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True-to-Life Emulation

June 1, 2015

By Geraldine A. Hamilton, PhD President and Chief Scientific Officer
By Geraldine A. Hamilton, PhD President and Chief Scientific Officer

Image:

Human Intestinal Cells

True-to-Life Emulation

Using engineering principles we are able to control critical aspects of the living cellular microenvironment within our Organ-Chips.

We have designed our Organs-on-Chips technology to fully recreate the complex, dynamic state in which living cells function within a real human organ: substrate (extracellular matrix), tissue-tissue interface, mechanical forces, immune cells and blood components, and biochemical surroundings. This unique design approach enables us to accurately recreate and modulate human biology and disease states.

“Our team has developed working models of the lung, liver, intestine and skin. We are also developing designs for other organ systems such as the kidney, heart and brain.”

Video above: Instestine-Chip under peristaltic stretch

Our Organ-Chips recreate living human physiology. The key aspects of our system that allow us to emulate human biology include:

1) Extracellular Matrix

Cells of an organ require a physical surface so they can attach and function. This is the extracellular matrix, comprised of molecules secreted by cells that provide the structural and biochemical support to the surrounding cells in a tissue.

We recreate this key component of in vivo biology with a porous membrane in the central channel of our Organ-Chips. This membrane is coated with extracellular matrix proteins that are found in the native organ to promote cell attachment and assembly.

2) Tissue-Tissue Interface

Our Organ-Chips direct the proper orientation of cells and their interactions with other neighboring cells. They are designed to produce the essential tissue-tissue interface found in living organs. This tissue is comprised of epithelial cells (organ specific cells) and endothelial cells (blood vessel capillary cells) in a physiologically relevant architecture.

3) Mechanical Forces

Our Organ-Chips emulate the physical forces that cells experience within the body.  These physical forces have long been recognized as key determinants of cellular function, cell signaling, and gene expression.  Mechanotransduction, as it is called, is the process by which cells sense external mechanical forces and then translate them into biochemical signals that  direct cell function, differentiation and cytoarchitecture.

Cells experience mechanical and fluidic forces in vivo through various mechanisms such as expansion of the lungs during breathing, peristalsis in the gut, and flow of blood in the capillaries. In our Organ-Chips, we emulate the shear stress forces arising from blood flow by pumping fluid through the microchannels.  We are also able to recreate the mechanical forces cells experience during breathing by cyclic stretching of the membrane within the Lung-Chip.

4) Biochemical Surroundings

The biochemical surroundings of cells are the soluble factors that provide cues for appropriate cell function and are required for cell survival.  These include growth factors, hormones, dissolved gases, and small molecules such as salts and nutrients.

We can precisely recreate and control the biochemical environment within our Organ-Chips by continuously flowing blood or blood substitutes that bring in fresh nutrients, soluble factors, and dissolved gases, while washing away waste. This enables us to recreate the spatiotemporal gradients of chemicals that allow cells and tissues to thrive in vivo.

5) Immune Cells and Blood Components

Immune cells – such as white blood cells – play an important role in defending our bodies against infection, and are key mediators of inflammation.  Inflammation is implicated in many pathologies and disease states including asthma, diabetes, and cancer.  The fluidic nature of our Organs-on-Chips technology not only allows us to bring in nutrients and gases, but also enables us to introduce immune cells to the system – in a manner that mimics the dynamics found in the capillaries.

This is a key advantage of our approach – allowing us to mechanistically study the role of immune cells and inflammation in health, and disease in different tissues.  In addition, we can also elucidate the interaction between certain drugs and blood components.

Image:

Sendai Virus Infection inside our Organ-Chip.

"Precise tuning of extracellular matrix, tissue-tissue interfaces, mechanical microenvironment, chemical surroundings, and immune components results in a biologically accurate model of human physiology."

Our Organ-Chips uniquely emulate the complex organ-level function in our bodies that require interactions and cell signaling between different cell types and tissues, in a coordinated manner.  This provides the opportunity to emulate normal human biology, model the different aspects of diseases, and facilitate the discovery of novel treatments.

Examples of Human Emulation:

Inflammation and Immune Response:

We have used our system to recreate and quantify key aspects of inflammation and immune response in the lung after bacterial infection. In our Lung-Chip we show in real-time how immune cells are recruited from the vasculature upon inflammation, observing how they enter the lung tissue, and then engulf invading bacteria – just as it occurs in the human body.  This provides the unique window into the mechanisms involved in the body’s immune response.

Pathology of Pulmonary Edema: In our Lung-Chip we were able to show that mechanical forces generated when you simulate breathing, actually made this condition worse, adding new knowledge to the injury mechanism. The Lung-Chip model was also used to test the efficacy of a drug candidate on pulmonary edema.

Mucocialiry Clearance of Particles: We have recreated other aspects of lung biology, including mucociliary clearance of particles from the lung, which are critical for lung health and can be affected in diseases such as cystic fibrosis. We have also modeled other critical disease states such as acute inflammation in asthma, and infection of our Lung-Chip with viruses.

Intestinal Peristalsis:

We can create intestinal peristalsis-like motions and flow within our human Intestine-Chip. The epithelial cells form structural folds within the chip that resemble intestinal villi. They also reconstruct a high integrity barrier to small molecules, that better recreates the intestinal barrier in the gut when compared to conventional culture systems. Our human Intestine-Chip can also be colonized by microbial flora.  We were able to reproduce the beneficial effects of these probiotic bacteria on barrier function in the gut.