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Lung simulation could improve respiratory failure treatment

Contact: Gabe Cherry, 734-763-2937, gcherry@umich.edu

ANN ARBOR – The first computer model that predicts the flow of liquid medication in human lungs is providing new insight into the treatment of respiratory failure. University of Michigan researchers are using the new technology to uncover why a treatment that saves the lives of premature babies has been largely unsuccessful in adults.

Acute respiratory distress syndrome, or ARDS, is a sudden failure of the respiratory system that kills 74,000 adults each year in the United States alone. It’s most common among the critically ill or those with major lung damage. The treatment, called surfactant replacement therapy, delivers a liquid medication into the lungs that makes it easier for them to inflate. It’s widely used to treat a similar condition in premature babies, who sometimes lack the surfactant necessary to expand their lungs. The treatment has contributed to a dramatic reduction in mortality rates of premature babies. But attempts to use it in adults have been largely unsuccessful despite nearly two decades of research.

“The medication needs to work its way from the trachea to tiny air sacs deep inside the lungs to be effective,” explains James Grotberg, the leader of the team that developed the technology. Grotberg is a professor of biomedical engineering in the U-M College of Engineering and a professor of surgery at the U-M Medical School. “This therapy is relatively straightforward in babies but more complex in adults, mostly because adult lungs are much bigger.”

A 1997 clinical study that administered the treatment to adults showed promise, cutting the mortality rate among those who received the medication from 40 percent to 20 percent. But two larger studies in 2004 and 2011 showed no improvement in mortality. As a result, the treatment is not used on adults today.

“Everyone walked away from this therapy after the 2011 study failed,” Grotberg said. “Adult surfactant replacement therapy has been a great disappointment and puzzlement to the community ever since. But now, we think we’ve discovered why the later studies didn’t improve mortality.”

Grotberg’s team brought an engineering perspective to the puzzle, building a mathematical computer model that provided a three-dimensional image of exactly how the surfactant medication flowed through the lungs of patients in all three trials. When the simulations were complete, the team quickly saw one detail that set the successful 1997 study apart: a less concentrated version of the medication.

“The medication used in the 1997 study delivered the same dose of medication as the later studies, but it was dissolved in up to four times more liquid,” Grotberg said. “The computer simulations showed that this additional liquid helped the medication reach the tiny air sacs in the lungs. So a possible route for success is to go back to the larger volumes used in the successful 1997 study.”

The simulations showed that the thickness, or viscosity, of the liquid matters too. This is a critical variable, since different types of surfactant medication can be manufactured with different viscosities. The team believes that doctors may be able to use the modeling technology to optimize the medication for individual patients. They could run personalized simulations of individual patients’ lungs, then alter variables like volume, viscosity, patient position and flow rate of the medication to account for different lung sizes and medical conditions.

“We created this model to be simple, so that it can provide results quickly without the need for specialized equipment,” said Cheng-Feng Tai, a former postdoctoral student in Grotberg’s lab who wrote the initial code for the model. “A physician could run it on a standard desktop PC to create a customized simulation for a critically ill patient in about an hour.”

Tai accomplished this by creating a model that provides similar results to traditional fluid dynamics modeling, but requires far less time and processing power.

“Fully three-dimensional fluid dynamics models require a specialized supercomputer and days or weeks of processing time,” he said. “But critically ill hospital patients don’t have that kind of time. So we streamlined the code to produce a simulated three-dimensional image with much less computing power and processing time.”

Grotberg says the modeling technology could be used in other types of research as well, including more precise targeting of other medications in the lungs and projecting results from animal research to humans.

The findings are detailed in a new paper published in Proceedings of the National Academy of Sciences. The paper is titled “A three dimensional model of surfactant replacement therapy.” Funding was provided by the National Institutes of Health (grant numbers HL85156 and HL84370). The team also received assistance with anatomy, physiology, and further code development and support from M. Filoche, CNRS research director at Ecole Polytechnique and the French Agence Nationale de la Recherche.

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July 21st, 2015 by Brandon Baier


What makes cancer cells spread? New device offers clues

From: Nicole Fawcett
U-M Health System

Why do some cancer cells break away from a tumor and travel to distant parts of the body? A team of oncologists and engineers from the University of Michigan teamed up to help understand this crucial question.

In a paper published in Scientific Reports, researchers describe a new device that is able to sort cells based on their ability to move. The researchers were then able to take the sorted cells that were highly mobile and begin to analyze them on a molecular level.

“People have used microfluidic devices before to look at the movement of cells, but the story typically ended there. We developed a device that separates the mobile cells and allows us to determine the gene expression of those highly mobile cells in comparison to the less mobile ones. By studying these differences in live cells, we hope to gain an understanding of what makes some cancer cells able to spread to other areas of the body,” says study author Steven G. Allen, an M.D./Ph.D. student in the University of Michigan Medical School’s Medical Scientist Training Program.

The highly mobile cells are believed to be the more aggressive cells that cause metastases, the spread of cancer through the body. By understanding how those cells tick, researchers believe they can develop targeted treatments to try to prevent metastasis.

“Using advanced micro-fabrication technologies, we can create micro-structures comparable to the size of cells. Living cells can then be manipulated on-chip at single-cell resolution. Using this technology, we can investigate the differences among individual cancer cells, while conventional approaches can study only the collective average behaviors,” says study co-lead author Yu-Chih Chen, a postdoctoral researcher in the Department of Electrical Engineering and Computer Science.

The differences in individual cancer cells are a key aspect of how cancer evolves, becomes resistant to current therapies or recurs.

“A primary tumor is not what kills patients. Metastases are what kill patients. Understanding which cells are likely to metastasize can help us direct more targeted therapies to patients,” says study author Sofia D. Merajver, M.D., Ph.D., scientific director of the breast oncology program at the University of Michigan Comprehensive Cancer Center and a professor at the U-M Medical School and U-M School of Public Health.
The researchers believe this type of device might some day help doctors understand an individual patient’s cancer. Which cells in this patient’s tumor are really causing havoc? Is there a large population of aggressive cells? Are there specific markers or variants on those individual cells that could be targeted with treatment?

“This work demonstrates an elegant approach to the study of cancer cell metastasis by combining expertise in engineering and biology,” says study author Euisik Yoon, a professor of electrical engineering and computer science and of biomedical engineering and director of the Lurie Nanofabrication Facility.

“In past decades, engineers have developed biological tools with better resolution, higher sensitivity, selectivity and higher throughput,” Yoon adds. “However, without compelling applications, these engineering tools have little practical relevance. The goal of our lab is to develop tools that can be widely disseminated to the biology community to eventually impact clinical care for patients.”
In this work, extensive studies were performed on cell lines representing various types of cancer. The new device was designed to trace how cells move, sorting individual cells by their movement. It has a series of choke points that mimic the lymphatic systems in which cancer cells typically travel. Unlike other similar devices, in this case the captured and sorted cells can be harvested live for further study and analysis.
In a test using aggressive metastatic breast cancer cells, the researchers were able to sort the cells based on their motion, collect the sorted cells and send them through the device again. The cells maintained the same highly mobile characteristic upon repeated testing. The researchers also found that the more mobile cells had the characteristics and appearance under the microscope of metastatic cells and expressed significantly higher levels of markers associated with metastatic cancer.

“Understanding specific differences that lead some cancer cells to leave the primary tumor and seed metastases is of great benefit to develop and test anti-metastatic strategies,” Merajver says.
The device needs further testing and validation before it can begin to influence clinical care. Patients seeking more information about their options for cancer treatment can call the U-M Cancer AnswerLine at 800-865-1125.

Funding for the research is provided by the U.S. Department of Defense grant W81XWH-12-1-0325; National Institutes of Health grants R21 CA17585701, F30 CA173910-01A1; University of Michigan Rackham Predoctoral Fellowship; Breast Cancer Research Foundation; Avon Foundation; Metavivor Foundation

Article from: Michigan Engineering

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June 17th, 2015 by Brandon Baier


Heartbeat on a chip

From: Kelly O’Sullivan
MconneX

The ability to accurately test drugs and therapies for human use is a goal we desperately need to reach. Often animals are used to test drugs intended for human use, which not only puts them at risk but many times does not produce results helpful to making these remedies safer for us. At the same time drugs tested on human cells grown in a petri dish doesn’t exactly represent how those drugs will react in a living, breathing body.

Fortunately, a development made by Michigan engineers has taken a major step in drug testing by reproducing the heartbeat in a simplified gravity-driven microfluidic circuit. This new device performs operations that once required a large amount of peripheral equipment as well as a dedicated lab technician to run. Beyond that, the chip can execute multiple experiments at once as well as mimic a variety of heart rates. With the help of this microfluidic chip we could see the testing phases for new therapies drastically shortened, allowing newer, more effective medicines finding their way into patients much faster.

MichEpedia Page Link
Michigan Engineering YouTube Link

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June 17th, 2015 by Brandon Baier


Zhen Xu PhD Receives Lizzie Award From ISTU

Assistant Professor of Biomedical Engineering, Zhen Xu received the 2015 Frederic Lizzi Early Career Award from the International Society of Therapeutic Ultrasound (ISTU). Every year, Lizzi Award is given to a researcher at early stage of career who has achieved significant accomplishment and contribution to the field of therapeutic ultrasound.

Posted in All News, Faculty News

May 18th, 2015 by Brandon Baier


Startup PuffBarry Wins Seed Funding.

Allison Powell (BSE) and Kyle Bettinger (BSE) co-founded a startup called “PuffBarry” to develop a device aiding people living with ALS, multiple sclerosis, and muscular dystrophy. Born out of their BME 458 team project the PuffBarry device uses puffs of air as code that a computer can interpret and translate into speech as an alternative communication device for those who have lost the ability to speak. Their passion for helping those with ALS came after a family friend of Allison passed away during her college career. Allison and Kyle took their idea to the U-M Center for Entrepreneurship competition “The StartUp” and came away with $3000 in seed funding among 16 others in the field of 60 and eventually won the grand prize of $15,000 and entry into TechArb. They also received an additional $1000 by winning the TedXUofM prize. Allison will attend TedXTraverseCity in May as one of the invited speakers.

Posted in All News, Student/Post-Doc News

May 18th, 2015 by Brandon Baier


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