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Elimate False Leads Before Clinical Trials - Cellix Webinars

 

Title: Cardiovascular: VenaFluxTM Platform & Biochips mimicking human capillaries in an in-vitro set-up for the investigation of the role of different stimuli in the development of atherosclerosis

Time:  9.45am EST and 2.45pm GMT 

Date:  16th March 2010 

 

Register Here 

 

Atherosclerosis is a complex multifactorial inflammatory disease influenced by signalling cascades which involve different adhesion molecules, chemokines and lipids.  Cellix technology offers the possibility to perform physiological relevant functional assays to study the individual mechanisms or the combined effects of said stimuli.

That's why companies like AstraZeneca, Pfizer, Sanofi-Aventis and Servier are already using Cellix.

" The Cellix website is easy to navigate and informative - the video demonstration really helps to show how their unique cell-based assay products can be applied to an individual's reasearch, narrowing the gap between in-vitro and in vivo results."

Dr. Sarah Hudson,
Langerlab, MIT, Boston, MA
Magner Group, MSSI, UL Limerick, Ireland

  

In vitro cell-based flow assays can be designed to reproduce and study adhesion systems under defined shear stress conditions, given the importance of shear in many steps of the adhesion cascade.

The shear stress can be calculated from the channel geometry and the flow rate, also taking into account the viscosity of the liquid perfused.

Cellix provide the researcher with reliable tools to mimic physiological flow conditions in vitro, ensuring laminar flow with highly controlled shear stresses.

Adhesion on purified ligands or endothelial cells can be studied, using different cell suspension or even whole blood, providing important insights on drug effectiveness, disease development, adhesion mechanisms in inflammation.

Parallel Plate Flow Chambers

The most common type of flow chamber system is the parallel plate type, where cells are introduced in a laminar flow field between two flat surfaces. Parallel plate flow chambers are used in dynamic studies of cell adhesion under well-defined shear forces.

Parallel plate flow chamber provides a controlled environment for determinations of the shear stress at which cells in suspension can bind to endothelial cell monolayers.

In traditional parallel plate flow chambers the lowest volume for 5 minute assay is 133µl compared to the Cellix Vena8 Biochip which only uses 13µl.

As a result the cost per assay is reduced when using the Cellix VenaFlux Platform as opposed to traditional parallel plate flow chambers.

Inflammation

Inflammation is traditionally defined by the four Latin words calor, dolor, rubor and tumor, meaning heat, pain, redness and swelling, all of which reflect the effects of cytokines and other inflammatory mediators on the local blood vessels.

Cytokines have important effects on the adhesive properties of the endothelium, causing circulating leukocytes to stick to the endothelial cells of the blood vessel wall and migrate between them to the site of infection, to which they are attracted by chemokines.

Leukocyte

The leukocyte adhesion cascade is a sequence of activation and adhesion events that ends with extravasation of the leukocyte, whereby the cell exerts its effects on the inflamed site.

The traditional three-step cascade involves selectin-mediated rolling, chemokine-triggered activation and integrin-dependent arrest, but is has recently been augmented and refined including slow rolling, adhesion strengthening, intraluminal crawling and paracellular and transcellular migration, and migration through the basement membrane.

Selectins

Selectins are a family of single-chain transmembrane glycoproteins, expressed on the surface of leukocytes and activated endothelial cells.

L-selectin is the smallest of the vascular selectins, and can be found on most leukocytes. P-selectin, the largest selectin, is expressed on activated platelets and endothelial cells primarily.

E-selectin is expressed on activated endothelium with chemically or cytokine-induced inflammation

As the inflammatory response progresses, chemokines released by injured tissue enter the blood vessels and activate the rolling leukocytes, which are now able to tightly bind to the endothelial surface and begin making their way into the tissue.

Chemokines cause surface integrin molecules to switch from a low-affinity state to a high-affinity state. In the activated state, integrins bind tightly to complementary receptors expressed on endothelial cells.

This causes the firm adhesion of the leukocytes through integrin-ligand binding, such as VLA-4 and VCAM-1, or LFA-1 and ICAM-1

Transmigration

Transmigration through venular walls is the final step in the process of leukocyte emigration into inflamed tissues and can occur with minimal disruption to the complex structure of vessel walls.

Before crossing the walls of postcapillary venules, neutrophils and monocytes crawl inside blood vessels, seeking preferred sites of transmigration. Leukocyte migration through the endothelial-cell barrier can be rapid (<2–5 minutes), but penetrating the endothelial-cell basement membrane can take much longer (>5–15 minutes).

Transendothelial cell migration can be triggered by luminal chemoattractants that may act in concert with shear flow. The interaction of leukocyte integrins with their endothelial-cell ligands (such as ICAM1 and VCAM1) may also stimulate endothelial cells in a manner that promotes leukocyte migration through the endothelium.
 

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