An “occlusive thrombosis-on-a-chip” microfluidic device for investigating the effect of anti-thrombotic drugs

Berry, Jess; Peaudecerf, François J.; Masters, Nicole A.; Neeves, Keith B.; Goldstein, Raymond E.; Harper, Matthew T.

doi:10.1039/d1lc00347j

Cited by 25 publications

(39 citation statements)

References 82 publications

(124 reference statements)

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“…Occlusive thrombi do not form in many published models, as blood flow as a syringe pump delivers blood at constant flow. In contrast, the bifurcated design of our model allows thrombosis to continue until the channel is occluded 18 . Our data are consistent with a study using the Total Thrombus‐Formation System, a commercially available microfluidic model of occlusive thrombosis.…”

Section: Discussionsupporting

confidence: 87%

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Protease‐activated receptor antagonists prevent thrombosis when dual antiplatelet therapy is insufficient in an occlusive thrombosis microfluidic model

Berry

Harper

2022

Research and Practice in Thrombosis and Haemostasis

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Background Platelet activation and arterial thrombosis on a ruptured atherosclerotic plaque is a major cause of myocardial infarction. Dual antiplatelet therapy (DAPT), the combination of platelet aggregation inhibitors, aspirin and a P2Y12 antagonist, is used to prevent arterial thrombosis. However, many people continue to have arterial thrombosis and myocardial infarction despite DAPT, indicating that additional therapies are required where DAPT is insufficient. Objectives To determine whether antagonists of protease‐activated receptors (PARs) can prevent occlusive thrombosis under conditions where DAPT is insufficient. Methods We used human whole blood in a microfluidic model of occlusive thrombosis to compare conditions under which DAPT is effective to those under which DAPT was not. Cangrelor (a P2Y12 antagonist) and aspirin were used to mimic DAPT. We then investigated whether the PAR1 antagonist vorapaxar or the PAR4 antagonist BMS 986120, alone or in combination with DAPT, prevented occlusive thrombosis. Results and Conclusions A ruptured plaque exposes collagen fibers and is often rich in tissue factor, triggering activation of platelets and coagulation. Occlusive thrombi formed on type I collagen in the presence or absence of tissue factor (TF). However, although DAPT prevented occlusive thrombosis in the absence of TF, DAPT had little effect when TF was also present. Under these conditions, PAR antagonism was also ineffective. However, occlusive thrombosis was prevented by combining DAPT with PAR antagonism. These data demonstrate that PAR antagonists may be a useful addition to DAPT in some patients and further demonstrate the utility of in vitro models of occlusive thrombosis.

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Section: Discussionsupporting

confidence: 87%

“…In brief, devices were fabricated as described previously 18 using polydimethylsiloxane (PDMS) molded to a silicon wafer generated by photolithography. PDMS was vacuum sealed to a glass coverslip such that a 2 μl spot of prothrombotic trigger was positioned in one channel of the device.…”

Section: Methodsmentioning

confidence: 99%

Protease‐activated receptor antagonists prevent thrombosis when dual antiplatelet therapy is insufficient in an occlusive thrombosis microfluidic model

Berry

Harper

2022

Research and Practice in Thrombosis and Haemostasis

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“…Scale bar = 50 μm. (F) A chaotic mixer from Berry et al (2021) ; Top: Schematic of the chaotic mixer; Bottom: Confocal images of platelets (and leukocytes) and fibrin in EDTA-quenched channel (left) and the eptifibatide channel (right). (G) An active micropump mixer with micropump valve chambers and pneumatic actuation chambers from Szydzik et al (2019) .…”

Section: Novel Microfluidic Approaches For Platelet Function Assessment and Anti-platelet Drug Screeningmentioning

confidence: 99%

“…To enable efficient and accurate antiplatelet drug screening from a large library in the presence of hemodynamic microenvironment, the microsystem should include the following characteristics: 1) cheap and easy-to-use with small volume requirement of blood samples; 2) Simple and user-friendly operation; 3) accurate and rapid testing; 4) high-throughput to test a large number of drug candidates ( Meagher et al, 2008 ; Gubala et al, 2012 ; Myers et al, 2017 ; Berry et al, 2021 ). Hereby we reviewed several integrated and multiplexed microfluidic systems that meet these requirements, demonstrating great potentials towards rapid, automated and high-throughput antiplatelet drug screening.…”

Section: Novel Microfluidic Approaches For Platelet Function Assessment and Anti-platelet Drug Screeningmentioning

confidence: 99%

“…Here, dot array occupancy indicates platelet adhesion and the system has been used to screen GPIIb/IIIa and P2Y 12 antagonists. Moreover, Berry et al (2021) designed an occlusive thrombosis-on-a-chip model that incorporates two branching channels—a chaotic mixer for testing the EDRA quenching effects on platelet activation, and a collagen/tissue factor-coated channel for coagulation evaluation ( Figure 1F ). This model is simple and robust to measure occlusion time and can be utilized to screen potent antiplatelet drugs that inhibits channel occlusion and presumably blood vessel occlusion.…”

Section: Novel Microfluidic Approaches For Platelet Function Assessment and Anti-platelet Drug Screeningmentioning

confidence: 99%

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Platelet Mechanobiology Inspired Microdevices: From Hematological Function Tests to Disease and Drug Screening

et al. 2022

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Platelet function tests are essential to profile platelet dysfunction and dysregulation in hemostasis and thrombosis. Clinically they provide critical guidance to the patient management and therapeutic evaluation. Recently, the biomechanical effects induced by hemodynamic and contractile forces on platelet functions attracted increasing attention. Unfortunately, the existing platelet function tests on the market do not sufficiently incorporate the topical platelet mechanobiology at play. Besides, they are often expensive and bulky systems that require large sample volumes and long processing time. To this end, numerous novel microfluidic technologies emerge to mimic vascular anatomies, incorporate hemodynamic parameters and recapitulate platelet mechanobiology. These miniaturized and cost-efficient microfluidic devices shed light on high-throughput, rapid and scalable platelet function testing, hematological disorder profiling and antiplatelet drug screening. Moreover, the existing antiplatelet drugs often have suboptimal efficacy while incurring several adverse bleeding side effects on certain individuals. Encouraged by a few microfluidic systems that are successfully commercialized and applied to clinical practices, the microfluidics that incorporate platelet mechanobiology hold great potential as handy, efficient, and inexpensive point-of-care tools for patient monitoring and therapeutic evaluation. Hereby, we first summarize the conventional and commercially available platelet function tests. Then we highlight the recent advances of platelet mechanobiology inspired microfluidic technologies. Last but not least, we discuss their future potential of microfluidics as point-of-care tools for platelet function test and antiplatelet drug screening.

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A Vascular Graft On‐a‐Chip Platform for Assessing the Thrombogenicity of Vascular Prosthesis and Coatings with Tuneable Flow and Surface Conditions

Bot

Shakeri

Weitz

et al. 2022

Adv Funct Materials

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Vascular grafts are essential for the management of cardiovascular disease. However, the lifesaving potential of these devices is undermined by thrombosis arising from material and flow interactions on the blood contacting surface. To combat this issue, antithrombogenic coatings have emerged as a promising strategy for modulating blood and graft interaction in vivo. Although an important determinant of graft performance, hemodynamics are frequently overlooked for in vitro testing of coatings and their translatability remains poorly understood. Herein, this limitation is addressed with a microscale graft on-a-chip platform incorporating vascular prosthesis and coatings with tuneable flow and surface conditions in vitro. As a proof of concept, the platform is used to test the thrombogenicity of a novel class of lubricant-infused surface (LIS) and antibody lubricant-infused (anti-CD34 LIS) coated expanded polytetrafluoroethylene (ePTFE) vascular grafts in the presence of arterial wall shear stress with and without endothelial cells. The findings suggest LIS ePTFE is thromboresistant under flow with significantly reduced fibrin(ogen) deposition, thrombin activity, and blood cell adhesion compared to uncoated controls. It is moreover apparent that the microscale properties of the device are advantageous for the testing and translation of novel antithrombogenic coatings and blood-contacting materials in general.

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An “occlusive thrombosis-on-a-chip” microfluidic device for investigating the effect of anti-thrombotic drugs

Abstract: Cardiovascular disease remains one of the world’s leading causes of death. Myocardial infarction (heart attack) is triggered by occlusion of coronary arteries by platelet-rich thrombi (clots). The development of new...

Cited by 25 publications

References 82 publications

Protease‐activated receptor antagonists prevent thrombosis when dual antiplatelet therapy is insufficient in an occlusive thrombosis microfluidic model

Protease‐activated receptor antagonists prevent thrombosis when dual antiplatelet therapy is insufficient in an occlusive thrombosis microfluidic model

Platelet Mechanobiology Inspired Microdevices: From Hematological Function Tests to Disease and Drug Screening

A Vascular Graft On‐a‐Chip Platform for Assessing the Thrombogenicity of Vascular Prosthesis and Coatings with Tuneable Flow and Surface Conditions

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