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The design of the multi-trap nanophysiometer (MTN) is seen on the left, with a cad rendering on the top right and the actual manufactured device on the bottom right. The MTN allows an unprecedented look at how cell signaling works.  (Source: Vanderbilt)

An artist's rendering of the completed MTN shows cells trapped inside as signals travel to them.  (Source: Vanderbilt)

A photo shows cells trapped in the MTN. The dark gray areas are the trap and the circle inside is a trapped cell. The inset picture shows a fluorescent indicator to cells reacting to a paracrine message. This shows that cells downstream are being signaled.  (Source: Vanderbilt)
A new sensor allows an unprecedented look at cell signaling and may save lives one day

Scientists have developed nanomachines which have targeted cancer cells delivering deadly poisons to kill them, without harming healthy cells.  However, the key to nanodrugs is not merely their creation, but their targeting. 

Just like a missile needs a guidance system to make properly score a hit on its target, the drugs of the future will need means of detecting their enemies.  New breakthroughs in the field of paracrine signaling may soon make such targeting possible.

In the body, cells have multiple ways of signaling.  Some cells send signals to adjacent cells -- this method is very detectable and is well documented.  Sometimes cells send long distance chemical messengers in the blood stream, such as adrenaline.  These signals are also readily detectable.  However, a great deal of the body's signaling is thought to occur at short distances between non-connected cells, known as paracrine signaling.  Paracrine signaling is one of the least understood fields of physiology and just recently have scientists begun to recognize its significance.

The discovery of paracrine signaling, which is detailed in the journal Lab On A Chip.  The MTN was revolutionary in that it could detect minute quantities of paracrine chemicals, previously too dilute to be detected.  Now the researchers have developed a more advanced sensor which pumps cells into the MTN sensor, which traps and cultures them.  The new sensor monitors the trapped cells with a variety of digital and chemical methods to better understand paracrine signaling.

The new device was developed by a research team at the Vanderbilt Institute for Integrative Biosystems Research and Education headed by John P. Wikswo, the Gordon A. Cain University Professor at Vanderbilt.  The device has already provided a never-before-seen glimpse at how dendritic cells (a type of white blood cell) in the immune system signal T-Cells (another type of white blood cell) to destroy infection.

Co-author Derya Unutmaz, now an associate professor of microbiology at New York University's School of Medicine stated, "This is an important advance and potentially very useful technology.  The ability to study the behavior of single cells may not be as critical if you are studying the heart or muscles, which are mostly formed by uniform cells, but it is crucial for understanding how the immune system functions. The wide surveillance of the body that it conducts requires extensive communication between dozens of different kinds of immune cells."

Generally the immune system has stored T Cells in the lymph nodes.  When a dendritic cells sense an invader -- such as the Flu virus, a cancer cell, or the AIDS virus -- it signals T Cells to make preparations to the fight the intruder.  As only a certain percentage of T Cells are tuned to fight each type of intruder, the dendritic cells must properly recruit the right candidates for the job out of millions of cells, a daunting process that previously was a mystery.

Using plastic microfluid channels smaller than a human hair, cells and culture media is pumped into the nanodevice, molded into the bottom of a glass microscope cover slip.  In a special chamber cells are caught in special wells.  Fluid flows out holes in the bottoms of the wells, passively trapping the cells.  Thanks to the media they can be kept alive 24 hours or more, longer than normal.

A digital camera monitors the cells, snapping pictures every 30 seconds.  Software analyzes the cells actions.  In the presence of certain activity indicators such as calcium, phosphorescent dye lights up brightly. 

Graduate student Shannon Faley, now a postdoctoral research associate at the University of Glasgow, Scotland was the first to notice paracrine signaling occurring.  She used an MTN with trapped dendritic cells.  She noticed that the mature dendritic cells signaled some naive T cells that they were in contact with.  However, they also somehow signaled the correct T Cells downstream as well.  She described, "My reaction when I saw them was, 'What in the world is going on?'"

Professor Wikswo further added, "When she saw this, Shannon did a very clever thing.  She took one chamber and filled it with dendritic cells and took a second chamber and filled it with T-cells. Then she hooked the second chamber downstream of the first."

The cells in the second chamber reacted, indicating undeniable presence of a chemical agent.  While researchers still have not identified the precise chemical agent, or what its exact function is, they hope to soon find that out.

The researchers plan to look at paracrine responses to tumor cells, AIDS, and many other deadly diseases.  Based on studying how the immune system works and what "goes wrong" in severe cases like AIDS, better defenses can be developed.  Signaling between cancer cells can also be isolated and be used to target them.  Dana Marshall, associate professor at the Meharry Medical College, and Professor Wikswo have already submitted a proposal to use the device to study triple-negative breast tumors, one of the most deadly forms of breast cancer.

Some cancers such as the aforementioned one respond to chemotherapy for a time and then become immune.  Dr. Marshall stated, "Often, when therapy fails, the tumor responds to a chemotherapy treatment for a period of time and then it stops. This approach may let us figure out why that happens."

The research was funded by grants from the Defense Advanced Research Projects Agency, Air Force Office of Scientific Research, the National Institutes of Health, the Vanderbilt Institute for Integrative Biosystems Research and Education and the Systems Biology and Bioengineering Undergraduate Research Experience.





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