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Article: Automated Analysis of Platelet Aggregation on Cultured Endothelium in a Microfluidic Chip Perfused with Human Whole Blood.

Albers, Hugo J / Passier, Robert / van den Berg, Albert / van der Meer, Andries D

2019 Volume 10, Issue 11

Abstract: Organ-on-a-chip models with incorporated vasculature are becoming more popular to study platelet biology. A large variety of image analysis techniques are currently used to determine platelet coverage, ranging from manually setting thresholds to scoring ... ...

Abstract	Organ-on-a-chip models with incorporated vasculature are becoming more popular to study platelet biology. A large variety of image analysis techniques are currently used to determine platelet coverage, ranging from manually setting thresholds to scoring platelet aggregates. In this communication, an automated methodology is introduced, which corrects misalignment of a microfluidic channel, automatically defines regions of interest and utilizes a triangle threshold to determine platelet coverages and platelet aggregate size distributions. A comparison between the automated methodology and manual identification of platelet aggregates shows a high accuracy of the triangle methodology. Furthermore, the image analysis methodology can determine platelet coverages and platelet size distributions in microfluidic channels lined with either untreated or activated endothelium used for whole blood perfusion, proving the robustness of the method.
Language	English
Publishing date	2019-11-14
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2620864-7
ISSN	2072-666X
ISSN	2072-666X
DOI	10.3390/mi10110781
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: In Vitro Microfluidic Disease Model to Study Whole Blood-Endothelial Interactions and Blood Clot Dynamics in Real-Time.

Manz, Xue D / Albers, Hugo J / Symersky, Petr / Aman, Jurjan / van der Meer, Andries D / Bogaard, Harm Jan / Szulcek, Robert

Journal of visualized experiments : JoVE

2020 , Issue 159

Abstract: The formation of blood clots involves complex interactions between endothelial cells, their underlying matrix, various blood cells, and proteins. The endothelium is the primary source of many of the major hemostatic molecules that control platelet ... ...

Abstract	The formation of blood clots involves complex interactions between endothelial cells, their underlying matrix, various blood cells, and proteins. The endothelium is the primary source of many of the major hemostatic molecules that control platelet aggregation, coagulation, and fibrinolysis. Although the mechanism of thrombosis has been investigated for decades, in vitro studies mainly focus on situations of vascular damage where the subendothelial matrix gets exposed, or on interactions between cells with single blood components. Our method allows studying interactions between whole blood and an intact, confluent vascular cell network. By utilizing primary human endothelial cells, this protocol provides the unique opportunity to study the influence of endothelial cells on thrombus dynamics and gives valuable insights into the pathophysiology of thrombotic disease. The use of custom-made microfluidic flow channels allows application of disease-specific vascular geometries and model specific morphological vascular changes. The development of a thrombus is recorded in real-time and quantitatively characterized by platelet adhesion and fibrin deposition. The effect of endothelial function in altered thrombus dynamics is determined by postanalysis through immunofluorescence staining of specific molecules. The representative results describe the experimental setup, data collection, and data analysis. Depending on the research question, parameters for every section can be adjusted including cell type, shear rates, channel geometry, drug therapy, and postanalysis procedures. The protocol is validated by quantifying thrombus formation on the pulmonary artery endothelium of patients with chronic thromboembolic disease.
MeSH term(s)	Blood Coagulation ; Blood Platelets/metabolism ; Endothelial Cells/cytology ; Endothelial Cells/metabolism ; Fibrinolysis ; Hemostasis ; Humans ; Microfluidics/instrumentation ; Microfluidics/methods ; Platelet Adhesiveness ; Platelet Aggregation ; Thrombosis/physiopathology
Language	English
Publishing date	2020-05-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Video-Audio Media
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/61068
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: In vitro microfluidic disease model to study whole blood-endothelial interactions and blood clot dynamics in real-time

Manz, Xue D / Albers, Hugo J / Symersky, Petr / Aman, Jurjan / van der Meer, Andries D / Bogaard, Harm Jan / Szulcek, Robert

Journal of visualized experiments. 2020 May 24, , no. 159

2020

Abstract	The formation of blood clots involves complex interactions between endothelial cells, their underlying matrix, various blood cells, and proteins. The endothelium is the primary source of many of the major hemostatic molecules that control platelet aggregation, coagulation, and fibrinolysis. Although the mechanism of thrombosis has been investigated for decades, in vitro studies mainly focus on situations of vascular damage where the subendothelial matrix gets exposed, or on interactions between cells with single blood components. Our method allows studying interactions between whole blood and an intact, confluent vascular cell network. By utilizing primary human endothelial cells, this protocol provides the unique opportunity to study the influence of endothelial cells on thrombus dynamics and gives valuable insights into the pathophysiology of thrombotic disease. The use of custom-made microfluidic flow channels allows application of disease-specific vascular geometries and model specific morphological vascular changes. The development of a thrombus is recorded in real-time and quantitatively characterized by platelet adhesion and fibrin deposition. The effect of endothelial function in altered thrombus dynamics is determined by postanalysis through immunofluorescence staining of specific molecules. The representative results describe the experimental setup, data collection, and data analysis. Depending on the research question, parameters for every section can be adjusted including cell type, shear rates, channel geometry, drug therapy, and postanalysis procedures. The protocol is validated by quantifying thrombus formation on the pulmonary artery endothelium of patients with chronic thromboembolic disease.
Keywords	adhesion ; blood coagulation ; coagulation ; data collection ; disease models ; drug therapy ; endothelium ; fibrin ; fibrinolysis ; fluorescent antibody technique ; geometry ; humans ; pathophysiology ; platelet aggregation ; pulmonary artery ; thrombosis
Language	English
Dates of publication	2020-0524
Size	p. e61068.
Publishing place	Journal of Visualized Experiments
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	2259946-0
ISSN	1940-087X
ISSN	1940-087X
DOI	10.3791/61068
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Targeting shear gradient activated von Willebrand factor by the novel single-chain antibody A1 reduces occlusive thrombus formation in vitro.

Hoefer, Thomas / Rana, Akshita / Niego, Be'eri / Jagdale, Shweta / Albers, Hugo J / Gardiner, Elizabeth E / Andrews, Robert K / Van der Meer, Andries D / Hagemeyer, Christoph E / Westein, Erik

Haematologica

2021 Volume 106, Issue 11, Page(s) 2874–2884

Abstract: Intraluminal thrombus formation precipitates conditions such as acute myocardial infarction and disturbs local blood flow resulting in areas of rapidly changing blood flow velocities and steep gradients of blood shear rate. Shear rate gradients are known ...

Abstract	Intraluminal thrombus formation precipitates conditions such as acute myocardial infarction and disturbs local blood flow resulting in areas of rapidly changing blood flow velocities and steep gradients of blood shear rate. Shear rate gradients are known to be pro-thrombotic with an important role for the shear-sensitive plasma protein von Willebrand factor (VWF). Here, we developed a single-chain antibody (scFv) that targets a shear gradient specific conformation of VWF to specifically inhibit platelet adhesion at sites of SRGs but not in areas of constant shear. Microfluidic flow channels with stenotic segments were used to create shear rate gradients during blood perfusion. VWF-GPIbα interactions were increased at sites of shear rate gradients compared to constant shear rate of matched magnitude. The scFv-A1 specifically reduced VWF-GPIbα binding and thrombus formation at sites of SRGs but did not block platelet deposition and aggregation under constant shear rate in upstream sections of the channels. Significantly, the scFv A1 attenuated platelet aggregation only in the later stages of thrombus formation. In the absence of shear, direct binding of scFv-A1 to VWF could not be detected and scFV-A1 did not inhibit ristocetin induced platelet agglutination. We have exploited the pro-aggregatory effects of SRGs on VWF dependent platelet aggregation and developed the shear-gradient sensitive scFv-A1 antibody that inhibits platelet aggregation exclusively at sites of shear rate gradients. The lack of VWF inhibition in non-stenosed vessel segments places scFV-A1 in an entirely new class of anti-platelet therapy for selective blockade of pathological thrombus formation while maintaining normal haemostasis.
MeSH term(s)	Blood Platelets ; Humans ; Platelet Adhesiveness ; Platelet Aggregation ; Platelet Glycoprotein GPIb-IX Complex ; Thrombosis/drug therapy ; von Willebrand Factor
Chemical Substances	Platelet Glycoprotein GPIb-IX Complex ; von Willebrand Factor
Language	English
Publishing date	2021-11-01
Publishing country	Italy
Document type	Journal Article
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2020.250761
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Article ; Online: Inhibition of Phosphodiesterase 3A by Cilostazol Dampens Proinflammatory Platelet Functions.

Coenen, Daniëlle M / Heinzmann, Alexandra C A / Oggero, Silvia / Albers, Hugo J / Nagy, Magdolna / Hagué, Perrine / Kuijpers, Marijke J E / Vanderwinden, Jean-Marie / van der Meer, Andries D / Perretti, Mauro / Koenen, Rory R / Cosemans, Judith M E M

Cells

2021 Volume 10, Issue 8

Abstract: Objective: platelets possess not only haemostatic but also inflammatory properties, which combined are thought to play a detrimental role in thromboinflammatory diseases such as acute coronary syndromes and stroke. Phosphodiesterase (PDE) 3 and -5 ... ...

Abstract	Objective: platelets possess not only haemostatic but also inflammatory properties, which combined are thought to play a detrimental role in thromboinflammatory diseases such as acute coronary syndromes and stroke. Phosphodiesterase (PDE) 3 and -5 inhibitors have demonstrated efficacy in secondary prevention of arterial thrombosis, partially mediated by their antiplatelet action. Yet it is unclear whether such inhibitors also affect platelets' inflammatory functions. Here, we aimed to examine the effect of the PDE3A inhibitor cilostazol and the PDE5 inhibitor tadalafil on platelet function in various aspects of thromboinflammation. Approach and results: cilostazol, but not tadalafil, delayed ex vivo platelet-dependent fibrin formation under whole blood flow over type I collagen at 1000 s Conclusions: this study demonstrated yet unrecognised roles for platelet PDE3A and platelet PDE5 in platelet procoagulant and proinflammatory responses.
MeSH term(s)	Animals ; Anti-Inflammatory Agents/pharmacology ; Blood Coagulation/drug effects ; Blood Platelets/drug effects ; Blood Platelets/enzymology ; Blood Platelets/immunology ; Cells, Cultured ; Chemokines/metabolism ; Cilostazol/pharmacology ; Cyclic Nucleotide Phosphodiesterases, Type 3/genetics ; Cyclic Nucleotide Phosphodiesterases, Type 3/metabolism ; Fibrin/metabolism ; Fibrinolytic Agents/pharmacology ; Humans ; Inflammation Mediators/metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Phosphodiesterase 3 Inhibitors/pharmacology ; Phosphodiesterase 5 Inhibitors/pharmacology ; Platelet Activation/drug effects ; Platelet Adhesiveness/drug effects ; Signal Transduction ; Tadalafil/pharmacology ; Mice
Chemical Substances	Anti-Inflammatory Agents ; Chemokines ; Fibrinolytic Agents ; Inflammation Mediators ; Phosphodiesterase 3 Inhibitors ; Phosphodiesterase 5 Inhibitors ; Tadalafil (742SXX0ICT) ; Fibrin (9001-31-4) ; Cyclic Nucleotide Phosphodiesterases, Type 3 (EC 3.1.4.17) ; PDE3A protein, human (EC 3.1.4.17) ; Pde3a protein, mouse (EC 3.1.4.17) ; Cilostazol (N7Z035406B)
Language	English
Publishing date	2021-08-05
Publishing country	Switzerland
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10081998
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Article ; Online: Advanced in vitro models of vascular biology: Human induced pluripotent stem cells and organ-on-chip technology.

Cochrane, Amy / Albers, Hugo J / Passier, Robert / Mummery, Christine L / van den Berg, Albert / Orlova, Valeria V / van der Meer, Andries D

Advanced drug delivery reviews

2018 Volume 140, Page(s) 68–77

Abstract: The vascular system is one of the first to develop during embryogenesis and is essential for all organs and tissues in our body to develop and function. It has many essential roles including controlling the absorption, distribution and excretion of ... ...

Abstract	The vascular system is one of the first to develop during embryogenesis and is essential for all organs and tissues in our body to develop and function. It has many essential roles including controlling the absorption, distribution and excretion of compounds and therefore determines the pharmacokinetics of drugs and therapeutics. Vascular homeostasis is under tight physiological control which is essential for maintaining tissues in a healthy state. Consequently, disruption of vascular homeostasis plays an integral role in many disease processes, making cells of the vessel wall attractive targets for therapeutic intervention. Experimental models of blood vessels can therefore contribute significantly to drug development and aid in predicting the biological effects of new drug entities. The increasing availability of human induced pluripotent stem cells (hiPSC) derived from healthy individuals and patients have accelerated advances in developing experimental in vitro models of the vasculature: human endothelial cells (ECs), pericytes and vascular smooth muscle cells (VSMCs), can now be generated with high efficiency from hiPSC and used in 'microfluidic chips' (also known as 'organ-on-chip' technology) as a basis for in vitro models of blood vessels. These near physiological scaffolds allow the controlled integration of fluid flow and three-dimensional (3D) co-cultures with perivascular cells to mimic tissue- or organ-level physiology and dysfunction in vitro. Here, we review recent multidisciplinary developments in these advanced experimental models of blood vessels that combine hiPSC with microfluidic organ-on-chip technology. We provide examples of their utility in various research areas and discuss steps necessary for further integration in biomedical applications so that they can be contribute effectively to the evaluation and development of new drugs and other therapeutics as well as personalized (patient-specific) treatments.
MeSH term(s)	Animals ; Blood Vessels ; Humans ; Induced Pluripotent Stem Cells/cytology ; Models, Biological ; Tissue Engineering/methods
Language	English
Publishing date	2018-06-23
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	639113-8
ISSN	1872-8294 ; 0169-409X
ISSN (online)	1872-8294
ISSN	0169-409X
DOI	10.1016/j.addr.2018.06.007
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Article ; Online: Compartmentalized 3D Tissue Culture Arrays under Controlled Microfluidic Delivery.

Gumuscu, Burcu / Albers, Hugo J / van den Berg, Albert / Eijkel, Jan C T / van der Meer, Andries D

Scientific reports

2017 Volume 7, Issue 1, Page(s) 3381

Abstract: We demonstrate an in vitro microfluidic cell culture platform that consists of periodic 3D hydrogel compartments with controllable shapes. The microchip is composed of approximately 500 discontinuous collagen gel compartments locally patterned in between ...

Abstract	We demonstrate an in vitro microfluidic cell culture platform that consists of periodic 3D hydrogel compartments with controllable shapes. The microchip is composed of approximately 500 discontinuous collagen gel compartments locally patterned in between PDMS pillars, separated by microfluidic channels. The typical volume of each compartment is 7.5 nanoliters. The compartmentalized design of the microchip and continuous fluid delivery enable long-term culturing of Caco-2 human intestine cells. We found that the cells started to spontaneously grow into 3D folds on day 3 of the culture. On day 8, Caco-2 cells were co-cultured for 36 hours under microfluidic perfusion with intestinal bacteria (E. coli) which did not overgrow in the system, and adhered to the Caco-2 cells without affecting cell viability. Continuous perfusion enabled the preliminary evaluation of drug effects by treating the co-culture of Caco-2 and E. coli with 34 µg ml
MeSH term(s)	Anti-Bacterial Agents/pharmacology ; Caco-2 Cells ; Cell Culture Techniques/instrumentation ; Cell Culture Techniques/methods ; Cell Proliferation/drug effects ; Cell Survival ; Chloramphenicol/pharmacology ; Coculture Techniques ; Escherichia coli/drug effects ; Escherichia coli/growth & development ; Humans ; Microfluidic Analytical Techniques/instrumentation
Chemical Substances	Anti-Bacterial Agents ; Chloramphenicol (66974FR9Q1)
Language	English
Publishing date	2017-06-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-017-01944-5
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Article ; Online: Mimicking arterial thrombosis in a 3D-printed microfluidic in vitro vascular model based on computed tomography angiography data.

Costa, Pedro F / Albers, Hugo J / Linssen, John E A / Middelkamp, Heleen H T / van der Hout, Linda / Passier, Robert / van den Berg, Albert / Malda, Jos / van der Meer, Andries D

Lab on a chip

2017 Volume 17, Issue 16, Page(s) 2785–2792

Abstract: Arterial thrombosis is the main instigating factor of heart attacks and strokes, which result in over 14 million deaths worldwide every year. The mechanism of thrombosis involves factors from the blood and the vessel wall, and it also relies strongly on ... ...

Abstract	Arterial thrombosis is the main instigating factor of heart attacks and strokes, which result in over 14 million deaths worldwide every year. The mechanism of thrombosis involves factors from the blood and the vessel wall, and it also relies strongly on 3D vessel geometry and local blood flow patterns. Microfluidic chip-based vascular models allow controlled in vitro studies of the interaction between vessel wall and blood in thrombosis, but until now, they could not fully recapitulate the 3D geometry and blood flow patterns of real-life healthy or diseased arteries. Here we present a method for fabricating microfluidic chips containing miniaturized vascular structures that closely mimic architectures found in both healthy and stenotic blood vessels. By applying stereolithography (SLA) 3D printing of computed tomography angiography (CTA) data, 3D vessel constructs were produced with diameters of 400 μm, and resolution as low as 25 μm. The 3D-printed templates in turn were used as moulds for polydimethylsiloxane (PDMS)-based soft lithography to create microfluidic chips containing miniaturized replicates of in vivo vessel geometries. By applying computational fluid dynamics (CFD) modeling a correlation in terms of flow fields and local wall shear rate was found between the original and miniaturized artery. The walls of the microfluidic chips were coated with human umbilical vein endothelial cells (HUVECs) which formed a confluent monolayer as confirmed by confocal fluorescence microscopy. The endothelialised microfluidic devices, with healthy and stenotic geometries, were perfused with human whole blood with fluorescently labeled platelets at physiologically relevant shear rates. After 15 minutes of perfusion the healthy geometries showed no sign of thrombosis, while the stenotic geometries did induce thrombosis at and downstream of the stenotic area. Overall, the novel methodology reported here, overcomes important design limitations found in typical 2D wafer-based soft lithography microfabrication techniques and shows great potential for controlled studies of the role of 3D vessel geometries and blood flow patterns in arterial thrombosis.
MeSH term(s)	Cell Culture Techniques ; Cell Line ; Computed Tomography Angiography ; Equipment Design ; Human Umbilical Vein Endothelial Cells ; Humans ; Lab-On-A-Chip Devices ; Models, Cardiovascular ; Printing, Three-Dimensional ; Thrombosis
Language	English
Publishing date	2017-05-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2056646-3
ISSN	1473-0189 ; 1473-0197
ISSN (online)	1473-0189
ISSN	1473-0197
DOI	10.1039/c7lc00202e
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Article: Automated Analysis of Platelet Aggregation on Cultured Endothelium in a Microfluidic Chip Perfused with Human Whole Blood.

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Article ; Online: In Vitro Microfluidic Disease Model to Study Whole Blood-Endothelial Interactions and Blood Clot Dynamics in Real-Time.

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Article: In vitro microfluidic disease model to study whole blood-endothelial interactions and blood clot dynamics in real-time

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Article ; Online: Targeting shear gradient activated von Willebrand factor by the novel single-chain antibody A1 reduces occlusive thrombus formation in vitro.

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Article ; Online: Inhibition of Phosphodiesterase 3A by Cilostazol Dampens Proinflammatory Platelet Functions.

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Article ; Online: Advanced in vitro models of vascular biology: Human induced pluripotent stem cells and organ-on-chip technology.

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In stock of ZB MED Cologne/Königswinter

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Article ; Online: Compartmentalized 3D Tissue Culture Arrays under Controlled Microfluidic Delivery.

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Article ; Online: Mimicking arterial thrombosis in a 3D-printed microfluidic in vitro vascular model based on computed tomography angiography data.

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