Unravelling Surface Modification Strategies for Preventing Medical Device-Induced Thrombosis

Abstract

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.

Keywords: medical devices; neoendothelialization; surface coatings; surface modification; thrombosis.

Figure 1

Illustrative depiction of various antithrombotic coatings, underlying mechanisms of action of A) titanium oxide, B) albumin, C) hydrophilic polymers and zwitterions, D) textured surfaces, E) omniphobic surfaces toward the inhibition of protein and cell adsorption. The interference of artificial stent could cause a F) thrombosis via the intrinsic pathway and inflammatory response via the complement activation.

Figure 2

Titanium dioxide nanotubes coated surfaces. A) Scanning electron microscopy images of TNTs on Ti surface: a–d) the TNTs anodized at 30–60 V; 1,2) the non‐ and annealing heating, and 3) the cross‐sectional morphologies of (a1)–(d1). B) The SEM images of platelet adhered to a) nonannealed surfaces and b) annealed surfaces (a1) Ti; a2) TNTs‐30; a3) TNTs‐40; a4) TNTs‐50; a5) TNTs‐60; b1) Ti‐A; b2) TNTs‐30A; b3) TNTs‐40A; b4) TNTs‐50A; b5) TNTs‐60A), and c,d) the corresponding number of adhered platelets on different substrates. Reproduced with permission.^{[ 63 ]} Copyright 2019, Elsevier. C) Aluminum oxide was coated on PVC surfaces. a) Red blood cells adhesion on blank PVC, thermal atomic layer deposition (T‐ALD) and plasma‐enhanced ALD (PE‐ALD) Al₂O₃ films after 1 h incubating with freshly drawn human whole blood. b) Activation of blood cells evaluated by a fluorescence‐activated cell sorter, as evident in CD3⁺/CD4⁺/CD8⁺, CD61⁺/CD62P⁺, and CD45⁺/CD42b⁺ populations. Reproduced with permission.^{[ 61 ]} Copyright 2022, Wiley Periodicals LLC.

Figure 3

Starch‐based zwitterionic hydrogel coatings. I) Depiction of zwitterionic hydrogel coatings. II) Pristine PET fabric and SSD18/PET fabric A) before and B) after filling with blood, cross‐sectional and formed thrombus pictures of C,D) PET fabric and SSD18/PET fabric after exposed for 1 h, SEM images of E) pristine PET fabric and F) SSD18/PET fabric, G) thrombus weight determination, H) APTT and TT tests. III) Fluorescence images of competitive adhesion of A–C) HUVECs and HASMCs, proliferation of D) HUVECs and E) HASMCs within 72 h and F) their ratios grown on bare and coated surfaces, H) fluorescence images of scratch healing assay, and scratch width changes on PET and SSDR/PET surfaces at 0, 12, and 24 h (^* p < 0.05, ^** p < 0.01, ^*** p < 0.001). Reproduced with permission.^{[ 188 ]} Copyright 2021, Elsevier. Another strategy that used gelatin and alginate for nitric oxide‐eluting (NOE) hydrogel coating on vascular stent to sustain nitric oxide release and suppress neointimal. IV) Schematic design of the NOE hydrogel coating. V) Macroscopic photos and VI) fluorescence images of the NOE hydrogel‐coated stent before and after dilation. Reproduced with permission.^{[ 189 ]} Copyright 2021, Springer Nature.

Figure 4

PTFEP–Al₂O₃ hybrid nanowires preventing biofouling and thrombosis. A) Helium ion microscopy images of a) pristine Al₂O₃ nanowires and c) PTFEP–Al₂O₃ nanowires, schematic illustrations of b) the surface morphology of Al₂O₃ nanowires, and d) photos of PTFEP–Al₂O₃ nanowires coated cardiovascular implants. B) Contact angle analysis and cross‐sectional images of a) the corresponding droplets. Comparison of b) blood drop sliding on (video‐captured images) PTFEP–Al₂O₃ nanowires versus the glass (control) substrate and c) PTFEP–Al₂O₃ nanowires versus pristine Al₂O₃ nanowires. Reproduced with permission.^{[ 223 ]} Copyright 2019, Royal Society of Chemistry. C) SEM images revealed platelet adhesion and activation on different titanium‐based substrates. Reproduced with permission.^{[ 224 ]} Copyright 2017, John Wiley and Sons Ltd. D) Fabrication process of superhydrophobic titanium plates. E) Magnified image of the microtexture and fluorescent microscope images of adsorbed albumin and fibrinogen on different surfaces. Reproduced with permission.^{[ 225 ]} Copyright 2021, Elsevier. F) Schematic illustration of preparing lubricant‐infused PET surfaces using silanized CD34–APTES nanoprobes. Reproduced with permission.^{[ 226 ]} Copyright 2019, Wiley‐VCH GmbH.

Figure 5

Illustration of several bioactive coatings, describing mechanisms of A) action of heparin, B) gasotransmitter‐releasing, and C) endothelialization toward the inhibition of coagulation factors.

Figure 6

Macroscopic photographs of the lumen of an ePTFE vascular graft containing the CARMEDA BioActive Surface Heparin Surface compared to an uncoated control after 2 h in a challenging non‐anticoagulated canine carotid interpositional model. The coated surface eliminated thrombotic occlusion, decreased inflammatory response, infection rates, and neointimal hyperplasia. Reproduced with permission.^{[ 249 ]} Copyright 2017, Elsevier.

Figure 7

Endothelium‐mimicking surface combining both biopassive and/or bioactive defenses to combat thrombosis and biofouling. A) The multilayer coatings consisted of endogenous donor S‐nitrosoglutathione (GSNO), copper nanoparticle (Cu⁰), and CarboSil layers. Reproduced with permission.^{[ 297 ]} Copyright 2019, American Chemical Society. B) The NO donor (S‐nitroso‐N‐acetylpenicillamine, SNAP) was embedded into CarboSil coating and covalently grafted with antifouling zwitterionic terpolymer (2‐methacryloyloxyethyl phosphorylcholine‐co‐butyl methacrylate‐co‐benzophenone, BPMPC). Reproduced with permission.^{[ 298 ]} Copyright 2017, American Chemical Society. C) The PVC tubing with hyaluronic acid (HA) and tri‐tert‐butyl 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetate‐chelated Cu²⁺ (DTris@Cu) coatings. Reproduced with permission.^{[ 299 ]} Copyright 2021, Wiley‐VCH GmbH.