activation of FXII is proposed. Using surface plasmon resonance it is demonstrated that this coating system effectively repels blood plasma proteins, including FXII, while exhibiting high activity against activated FXII and plasma kallikrein under physiological conditions. This unique property enables the modulation of FXII activation without interfering with the overall hemostasis process. Furthermore, through dynamic Chandler loop studies, it is shown that this coating significantly improves the hemocompatibility of polymeric surfaces commonly used in medical devices. By addressing the root cause of contact activation, the synergistic interplay between the antifouling polymer brushes and the modulatory C1INH is expected to lay the foundation to enhance the hemocompatibility of medical device surfaces.

Interactions to plasm protein and application potentials of carbon nanotubes in blood-contacting medical devices

Interactions to plasm protein and application potentials of carbon nanotubes in blood-contacting medical devices

Accelerated Hemocompatibility Testing of Rotary Blood Pumps.

Ex vivo hemocompatibility testing is a vital element of preclinical assessment for blood-contacting medical devices. Current approaches are resource intensive; thus, we investigated the feasibility of accelerating hemocompatibility testing by standardizing the number of pump exposures in loops of various sizes. Three identical blood loops were constructed, each with a custom-molded reservoir able to facilitate large-volume expansion. Using the HVAD rotary blood pump operating at 5 L·min-1 and 100 mmHg, three test volumes (80, 160, and 320 ml) were circulated for 4000 pump exposures. Blood sampling was performed at individualized intervals every one-sixth of total duration for the assessment of hemolysis and von Willebrand Factor (vWF) degradation. While steady increases in hemolysis (~24 mg·dl-1) were identified in all tests at completion, loop volume was not a primary discriminator. The normalized index of hemolysis did not vary significantly between loops (4.2-4.9 mg·100 L-1). vWF degradation progressively occurred with duration of testing to a similar extent under all conditions. These data support an accelerated approach to preclinical assessment of ex vivo blood damage. Adopting this approach enables: enhanced efficiency for rapid prototyping; reduced ex vivo blood aging, and; greater utility of blood, which is presently limited if 450 ml loops are desired.

Challenge of material haemocompatibility for microfluidic blood-contacting applications.

Biological applications of microfluidics technology is beginning to expand beyond the original focus of diagnostics, analytics and organ-on-chip devices. There is a growing interest in the development of microfluidic devices for therapeutic treatments, such as extra-corporeal haemodialysis and oxygenation. However, the great potential in this area comes with great challenges. Haemocompatibility of materials has long been a concern for blood-contacting medical devices, and microfluidic devices are no exception. The small channel size, high surface area to volume ratio and dynamic conditions integral to microchannels contribute to the blood-material interactions. This review will begin by describing features of microfluidic technology with a focus on blood-contacting applications. Material haemocompatibility will be discussed in the context of interactions with blood components, from the initial absorption of plasma proteins to the activation of cells and factors, and the contribution of these interactions to the coagulation cascade and thrombogenesis. Reference will be made to the testing requirements for medical devices in contact with blood, set out by International Standards in ISO 10993-4. Finally, we will review the techniques for improving microfluidic channel haemocompatibility through material surface modifications-including bioactive and biopassive coatings-and future directions.

Incorporating Anticoagulant and Antiplatelet Dual Functional Groups into Thermosetting Polymer Chain for Enhancing Antithrombogenicity.

In clinical practice, high-effective antithrombosis remains a challenge for blood-contacting medical devices. Inspired by the enhanced antithrombogenicity of anticoagulant and antiplatelet combination therapy, a strategy is proposed to synthesize dual-pathway antithrombotic polymers by incorporating anticoagulant and antiplatelet dual functional groups into a single thermosetting polymer chain. The synthesized polymer shows increased antithrombogenicity in vitro, with prolonged activated partial thromboplastin time (APTT) and decreased platelet adhesion. Additionally, it downregulates the expression of coagulation- and inflammation-related factors in rabbit plasma after ex vivo arteriovenous shunt assay and maintains patency of small vascular grafts for at least 6 months without thrombosis on the luminal surface after invivoreplacement of rabbit carotid artery. Thiswork provides a new approach to producing novel antithrombotic polymers for blood-contacting medical devices.

Progress in Application of Heparin Coating in Blood Contact Medical Devices

Blood compatibility is the main restriction of blood-contacting medical devices in clinical application, especially long-term blood-contacting medical devices will stimulate the immune defense mechanism of the host, resulting in thrombosis. Heparin anticoagulant coating links heparin molecules to the surface of medical device product materials, improves the compatibility between the material surface interface and the body, and reduces the host immune defense reactions. This study reviews the structure and biological properties of heparin, the market application status of heparin-coated medical products, the insufficiency and improvement of heparin coating, which can provide a reference for the application research of blood contact medical devices.