Mimicking the fibrinolytic system on material surfaces

Li, Dan; Chen, Hong; Brash, John L.

doi:10.1016/j.colsurfb.2011.04.003

Cited by 53 publications

(29 citation statements)

References 46 publications

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“…Surface modification with bioactive agents capable of combating thrombosis is the most widely used strategy for developing antithrombotic biomaterials . These agents either inhibit fibrinogenesis by “cutting off” the coagulation pathways (e.g., heparin), or promote fibrinolysis so that nascent clots are broken down (e.g., plasminogen activators) . However, the exposure of blood to the antithrombotic agent may cause disorders of hemostasis under normal conditions.…”

Section: Introductionmentioning

confidence: 99%

Thrombosis‐Responsive Thrombolytic Coating Based on Thrombin‐Degradable Tissue Plasminogen Activator (t‐PA) Nanocapsules

Liu

Yang

et al. 2017

Adv Funct Materials

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Surface modification with bioactive agents capable of combating thrombosis is a widely used strategy for developing antithrombotic biomaterials. However, exposure of the blood to the antithrombotic agent on the material surface may cause hemostatic disorders under normal conditions. Ideally an implanted biomaterial should respond appropriately on demand to a specific change in the physiologic environment, as happens in the body itself. In the present study, a thrombosis-responsive surface coating with the ability to lyse fibrin as it forms is reported. The coating consists of nanocapsules (NCs) in which the fibrinolysis activator t-PA is encapsulated in a thrombin-degradable hydrogel shell. The t-PA NCs are attached to several materials covalently through a polydopamine adhesive layer. The resulting surfaces are treated with the antifouling agent glutathione (GSH) to prevent further interactions with blood/plasma components. The t-PA NCs/GSHcoated surface is stable and remain inert in normal plasma environment while releasing t-PA and promoting fibrinolysis when thrombin is present. The fibrinolytic activity increases with increasing thrombin concentration, and therefore presumably with the extent of thrombosis. This work constitutes the first report of an antithrombotic coating whose function is triggered and regulated, respectively, by the appearance of thrombin and the extent of coagulation.

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Section: Introductionmentioning

confidence: 99%

Thrombosis‐Responsive Thrombolytic Coating Based on Thrombin‐Degradable Tissue Plasminogen Activator (t‐PA) Nanocapsules

Liu

Yang

et al. 2017

Adv Funct Materials

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“…We then investigated the adsorption of Plg, the central protein of the fibrinolytic system. [6a] Both Plg and t‐PA are known to bind to lysine moieties on the surface of fibrin clot via their lysine binding sites to form a ternary complex whereby Plg is activated to plasmin; therefore, lysine has been used as a ligand for binding Plg . As shown in Figure , the surfaces without lysine exhibited low levels of Plg adsorption (<20 ng cm −2 ), suggesting that nonspecific adsorption of this protein is limited.…”

Section: Resultsmentioning

confidence: 99%

“…To date, however, this approach has not produced any material that is sufficiently resistant to thrombus formation. Alternatively, we and other groups have proposed an offensive strategy whereby the fibrinolytic system is activated so that nascent clots that form on the surface are broken down . Based on this strategy, we have developed several surfaces which were shown to capture plasminogen (Plg) and tissue type plasminogen activator (t‐PA) selectively when in contact with blood to generate plasmin and lyse nascent clots formed on the surface …”

Section: Introductionmentioning

confidence: 99%

“…Lysine is a ligand with high affinity for Plg and t‐PA, facilitating the generation of plasmin to lyse incipient clots. [6a] To incorporate these two ligands, PU surfaces were modified with a copolymer of poly(2‐hydroxyethyl methacrylate‐ co ‐1‐adamantan‐1‐ylmethyl methacrylate) (poly(HEMA‐co‐AdaMA)), which provides attachment sites for REDV peptide through covalent bonding, and for β‐CD‐(Lys) 7 through host–guest interaction. The successful preparation of this surface was confirmed using a series of characterization methods and assays.…”

Section: Introductionmentioning

confidence: 99%

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Bioinspired Blood Compatible Surface Having Combined Fibrinolytic and Vascular Endothelium‐Like Properties via a Sequential Coimmobilization Strategy

Zhan

Shi

et al. 2015

Adv Funct Materials

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Developing surfaces with antithrombotic properties is of great interest for the applications of blood-contacting biomaterials and medical devices. It is promising to coimmobilize two or more biomolecules with different and complementary functions to improve blood compatibility. However, the general one-pot strategy usually adopted by previous studies suffers the problems of inevitable competition between diverse biomolecules and uncontrollability of the relative quantities of the immobilized biomolecules. To solve these problems, a new sequential coimmobilization strategy is proposed and applied to fabricate a blood compatible surface. Polyurethane surface is modifi ed with a copolymer, poly(2-hydroxyethyl methacrylate-co-1-adamantan-1-ylmethyl methacrylate), which serves as a linker-spacer for sequential attachment of two functional molecules, a hexapeptide containing REDV (Arg-Glu-Asp-Val) sequence, and a modifi ed cyclodextrin bearing 7 lysine ligands, through covalent bonding and host-guest interaction, respectively. The resulting surface combines the antithrombogenic properties of the vascular endothelium and the clot lysing properties of the fi brinolytic system. Importantly, neither of the two functions of REDV peptide and lysine is compromised by the presence of the other, suggesting the enhanced blood compatibility. These results suggest a new strategy to engineer multifunctional surfaces by coimmobilization of bioactive molecules having unique functionalities.

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“…Various strategies have been used to control surface coagulation including coating the surface with proteinresistant polymers, (7)(8)(9) active molecules such as anticoagulants [10,11] or fibrinolysis promoters, [12][13][14][15] endothelial cells [16,17] or polymers mimicking their membrane, [18,19] and last but not least inorganic thin films conferring various surface properties as reviewed by Mani and colleagues [20]. A strategy not comprised in this list was proposed by P. N. Sawyer more than 40 years ago and consisted in cathodically polarizing the implant's surface.…”

Section: Introductionmentioning

confidence: 99%

Coagulation at the Blood–Electrode Interface: The Role of Electrochemical Desorption and Degradation of Fibrinogen

et al. 2014

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The influence of electrochemistry on the coagulation of blood on metal surfaces was demonstrated several decades ago. In particular, the application of cathodic currents resulted in reduced surface thrombogenicity, but no molecular mechanism has been so far proposed to explain this observation. In this article we used for the first time the quartz crystal microbalance with dissipation monitoring technique coupled with an electrochemical setup (EQCM-D) to study thrombosis at the blood-electrode interface. We confirmed the reduced thrombus deposition at the cathode, and we subsequently studied the effect of cathodic currents on adsorbed fibrinogen (Fg). Using EQCM and mass spectrometry, we found that upon applying currents Fg desorbed from the electrode and was electrochemically degraded. In particular, we show that the flexible N-terminus of the -chain, containing an important polymerization site, was cleaved from the protein, thus affecting its clottability. Our work proposes a molecular mechanism that at least partially explains how cathodic currents reduce thrombosis at the blood-electrode interface and is a relevant contribution to the rational development of medical devices with reduced thrombus formation on their surface. ABSTRACTThe influence of electrochemistry on the coagulation of blood on metal surfaces was demonstrated several decades ago. In particular, the application of cathodic currents resulted in reduced surface thrombogenicity, but no molecular mechanism has been so far proposed to explain this observation. In this article we used for the first time the quartz crystal microbalance with dissipation monitoring technique coupled with an electrochemical setup (EQCM-D) to study thrombosis at the blood-electrode interface. We confirmed the reduced thrombus deposition at the cathode, and we subsequently studied the effect of cathodic currents on adsorbed fibrinogen (Fg). Using EQCM and mass spectrometry, we found that upon applying currents Fg desorbed from the electrode and was electrochemically degraded. In particular, we show that the flexible N-terminus of the α-chain, containing an important polymerization site, was cleaved from the protein, thus affecting its clottability. Our work proposes a molecular mechanism that at least partially explains how cathodic currents reduce thrombosis at the blood-electrode interface and is a relevant contribution to the rational development of medical devices with reduced thrombus formation on their surface.2

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Mimicking the fibrinolytic system on material surfaces

Cited by 53 publications

References 46 publications

Thrombosis‐Responsive Thrombolytic Coating Based on Thrombin‐Degradable Tissue Plasminogen Activator (t‐PA) Nanocapsules

Thrombosis‐Responsive Thrombolytic Coating Based on Thrombin‐Degradable Tissue Plasminogen Activator (t‐PA) Nanocapsules

Bioinspired Blood Compatible Surface Having Combined Fibrinolytic and Vascular Endothelium‐Like Properties via a Sequential Coimmobilization Strategy

Coagulation at the Blood–Electrode Interface: The Role of Electrochemical Desorption and Degradation of Fibrinogen

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