ICAM-1–targeted thrombomodulin mitigates tissue factor–driven inflammatory thrombosis in a human endothelialized microfluidic model

Greineder, Colin F.; Johnston, Ian; Villa, Carlos H.; Gollomp, Kandace; Esmon, Charles T.; Cines, Douglas B.; Poncz, Mortimer; Muzykantov, Vladimir R.

doi:10.1182/bloodadvances.2017007229

Cited by 32 publications

(53 citation statements)

References 65 publications

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“…Microchannels were endothelialized with human umbilical vein endothelial cells as described previously, 37 which typically resulted in complete coverage of the microchannels. Channels were treated with tumor necrosis factor-a (TNF-a; 10 ng/mL) under flow (at shear stress of 5 dyne/cm 2 ) for 6 hours to flow condition and induce activation prior to exposure to whole blood.…”

Section: Microfluidic Assaymentioning

confidence: 99%

“…37 In this model, fully endothelialized microchannels are activated with an inflammatory mediator (eg, TNF-a), inducing leukocyte and platelet adhesion and widespread fibrin generation when the channels are exposed to flowing human whole blood. We hypothesized that if the fusions maintain their activity in whole blood, they would significantly reduce fibrin and platelet deposition in response to inflamed endothelium.…”

Section: Therapeutic Effectiveness Of Rbc Cargoesmentioning

confidence: 99%

“…The efficacy of these human RBCcoupled TMs was compared using a whole-blood, microfluidic model of inflammatory thrombosis recently described by our group. 37 …”

Section: Introductionmentioning

confidence: 99%

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Biocompatible coupling of therapeutic fusion proteins to human erythrocytes

et al. 2018

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Key Points• Thrombomodulin was fused to scFvs targeting RhCE (Rh17 epitope) and band 3/GPA (Wr b epitope).• Fusion proteins were efficacious in a humanized microfluidic model of inflammatory thrombosis. fibrin deposition induced by tumor necrosis factor-a in an endothelialized microfluidic model using human whole blood. RhCE-bound hTM-scFv more effectively reduced platelet and leukocyte adhesion, whereas anti-Wr b scFv appeared to promote platelet adhesion.These data provide a translational framework for the development of engineered affinity ligands to safely couple therapeutics to human RBCs.

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Section: Microfluidic Assaymentioning

confidence: 99%

Section: Therapeutic Effectiveness Of Rbc Cargoesmentioning

confidence: 99%

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Biocompatible coupling of therapeutic fusion proteins to human erythrocytes

et al. 2018

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“…An explanation for this is that at high TF levels, the amounts of thrombin formed under flow are too high to be targeted the coagulation factor‐inactivating thrombomodulin. In an inflammatory endothelial model, it was also found that the introduction of thrombomodulin suppresses fibrin deposition …”

Section: Discussionmentioning

confidence: 96%

“…Our approach herein differs from other vessel‐on‐a‐chip methods, mostly using a confluent monolayer of endothelial cells, which is activated with tumor necrosis factor‐α or is damaged mechanically or by FeCl 3 . Those methods can be considered to reflect conditions of inflammation or severe endothelial injury and may lack the presence of a “healthy” endothelium.…”

Section: Discussionmentioning

confidence: 99%

Localized endothelial‐based control of platelet aggregation and coagulation under flow: A proof‐of‐principle vessel‐on‐a‐chip study

Brouns

Provenzale

Geffen

et al. 2020

Journal of Thrombosis and Haemostasis

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Background In the intact vessel wall, endothelial cells form a barrier between the blood and the remaining vascular structures, serving to maintain blood fluidity and preventing platelet activation and fibrin clot formation. The spatiotemporal space of this inhibition is largely unknown. Objective To assess the local inhibitory roles of a discontinuous endothelium, we developed a vessel‐on‐a‐chip model, consisting of a microfluidic chamber coated with the thrombogenic collagen and tissue factor (TF), and covered with patches of human endothelial cells. By flow perfusion of human blood and plasma, the heterogeneous formation of platelet aggregates and fibrin clots was monitored by multicolor fluorescence microscopy. Results On collagen/TF coatings, a coverage of 40% to 60% of human umbilical vein endothelial cells resulted in a strong overall delay in platelet deposition and fibrin fiber formation under flow. Fibrin formation colocalized with the deposited platelets, and was restricted to regions in between endothelial cells, thus pointing to immediate local suppression of the clotting process. Fibrin kinetics were enhanced by treatment of the cells with heparinase III, partially disrupting the glycocalyx, and to a lesser degree by antagonism of the endothelial thrombomodulin. Co‐coating of purified thrombomodulin and collagen had a similar coagulation‐suppressing effect as endothelial thrombomodulin. Conclusions In this vessel‐on‐a‐chip system with patches of endothelial cells on thrombogenic surfaces, the coagulant activity under flow is regulated by: (a) the residual exposure of trigger (collagen/TF), (b) the endothelial glycocalyx, and (c) to a lesser degree the endothelial thrombomodulin.

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Reactive Oxygen Species Scavenging Nanomedicine for the Treatment of Ischemic Heart Disease

Zhang

Dalan

et al. 2022

Advanced Materials

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Ischemic heart disease (IHD) is the leading cause of disability and mortality worldwide. Reactive oxygen species (ROS) have been shown to play key roles in the progression of diabetes, hypertension, and hypercholesterolemia, which are independent risk factors that lead to atherosclerosis and the development of IHD. Engineered biomaterial‐based nanomedicines are under extensive investigation and exploration, serving as smart and multifunctional nanocarriers for synergistic therapeutic effect. Capitalizing on cell/molecule‐targeting drug delivery, nanomedicines present enhanced specificity and safety with favorable pharmacokinetics and pharmacodynamics. Herein, the roles of ROS in both IHD and its risk factors are discussed, highlighting cardiovascular medications that have antioxidant properties, and summarizing the advantages, properties, and recent achievements of nanomedicines that have ROS scavenging capacity for the treatment of diabetes, hypertension, hypercholesterolemia, atherosclerosis, ischemia/reperfusion, and myocardial infarction. Finally, the current challenges of nanomedicines for ROS‐scavenging treatment of IHD and possible future directions are discussed from a clinical perspective.

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ICAM-1–targeted thrombomodulin mitigates tissue factor–driven inflammatory thrombosis in a human endothelialized microfluidic model

Abstract: Key Points• A microfluidic model of TF-driven thrombosis allows testing of human-specific, antibody-targeted therapeutics in whole blood under flow.• hTM/R6.5 inhibits inflammatory thrombosis more effectively than untargeted agents (eg, shTM) and shows synergy with supplemental PC.

Cited by 32 publications

References 65 publications

Biocompatible coupling of therapeutic fusion proteins to human erythrocytes

Biocompatible coupling of therapeutic fusion proteins to human erythrocytes

Localized endothelial‐based control of platelet aggregation and coagulation under flow: A proof‐of‐principle vessel‐on‐a‐chip study

Reactive Oxygen Species Scavenging Nanomedicine for the Treatment of Ischemic Heart Disease

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