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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
From: Kelly O’Sullivan
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.
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.
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.
ANN ARBOR, Mich. — Kaiba was just a newborn when he turned blue because his little lungs weren’t getting the oxygen they needed. Garrett spent the first year of his life in hospital beds tethered to a ventilator, being fed through his veins because his body was too sick to absorb food. Baby Ian’s heart stopped before he was even six months old.
Three babies all had the same life-threatening condition: a terminal form of tracheobronchomalacia, which causes the windpipe to periodically collapse and prevents normal breathing. There was no cure and life-expectancies were grim.
The three boys became the first in the world to benefit from groundbreaking 3D printed devices that helped keep their airways open, restored their breathing and saved their lives at the University of Michigan’s C.S. Mott Children’s Hospital. Researchers have closely followed their cases to see how well the bioresorable splints implanted in all three patients have worked, publishing the promising results in today’s issue of Science Translational Medicine.
“These cases broke new ground for us because we were able to use 3D printing to design a device that successfully restored patients’ breathing through a procedure that had never been done before,” says senior author Glenn Green, M.D., associate professor of pediatric otolaryngology at C.S. Mott Children’s Hospital.
“Before this procedure, babies with severe tracheobronchomalacia had little chance of surviving. Today, our first patient Kaiba is an active, healthy 3-year-old in preschool with a bright future. The device worked better than we could have ever imagined. We have been able to successfully replicate this procedure and have been watching patients closely to see whether the device is doing what it was intended to do. We found that this treatment continues to prove to be a promising option for children facing this life-threatening condition that has no cure.”
The findings reported today suggest that early treatment of tracheobronchomalacia may prevent complications of conventional treatment such as a tracheostomy, prolonged hospitalization, mechanical ventilation, cardiac and respiratory arrest, food malabsorption and discomfort. None of the devices, which were implanted in then 3-month-old Kaiba, 5-month-old Ian and 16-month-old Garrett have caused any complications.
The findings also show that the patients were able to come off of ventilators and no longer needed paralytics, narcotics and sedation. Researchers noted improvements in multiple organ systems. Patients were relieved of immunodeficiency-causing proteins that prevented them from absorbing food so that they no longer needed intravenous therapy.
Kaiba Gionfriddo made national headlines after he became the first patient to benefit from the procedure in 2012, and the procedure was repeated with Garrett Peterson and Ian Orbich. Using 3D printing, Green and his colleague Scott Hollister, Ph.D., professor of biomedical engineering and mechanical engineering and associate professor of surgery at U-M, were able to create and implant customized tracheal splints for each patient. The device was created directly from CT scans of their tracheas, integrating an image-based computer model with laser-based 3D printing to produce the splint.
The specially- designed splints were placed in the three patients at C.S. Mott Children’s Hospital. The splint was sewn around their airways to expand the trachea and bronchus and give it a skeleton to aid proper growth. The splint is designed to be reabsorbed by the body over time. The growth of the airways were followed with CT and MRI scans, and the device was shown to open up to allow airway growth for all three patients.
Doctors received emergency clearance from the FDA to do the procedures.
“We were pleased to find that all of our cases so far have proven to improve these patients’ lives,” Green says. “The potential of 3D-printed medical devices to improve outcomes for patients is clear, but we need more data to implement this procedure in medical practice.”
Authors say the recent report was not designed for device safety and that rare potential complications of the therapy may not yet be evident. However, Richard G. Ohye, M.D., head of pediatric cardiovascular surgery at C.S. Mott who performed the surgeries, says the cases provide the groundwork to potentially explore a clinical trial that could help other children with less-severe forms of tracheobronchomalacia in the future.
Kaiba, now a curious, active 3-year-old who loves playing with his siblings and who recently saw his favorite character Mickey Mouse at Disney World thanks to the Make-a-Wish Foundation, was back at Mott in April for a follow-up appointment.
The splint is dissolving just how it’s supposed to and doctors expect that eventually, his trachea will reflect that of his peers with no signs of the tracheobronchomalacia that nearly killed him as a newborn.
“The first time he was hospitalized, doctors told us he may not make it out,” Kaiba’s mom April Gionfriddo remembers. “It was scary knowing he was the first child to ever have this procedure, but it was our only choice and it saved his life.”
Now an energetic 2-and-a-half-year-old with a contagious laugh, Garrett is able to breathe on his own and spend his days ventilator-free. Ian, now 17 months old, is known for his huge grins, enthusiastic high fives and love for playing with his big brother, Owen. Ian had the splint procedure done at Mott exactly one year ago this month.
“We were honestly terrified, just hoping that we were making the right decision,” his mother Meghan Orbich remembers. “I am thankful every single day that this splint was developed. It has meant our son’s life. I am certain that if we hadn’t had the opportunity to bring Ian to Mott, he would not be here with us today.”
To learn more:
Support this important research by making a gift to the 3D-Printed Airway Splint Fund.
Watch a video demonstrating 3D printing
Read blog post from Dr. Glenn Green that goes behind the scenes on what led to the 3D printed devices to restore breathing in babies with tracheobronchomalacia.
See more on Kaiba’s story
See more on Garrett’s story
Additional Authors: Robert J. Morrison, Scott J. Hollister, Matthew F. Niedner, Maryam Ghadimi Mahani and Richard G. Ohye, all of U-M. Albert H. Park, of University of Utah; Deepak K. Mehta, of the Children’s Hospital of Pittsburgh of University of Pittsburgh Medical Center.
Funding: This work was funded in part by the National Institutes of Health (grant R21 HD076370-01) Morrison is supported by NIH grant T32 DC005356-12.
Disclosure: Hollister and Green have filed a patent application related to the device.
Reference: “Mitigation of Tracheobronchomalacia with 3D-Printed Personalized Medical Devices in Pediatric Patients,” Science Translational Medicine, April 29, 2015.
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