ANN ARBOR—The Rehabilitation Biomechanics Laboratory at the University of Michigan looks part playground, part film studio, part bionic woman.
A mechanical foot sliced off cleanly at the ankle sits on a shelf—a prosthesis for testing. Twenty cameras on tripods of various heights are aimed toward the center of the room at a cluster of random objects: A door that opens into nothing. A desk phone on a table. A pitcher of water and a glass. A chair. A long, shallow sandbox.
Actually, these objects aren't random at all, explains U-M doctoral student Susannah Engdahl. They've been carefully selected to measure and compare the range of motion of people who use prosthetics against those who don't.
This is Engdahl's area of research, and her own disability has proven helpful in setting up these experiments. Engdahl is missing both hands and most of both feet.
She shrugs and sips her coffee:
"I was born this way. The doctors never nailed down a cause."
Engdahl, 25, earned her bachelor's degree at Wittenberg University in Ohio, and says she decided on the U-M program in biomedical engineering because it "hit all the checkmarks"—health, math, science and the human body.
"Biomedical engineering is a broad field and prosthetics stood out because I already knew how important prosthetics can be in improving quality of life," Engdahl says.
She has been in U-M faculty member Deanna Gates' Rehabilitation Biomechanics Laboratory for three years. Part of the School of Kinesiology, the lab is tucked in the basement of the Central Campus Recreation Building in a converted racquetball court that still feels faintly humid.
Engdahl has been lucky with her own prosthetic hands, she says, because she's had very little pain or awkwardness, which is a huge problem among prosthetic users. Hers is among the family of prosthetics called myoelectric, which work by capturing electrical signals from the body—in this case, her arms—to control her hands.
Other prosthetics are body powered—they're held to the body by harnesses and move when cables are activated by body movement. Each has advantages and disadvantages, but one big upside of Engdahl's is that at first glance you don't even know she's wearing them. She received her first pair of prosthetics when she was about 2.
"The cosmetic factor probably helped my parents make that decision," Engdahl says, contemplating the flesh-colored stretchy sleeve that encases the hard plastic shell protecting the tiny electronics and motors that move the fingers of her hands.
But despite their natural look, the prosthetics can move only in one direction. The hands open with the thumb moving in opposition to the fingers, and close with the thumb moving towards the fingers. The thumb, index finger, and middle finger come together to create a "tripod" grip.
"Developing prosthetics that can move more similarly to a natural hand is an active area of research," Engdahl says, gripping her cardboard cup.
Quantifying how people use different types of prosthetics is one of Engdahl's dissertation research projects, and a career interest.
"It's important because most of the current research on prosthetic function is from patient feedback," says Gates, lab director and assistant professor with appointments in kinesiology and biomedical engineering.
"There's no clear direction to focus on improvements in quality of movement or range of motion, and no clear way to convince insurance companies to pay for advanced prosthetic devices."
It's natural to wonder how people with prosthetics perform everyday tasks: How do you type? Open doors? Tie your shoes? Engdahl doesn't even think about her own work-arounds, but compensations are a part of life for any prosthetic user.
Engdahl demonstrates one of these adaptations when she opens the prop door in the lab.
"It's hard for me to stand in front of the door, so I take a step over," she says. She doesn't have any wrist motion, so she moves slightly to one side of the knob for leverage, then turns the handle.
From real life to research to teaching
Engdahl not only uses her experiences with limb loss to inform her research, she also parlays them into teaching opportunities to spark future scientists. Every year, she helps Gates with the annual FEMMES event, which stands for Females Excelling More in Math, Engineering and the Sciences.
"We show the girls how the brain sends signals to muscles and how these can be measured and then used to control prosthetics," Gates says. "Susannah is generous enough to bring in one of her old sets of hands for the girls to try and she shows them how she uses them to do different things."
The girls spend the day measuring their muscle activity and making moveable hands of paper, string and straws.
"It's a great event that wouldn't be possible if Susannah weren't so open to talking with the girls about her experiences," Gates says.
When asked whether she's naturally optimistic, Engdahl says it's not easy to compare people in terms of "getting past" issues. She's always had access to the best health care and a supportive family, so it could be much simpler for her to overcome something that's difficult for someone without those advantages, she says.
"Although it did take me awhile to figure out all the tricks of the trade, I've found that most of the things I need to do in daily life can be accomplished with patience and creativity," Engdahl says. "I don't have a reason to feel intimidated by physical barriers because I'm usually able to find solutions. Admittedly, sometimes my solutions aren't ideal. But self-sufficiency is important to me, and I'd rather get a task done slowly than just not do it at all."
- Laura Bailey
by Aimee Balfe
“I believe this is the first time that virtual surgical planning was done for real and not as a retrospective theoretical exercise ,” says Figueroa.
Using a patient’s medical and imaging data, Figueroa was able to create a model of her unique vasculature and blood flow, then use it to guide U-M pediatric cardiologists Aimee Armstrong, Martin Bocks, and Adam Dorfman in placing a graft in her inferior vena cava to help alleviate complications from pulmonary arteriovenous malformations (PAVMs).
“I believe this is the first time that virtual surgical planning was done for real and not as a retrospective theoretical exercise.” Alberto Figueroa
The PAVMs – abnormal connections between the patient’s veins and arteries – are a common complication of a procedure performed early in the lives of children born with only a single functioning ventricle. Called the Fontan procedure, the operation had rewired the patient’s pulmonary circulation so that the venous return bypassed the heart and was connected directly to the pulmonary arteries for transport to the lungs.
While these surgeries can be lifesavers, the long-term consequences depend heavily on how evenly blood flow is distributed between a patient’s lungs. Patients with ideal hemodynamics do well; those with less-than-perfect flow patterns suffer a sting of life-threatening complications.
Unfortunately, the 20-year-old on whom Figueroa and his team were working had suffered many such complications, among them, the PAVMs that left her with low blood oxygen and elevated cardiac output. The surgery aimed to improve these measures by better balancing the flow to her lungs.
Simulation & Outcome: A Perfect Match
“This endovascular procedure had only been attempted once in the country before,” says Figueroa. “What we brought onto the table was, instead of going in blind, we’d simulate multiple slightly different ways of doing the procedure to see if there was an optimal one.”
The medical team gave his lab a month. Armed with detailed anatomical data from CT scans, Doppler data on velocity in various vessels, invasive catheterization data that showed pressures at multiple locations, and perfusion data from nuclear medicine tests, Figueroa’s team got to work. They first created a hemodynamic model of the patient that matched each of these data points. They then simulated six different ways of placing the stent graft using U-M's high performance Flux computing cluster, provided by Advanced Research Computing, to see if there was an ideal outcome. To Figueroa’s delight, one placement proved far superior.
They shared their recommendation with the medical team, and four days later, the cardiologists placed the graft with millimeter precision. The results amazed everyone – except Figueroa.
“I’d asked them ahead of time to verify everything with an angiogram – using a catheter to flush dye through the patient’s vessel to illuminate the blood flow,” he says. “They did this before and after the procedure, and the results matched completely what our computer simulation had predicted.” (See image.)
“The clinicians were amazed, but we told them we were just solving Newton’s law.” Alberto Figueroa
“The clinicians were amazed, but we told them we were just solving Newton’s law,” he says modestly.
In truth, he says that having proof that his physics-based planning worked was the highlight of his year.
The low point was realizing that the successful procedure wasn’t enough to save a gravely ill young woman.
Better Primary Surgeries
This patient’s passing hit the entire team hard, but Figueroa takes comfort in the belief that his simulations can allow surgeons to optimize initial procedures like the Fontan so that the complications this patient experienced – and the follow-up surgeries they require – may never happen at all.
Of the tens of thousands of patients undergoing Fontan operations each year, he says, roughly half experience major complications after 10 years. That’s because it’s almost impossible for surgeons to know exactly how to perform the procedure on patients with vessels of various sizes, shapes, and flows.
By accounting for these differences, Figueroa hopes his simulations will show surgeons where in the vasculature to make the surgical connections so that blood flow is ideally balanced between the lungs in each patient. He plans to continue working with Dr. Dorfman, who initiated the surgical planning collaboration, and U-M cardiac surgeon Edward Bove to do patient-specific Fontan planning.
And because his simulations add a layer of insight to any procedure where cardiologists and surgeons find that doing things the same way works in some patients and not others, Figueroa hopes they’ll soon become a ubiquitous planning tool, much like imaging is today.
As promising as it is, surgical planning is only the tip of the iceberg for Figueroa. His lab also works to further develop its simulation software and to use it to understand disease progression, always with an eye toward devising better treatments.
In the software arena, his lab is working on enhancements that will account for dynamic changes in blood flow caused by anything from a change in posture to anesthesia.
One of the lab’s clinical fellows is studying how blood vessels remodel in response to the grafts used in thoracic aneurysm repair. Another is modeling aortic dissection, aiming to discover precisely how the flap that shears from the vessel wall moves, deforms the aorta, and affects blood flow. This understanding is a first step toward designing a device specifically for this condition.
His lab also hosts BME students who are developing tools to better understand blood flow in the brain, clot-development in veins, and the progression of hypertension, including which types of vessels sustain various degrees of damage over time. Figueroa has recently submitted a collaborative grant to explore the progression of pulmonary hypertension, as well.
The breadth and clinical relevance of his work are in many ways why Figueroa came to U-M from King’s College, London, two years ago. Named the Edward B. Diethrich M.D. Research Professor of Biomedical Engineering and Vascular Surgery, Figueroa, a PhD, was drawn by his 50/50 appointment in BME and vascular surgery at an institution where medicine and engineering are deeply integrated.
It’s because of this connection that the rapid-response surgical planning was made possible, he says. It’s also given him ready access to talented students from the medical and engineering schools – and to usually hard-to-reach study participants, like aortic dissection patients, to gain critical insight into this and other life-threatening conditions.
A team of researchers at the University of Michigan has developed a new, revolutionary technique that has the potential to reshape the practice of surgery. Histotripsy — literally, the “crushing of tissue” — is a noninvasive therapy that uses high-intensity ultrasound pulses to liquify tissue inside the body without ever breaking the skin. With applications from congenital heart defects to brain tumors, Histotripsy will significantly impact quality of life for patients, who will be able to receive it at their physician’s office — potentially at the exact time of diagnosis — without sedation or a lengthy recovery.
From: Gabe Cherry
University of Michigan researchers have used a “kidney on a chip” device to mimic the flow of medication through human kidneys and measure its effect on kidney cells. The new technique could lead to more precise dosing of drugs, including some potentially toxic medicines often delivered in intensive care units.
Precise dosing in intensive care units is critical, as up to two-thirds of patients in the ICU experience serious kidney injury. Medications contribute to this injury in more than 20 percent of cases, largely because many intensive care drugs are potentially dangerous to the kidneys.
Determining a safe dosage, however, can be surprisingly difficult. Today, doctors and drug developers rely mainly on animal testing to measure the toxicity of drugs and determine safe doses. But animals process medications more quickly than humans, making it difficult to interpret test results and sometimes leading researchers to underestimate toxicity.
University of Michigan researchers used a “kidney on a chip” to mimic the flow of medication through human kidneys. This enabled them to study the dosing regimen for a common intensive care drug.
The paper, published in the journal Biofabrication, is titled “Pharmacokinetic profile that reduces nephrotoxicity of gentamicin in a perfused kidney-on-a-chip.” Funding and assistance for the project was provided by the National Institutes of Health (grant number GM096040), the University of Michigan Center for Integrative Research in Critical Care (MCIRCC), the University of Michigan Biointerfaces Institute, the National Research Foundation of Korea and the Korean Association of Internal Medicine Research Grant 2015.
Ann Arbor – In an entirely new approach to treating asthma and allergies, a biodegradable nanoparticle acts like a Trojan horse, hiding an allergen in a friendly shell to convince the immune system not to attack it, according to new research from the University of Michigan and Northwestern University. As a result, the allergic reaction in the airways is shut down long term and an asthma attack prevented.
The technology can be applied to food allergies as well. The nanoparticle is currently being tested in a mouse model of peanut allergy, similar to food allergy in humans.
“Small quantities of allergen have been used to de-sensitize patients, and that delivering the allergen using emerging nanotechnologies can provide a more efficient and effective system” said senior author Lonnie Shea, the William and Valerie Hall Chair and Professor of Biomedical Engineering at the University of Michigan and adjunct professor at Northwestern.
The treatment can be applied to any allergy simply by loading the nanoparticle with the target allergen – from ragweed pollen to peanut protein.
In addition, the treatment makes use of an already FDA-approved material; the nanoparticles are composed of PLGA, a biopolymer that includes lactic acid and glycolic acid.
When the loaded nanoparticle is injected into the bloodstream of mice, the immune system sees the particle as innocuous debris. Then the nanoparticle and its hidden cargo are consumed by a macrophage, essentially a vacuum-cleaner cell.
“The vacuum-cleaner cell presents the allergen to the immune system in a way that says, ‘No worries, this belongs here,’” said Stephen Miller, another senior author on the study and the Judy Gugenheim Research Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine. The immune system then shuts down its attack on the allergen, and the immune system is reset to normal.
The allergen, in this case egg protein, was administered into the lungs of mice who had been pretreated to be allergic to the protein and already had antibodies in their blood against it. After being treated with the nanoparticle, however, they no longer had an allergic response to the allergen.
The approach creates a more normal, balanced immune system by increasing the number of regulatory T cells – immune cells important for recognizing the airway allergens as normal – while turning off the allergy-causing Th2 T cells.
It’s the first time this method for creating tolerance in the immune system has been used in allergic diseases. The approach has been used in autoimmune diseases including multiple sclerosis and celiac disease in previous preclinical research at Northwestern, and a clinical trial using the nanoparticles to treat celiac disease is in development.
“The findings represent a novel, safe and effective long-term way to treat and potentially ‘cure’ patients with life-threatening respiratory and food allergies,” said Miller.
The asthma allergy study was in mice, but the technology is progressing to clinical trials in autoimmune disease. The nanoparticle technology is being developed commercially by Cour Pharmaceuticals Development Co. A clinical trial using the nanoparticles to treat celiac disease is in development.
More information: Biodegradable antigen-associated PLG nanoparticles tolerize Th2-mediated allergic airway inflammation pre- and postsensitization, PNAS, www.pnas.org/cgi/doi/10.1073/pnas.1505782113
The research was supported in part by grant EB-013198 from the National Institute of Biomedical Imaging and Bioengineering and grant NS-026543 from the National Institute of Neurological Disease and Stroke, both of the National Institutes of Health (NIH), the Dunard Fund and a predoctoral fellowship TL1R000108 from the NIH National Center for Research Resources and the National Center for Advancing Translational Sciences.
Michigan Engineering Professor Charles Cain outlines a new technique called "Histotripsy," which is a non-invasive ultrasonic approach for the treatment of benign disease and cancer. Cain says the knifeless surgical approach generates energetic microbubbles that oscillate very rapidly, almost like a "nano-blender." The procedure can be used for multiple applications, including treating newborn infants with heart defects, prostate patients and potentially diseases such as breast cancer.
Cain is the Founding Chair of Biomedical Engineering at the University of Michigan and the Richard A. Auhll Professor of Engineering. He and his research team have been developing the histotripsy technique for the last five years.
By Mary F. Masson
U-M Health System
Every day, their baby stopped breathing, his collapsed bronchus blocking the crucial flow of air to his lungs. April and Bryan Gionfriddo watched helplessly, just praying that somehow the dire predictions weren’t true.
“Quite a few doctors said he had a good chance of not leaving the hospital alive,” says April Gionfriddo, about her now 20-month-old son, Kaiba. “At that point, we were desperate. Anything that would work, we would take it and run with it.”
Bioresorbable splint used for first time ever at the University of Michigan’s C.S. Mott Children’s Hospital, successfully stopped life-threatening tracheobronchomalacia, case featured in New England Journal of Medicine.
They found hope at the University of Michigan, where a new, bioresorbable device that could help Kaiba was under development. Kaiba’s doctors contacted Glenn Green, M.D., associate professor of pediatric otolaryngology at the University of Michigan.
Green and his colleague, Scott Hollister, Ph.D., professor of biomedical engineering and mechanical engineering and associate professor of surgery at U-M, went right into action, obtaining emergency clearance from the Food and Drug Administration to create and implant a tracheal splint for Kaiba made from a biopolymer called polycaprolactone.
On February 9, 2012, the specially-designed splint was placed in Kaiba at C.S. Mott Children’s Hospital. The splint was sewn around Kaiba’s airway to expand the bronchus and give it a skeleton to aid proper growth. Over about three years, the splint will be reabsorbed by the body. The case is featured today in the New England Journal of Medicine.
“It was amazing. As soon as the splint was put in, the lungs started going up and down for the first time and we knew he was going to be OK,” says Green.
Green and Hollister were able to make the custom-designed, custom-fabricated device using high-resolution imaging and computer-aided design. The device was created directly from a CT scan of Kaiba’s trachea/bronchus, integrating an image-based computer model with laser-based 3D printing to produce the splint.
“Our vision at the University of Michigan Health System is to create the future of health care through discovery. This collaboration between faculty in our Medical School and College of Engineering is an incredible demonstration of how we achieve that vision, translating research into treatments for our patients,” says Ora Hirsch Pescovitz, M.D., U-M executive vice president for medical affairs and CEO of the U-M Health System.
“Groundbreaking discoveries that save lives of individuals across the nation and world are happening right here in Ann Arbor. I continue to be inspired and proud of the extraordinary people and the amazing work happening across the Health System.”
Kaiba was off ventilator support 21 days after the procedure, and has not had breathing trouble since then.
“The material we used is a nice choice for this. It takes about two to three years for the trachea to remodel and grow into a healthy state, and that’s about how long this material will take to dissolve into the body,” says Hollister.
“Kaiba’s case is definitely the highlight of my career so far. To actually build something that a surgeon can use to save a person’s life? It’s a tremendous feeling.”
The image-based design and 3D biomaterial printing process can be adapted to build and reconstruct a number of tissue structures. Green and Hollister have already utilized the process to build and test patient specific ear and nose structures in pre-clinical models. In addition, the method has been used by Hollister with collaborators to rebuild bone structures (spine, craniofacial and long bone) in pre-clinical models.
Severe tracheobronchomalacia is rare. About 1 in 2,200 babies are born with tracheobronchomalacia and most children grow out of it by age 2 or 3, although it often is misdiagnosed as asthma that doesn’t respond to treatment.
Severe cases, like Kaiba’s, are about 10 percent of that number. And they are frightening, says Green. A normal cold can cause a baby to stop breathing. In Kaiba’s case, the family was out at a restaurant when he was six weeks old and he turned blue.
“Severe tracheobronchomalacia has been a condition that has bothered me for years,” says Green. “I’ve seen children die from it. To see this device work, it’s a major accomplishment and offers hope for these children.”
Before the device was placed, Kaiba continued to stop breathing on a regular basis and required resuscitation daily.
“Even with the best treatments available, he continued to have these episodes. He was imminently going to die. The physician treating him in Ohio knew there was no other option, other than our device in development here,” Green says.
Kaiba is doing well and he and his family, including an older brother and sister, live in Ohio
“He has not had another episode of turning blue,” says April. “We are so thankful that something could be done for him. It means the world to us.
A Michigan Engineering researcher has discovered that one common approach to growing blood vessels in tissues actually produces leaky tubes. He’s found a solution.
Could cancer be diagnosed with a simple blood test? A new chip can trap the one cancer cell in a billion normal cells.
Sunitha Nagrath and her lab developed the chip with other members of the Translational Oncology team, which seeks to produce technologies for improving cancer diagnosis and treatment that are ready for the clinic, to help real patients quickly. When the team runs a blood sample through the chip, it can catch breast, lung and pancreatic cancer cells. These cells can then be grown on the chip to learn more about the disease in a specific patient.
Sunitha Nagrath is an assistant professor of chemical engineering and biomedical engineering at the University of Michigan College of Engineering. Her research goal is to bring the next generation of engineering tools to patient care, especially in cancer. Her major focus of research is to develop advanced MEMS tools for understanding cell trafficking in cancer through isolation, characterization and study of circulating cell in peripheral blood of cancer patients. Research at The Nagrath Lab pertains to developing microfluidic devices for isolating and studying circulating tumor cells (CTCs) as related to metastasis.