Validation of an MPC Polymer Coating to Attenuate Surface‐Induced Crosstalk between the Complement and Coagulation Systems in Whole Blood in In Vitro and In Vivo Models (original) (raw)
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In vitro blood reactivity to hydroxylated and non-hydroxylated polymer surfaces
Biomaterials, 2007
Complement activation on hydroxyl-group-bearing surfaces is regarded as the main reason for granulocyte activation in applications of blood-contacting medical devices such as extracorporeal blood purification. However, the factors inducing the cell adhesion so far remained ambiguous. For a dedicated research, whole blood was incubated with a set of structurally similar polymer coatings on glass with either hydroxy or ether functionalities. By co-incubation of an activating with a non-activating surface, the reaction of granulocytes activated by complement fragments on non-activating surfaces could be evaluated. As expected, hydroxyl-terminated polymer layers induced much higher levels of complement activation than those with ether functionalities. Leukocyte activation, as measured by the expression of CD11b, correlated closely with the presence of free complement fragment C5a. However, adhesion of leukocytes was rather associated with the adsorption of activated fragments of C3 than with the activation level of the cells. Moreover, it was found that adsorbed quantities of fibrin and fibrinogen had little influence on leukocyte adhesion. It is concluded that the activation of leukocytes is triggered by soluble complement factors such as C5a while their adhesion on hydroxy-bearing surfaces is mainly triggered by the presence of surface-bound complement fragment C3b. r
Biomaterials, 2014
Nitric oxide (NO) releasing (NORel) materials have been extensively investigated to create localized increases in NO concentration by the proton driven diazeniumdiolate-containing polymer coatings and demonstrated to improve extracorporeal circulation (ECC) hemocompatibility. In this work, the NORel polymeric coating composed of a diazeniumdiolated dibutylhexanediamine (DBHD-N 2 O 2 )-containing hydrophobic Elast-eon™ (E2As) polyurethane was combined with a direct thrombin inhibitor, argatroban (AG), and evaluated in a 4 h rabbit thrombogenicity model without systemic anticoagulation. In addition, the immobilizing of argatroban to E2As polymer was achieved by either a polyethylene glycolcontaining (PEGDI) or hexane methylene (HMDI) diisocyanate linker. The combined polymer film was coated on the inner walls of ECC circuits to yield significantly reduced ECC thrombus formation compared to argatroban alone ECC control after 4 h blood exposure (0.6 ± 0.1 AG/HMDI/NORel vs 1.7 ± 0.2 cm 2 AG/HMDI control). Platelet count (2.8 ± 0.3 AG/HMDI/NORel vs 1.9 ± 0.1 Â 10 8 /ml AG/HMDI control) and plasma fibrinogen levels were preserved after 4 h blood exposure with both the NORel/ argatroban combination and the AG/HMDI control group compared to baseline. Platelet function as measured by aggregometry remained near normal in both the AG/HMDI/NORel (63 ± 5%) and AG/HMDI control (58 ± 7%) groups after 3 h compared to baseline (77 ± 1%). Platelet P-selectin mean fluorescence intensity (MFI) as measured by flow cytometry also remained near baseline levels after 4 h on ECC to ex vivo collagen stimulation (16 ± 3 AG/HMDI/NORel vs 11 ± 2 MFI baseline). These results suggest that the combined AG/HMDI/NORel polymer coating preserves platelets in blood exposure to ECCs to a better degree than AG/PEGDI/NORel, NORel alone or AG alone. These combined antithrombin, NO-mediated antiplatelet effects were shown to improve thromboresistance of the AG/HMDI/NORel polymer-coated ECCs and move potential nonthrombogenic polymers closer to mimicking vascular endothelium.
Biomaterials, 2013
Activation of the thrombotic and complement systems is the main recognition and effector mechanisms in the multiple adverse biological responses triggered when biomaterials or therapeutic cells come into blood contact. We have created a surface which is auto-protective to human innate immunity by combining three fundamentally different strategies, all developed by us previously, which have been shown to induce substantial, but incomplete hemocompatibility when used separately. In summary, we have conjugated a factor Hebinding peptide; and an ADP-degrading enzyme; using a PEG linker on both material and cellular surfaces. When exposed to human whole blood, factor H was specifically recruited to the modified surfaces and inhibited complement attack. In addition, activation of platelets and coagulation was efficiently attenuated, by degrading ADP. Thus, by inhibiting thromboinflammation using a multicomponent approach, we have created a hybrid surface with the potential to greatly reduce incompatibility reactions involving biomaterials and transplantation.
Improving blood-compatibility of polymeric surface
Trends in Biomaterials and Artificial Organs
Biocompatibility has been defined by consensus, but not blood-compatibility. The interactions between blood and a surface depend on the blood composition, the blood flow and the surface of the material defined by its physicochemical features. Blood response is sensitive to surface features such as surface area, crystallinity, hydrophobicity/hydrophilicity, outermost structure and surface chemistry. Material surfaces are not blood-compatible, resulting in triggering of the non-specific self-protection mechanisms of blood. Improving blood-compatibility of polymeric surfaces requires that the surfaces are able to delay, or to control locally the biochemical events implied in these responses. Strategies such as the "repelling brush" or the heparinised and heparin-like surfaces are currently developed to improve blood-compatibility of polymeric surfaces.
Thrombosis and Haemostasis, 2005
Catheteru se has been associated with an increasedr isko f thrombotic complications.Theobjectivewas to makecatheters less thrombogenic withthe useofantithrombin-heparin covalentcomplex (ATH).Theantithrombotic activity of ATH-coated catheters was compared to uncoated(control) and heparincoated catheters in an acute rabbit model of acceleratedoccluding clot formation.Anaesthetizedrabbits were pre-injected with rabbit 125 I-fibrinogen,followedbyinsertion of test catheters into the jugular vein. Bloodw as drawn and held in as yringe,r einjected, thenf lushed with saline.The experiment wast erminatedwhenbloodcouldnolongerbewithdrawn (occluding clot). Efficacy wasdefinedasthe abilityofcatheterstor emain unoccluded. Clot formation,determined by measuring deposition of radiolabeled fibrin, wasas econdarye ndpoint. ATH-coatedc athetersw erer esistant to clotting fort he full 240-minute Keywords Anticoagulant, ATH, polyurethane,m odified catheters,s urface grafting duration,while uncoated and heparin-coatedc athetersh ad an average clottingt ime of 78 and 56 minutes, respectively. The patency ofATHcoatingwas dependantonintact heparin pentasaccharides equences, rather than the chemistrieso ft he basecoat, the PEOspacer arm, or theantithrombin (AT) protein.The ATHcoatingwas stabletoethylene oxidesterilization, modest abrasion,p roteasea ttack,a nd the coating didn ot appear to leach off the catheter.Surfacet ension measurements showed that the ATHm odified surfacew as moreh ydrophilic than uncoated control catheters or heparin-coated catheters.Thus, ATH-coatedc athetersa re better at preventing clots than uncoated or heparin-coated catheters and show promisea sa n alternative to the currentlya vailable catheters in reducing thrombotic complications associated with its use.
Hemocompatibility of chitosan/poly(acrylic acid) grafted polyurethane tubing
2013
The activation and adhesion of platelets or whole blood exposed to chitosan (CH) grafted surfaces is used to evaluate the hemocompatibility of biomaterials. The biomaterial surfaces are polyurethane (PU) tubes grafted with an inner poly(acrylic acid) (PAA) and an outer CH or quaternary ammonium modified CH (CH-Q) brush.
The Annals of Thoracic Surgery, 2004
Exposure of blood to artificial surfaces, as in cardiopulmonary bypass, induces an inflammatory response involving complement, leukocyte and platelet activation. To elucidate the specific role of complement in this process, studies were performed on blood circulated in polyvinyl chloride tubing in the absence and presence of complement inhibitors. Parallel experiments were performed with heparin-coated polyvinyl chloride tubing, which is known to prevent complement and cell activation.
Langmuir, 2012
Polyurethane (PU) was modified using isocyanate chemistry to graft polyethylene oxide (PEO) of various molecular weights (range 300−4600). An antithrombin−heparin (ATH) covalent complex was subsequently attached to the free PEO chain ends, which had been functionalized with N-hydroxysuccinimide (NHS) groups. Surfaces were characterized by water contact angle and X-ray photoelectron spectroscopy (XPS) to confirm the modifications. Adsorption of fibrinogen from buffer was found to decrease by ∼80% for the PEO-modified surfaces compared to the unmodified PU. The surfaces with ATH attached to the distal chain end of the grafted PEO were equally protein resistant, and when the data were normalized to the ATH surface density, PEO in the lower MW range showed greater protein resistance. Western blots of proteins eluted from the surfaces after plasma contact confirmed these trends. The uptake of ATH on the PEO-modified surfaces was greatest for the PEO of lower MW (300 and 600), and antithrombin binding from plasma (an indicator of heparin anticoagulant activity) was highest for these same surfaces. The PEO−ATH-and PEO-modified surfaces also showed low platelet adhesion from flowing whole blood. It is concluded that for the PEO−ATH surfaces, PEO in the low MW range, specifically MW 600, may be optimal for achieving an appropriate balance between resistance to nonspecific protein adsorption and the ability to take up ATH and bind antithrombin in subsequent blood contact.
A bioinspired omniphobic surface coating on medical devices prevents thrombosis and biofouling
Nat Biotechnol, 2014
medical devices cause significant morbidity and mortality worldwide. We describe a bioinspired coating that repels blood from virtually any material by covalently tethering a molecular layer of perfluorocarbon, which holds a thin liquid film of medical-grade perfluorocarbon on the substrate surface, mimicking the liquid layer certain plants use to prevent adhesion. This coating prevents fibrin attachment, reduces platelet adhesion and activation, suppresses biofilm formation, and is stable under blood flow in vitro. Surface-coated medical-grade tubing and catheters, assembled into arteriovenous shunts and implanted in living pigs, remain patent for at least 8 hours without anticoagulation. This coating technology offers the potential to significantly reduce anticoagulation in patients while preventing thrombotic occlusion and biofouling of medical devices.