Fifty years of Biomedical Engineering and Collaboration New Perspectives on What's Possible

The Biomedical Engineering department formally became a joint department of the U-M College of Engineering and the Medical School in 2012, just five years before celebrating its 50th anniversary in 2017. But the spirit and impact of the collaboration that spurred its founding five decades ago continue at an ever-increasing pace today.

At the heart of the Department’s many collaborative efforts lie clinicians’ desire to offer new and better solutions to their patients and engineers’ passion for applying their knowledge to solve important health and medical problems.

Take Jacqueline Jeruss, MD, PhD, a surgical oncologist who treats benign and malignant breast disease. An investigator focused on breast cancer biology, she’s also an associate professor of BME. “Once a patient becomes metastatic, that’s when what I as a surgeon can offer to patients falls into the background.”

That disheartening situation led Jeruss to ask, “If I can’t help these patients anymore through my surgical practice, what can I do in the lab?”

The answer: Quite a lot. Jeruss works with William and Valerie Hall Chair and Professor Lonnie Shea (the two also are married) to better understand the cellular changes that lead to metastasis and to devise new methods for detection.

Drs. Jeruss, Shea, and other collaborators have been working to engineer pre-malignant niche sites – areas in other parts of the body that are “primed” to shelter and nurture metastatic cancer cells. Engineered niches offer opportunities to observe how and where cancer cells travel, paving the way for new detection systems and therapies to thwart the process.

What enables such collaboration? “The real opportunity here is having a top-10 engineering school and a top-10 medical school co-located,” Shea says.

“Michigan is very unique in that it’s an incredibly collaborative environment, not just within a department or division but across the schools and colleges,” adds Dr. William Roberts. “It’s very simple and easy to pick up the phone and call someone in BME, talk about a problem and start to develop a research relationship.”

“It’s very simple and easy to pick up the phone and call someone in BME, talk about a problem and start to develop a research relationship.”William Roberts M.D.

Foundation of collaboration

The seeds of collaboration between what is today the BME department and the U-M Medical School were sowed in the 1960s. At the time, faculty from both schools were already working together on joint projects such as nuclear imaging, prosthetics, and signal processing in neurons.

Other early research included electrophysiological studies by Daniel Green that informed our understanding of how humans see in changing light. The work of Clyde Owings, who held appointments in both Pediatrics and BME, led to specialized medical care of abused children, including through the Child Abuse and Neglect Clinical and Teaching Services program he established.

A testament to the many joint projects between the Bioengineering Program and the Medical School, during a difficult time for the Program in the late 1970s, two Bioengineering faculty with Medical School appointments launched a letter-writing campaign. More than 20 distinguished faculty from nearly a dozen medical specialties responded by sharing their strong support.

Among the many fruitful research efforts of that era were development of the “spherocentric knee,” an early ball-in-socket, rather than hinge, design that more closely imitated typical human knee motion by David Sonstegard, Herbert Kaufer, and Larry Matthews. Groundbreaking work by Dr. Robert Bartlett on a new system – extracorporeal membrane oxygenation – provided life support to infants and children with acute respiratory failure. The now famous “Michigan probe,” a multi-channel neural probe still widely used in brain research, was developed by Kensall Wise and David Anderson.

Seeking opportunities

Further cementing collaboration in the early 1990s, then Bioengineering Program Director Charles Cain encouraged faculty from the College and the Medical School to propose joint research to the Whitaker Foundation. Their efforts resulted in a Special Opportunity Award in 1994.

Building on its success, two years later the newly formed BME department – thanks in no small part to Cain’s continued efforts – won a $3 million Whitaker Foundation Development Award to support its growth and continued collaborative work.

Research at the time included co-development of gene-activated matrix technology for wound repair by Steven Goldstein and Jeffrey Bonadio and in situ tissue engineering, which has become an important research technology. Work by Lawrence Schneider on the biomechanics of automotive injuries has led to improved crash-test dummy design and vehicle occupant safety, and advances in ultrasound and multimodal imaging by Paul Carson have led to improved imaging safety and effectiveness.

Creating a sustainable and translational model

With the aim of advancing promising joint engineering and medical research projects from the laboratory to market to clinical settings, in 2005, the Department won a $5 million Wallace H. Coulter Foundation Translational Research Partnership Award, one of only nine universities in the country to do so.

Matthew O’Donnell, BME chair from 1999 to 2006, was thrilled about the award. As he said in the Department’s history, Biomedical Engineering at Michigan: A Product of Vision and Persistence, “…how wonderful, especially for our junior faculty, to be exposed to a world where you don’t just write papers, you put out a device or process or new molecule that people will actually use in the clinic.” The program provided funding for four collaborative clinician-engineer teams in its first year alone.

Four BME department chairs gather for the 50th-anniversary celebration in September 2017. Left to Right: Doug Noll, Charles Cain, Lonnie Shea, and Matt O’Donnell. Photo: Brandon Baier.

Five years later, given its strong track record, U-M received an endowment through the U-M Coulter Partnership for Translational Biomedical Engineering Research. This time, U-M was one of only six universities nationwide to receive the $10 million endowment, with an additional $10 million in matching funds from the College of Engineering and the Medical School.

Coulter projects have led to impressive results, including 14 start-up companies that will no doubt have a positive impact on patients. For example, Charles Cain, J. Brian Fowlkes, Timothy Hall, William Roberts, and Zhen Xu have been developing a non-invasive ultrasonic technique to treat severe congenital heart disease in newborns as well as many other conditions.

“It was an organic thing that evolved,” said Cain, founding BME chair, of his and other long-standing collaborations. “There were [clinical] problems that needed a solution.”

Ever-increasing breadth, depth and impact

Since the early 2000s, collaborative research has expanded continuously. Other game-changing work over the past two decades includes:

  • Intravascular diagnostic ultrasound techniques to detect lipid pools within atherosclerotic plaque by Matthew O’Donnell.
  • Improved functional MRI techniques for brain imaging to improve speed and reduce distortion by Douglas Noll.
  • Advances in image reconstruction for multiple imaging modalities and a low-dose CT scan method that reduces radiation exposure by Jeffrey Fessler.
  • Mechanistic studies to improve ultrasound diagnostics and therapies, including drug and gene delivery by Cheri Deng.
  • Development of optical molecular imaging and diagnostics, including a new optical spectroscopy method to diagnose pancreatic cancer by Mary-Ann Mycek.
  • Creation of a “5-D protein fingerprint” by David Sept and Michael Mayer to provide insights into neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease.
  • Development of modular micro-tissues and biomaterials that direct cell phenotype in order to regenerate bone, cartilage, and blood vessels by Jan Stegemann.

Education to support collaboration and innovation

Enhancements to the BME curriculum over the years are ensuring students receive the training to follow in the footsteps of so many interdisciplinary engineering and medical researchers. Several design courses round out the common BME core. These include Biomedical Instrumentation & Design (BME 458), in which students design an instrument to take electrophysiological measurements, Biotechnology and Human Values (ENG 100), in which students design a new diagnostic test, and the senior capstone design course, BME 450, in which students design and test a prototype for actual stakeholders.

Broadening “bench to beside” translation, the design curriculum has been further bolstered with a year-long graduate course, BME 599, created by Aileen Huang-Saad to expose students to the full innovation process, including commercialization. Rachael Schmedlen introduced a year-long senior capstone design course (BME 451/452) and a clinical-needs-finding course (BME 499). Andrew Putnam created a new course in computer modeling in design (BME 350).

The Department also launched a new medical product development master’s concentration in 2015. Headed by Jan Stegemann, the program was designed to teach students how not only to design a medical device but to address the many regulatory, intellectual property and reimbursement-related factors involved in successfully bringing new products to a competitive market.

In addition, 2015 brought new clinical immersion and experiential learning opportunities to students through greater support for device prototyping, a collaboration with the Medical School’s Clinical Simulation Center, a Clinical Peer Mentors program and the Medical Device Sandbox. All offer the chance for BMEs and medical students and clinicians to work together – ultimately toward improved patient care and safety.

A novel “instructional incubator” course, launched by Huang-Saad in 2016 continues to build on the collaborative nature of biomedical engineering practice by having students themselves create several new short courses. Courses piloted in 2017 included 3D printing and prototype development, biological signaling in neural tissue, and computational modeling for drug development (See the related story: BME-in-Practice: Iterative curriculum design).

Cameron Louttit instructs students.
BME student Cameron Louttit instructs students on proper pipetting technique in Building a Tumor, an Introduction to Tissue Engineering.

Poised for a new era

With 12 new faculty hires in the past three years, BME is well positioned to address both intractable and new health and medical challenges with a next-generation arsenal that includes precision health (molecular imaging and diagnostics, gene and drug delivery, and histotripsy), data analytics (systems biology and multiscale modeling) and regenerative medicine (brain-machine interfaces, immune therapeutics, cell transplantation).

Explore all of the BME research by area, clinical application, or technology used.

In this last area, BME’s David Kohn is co-leading U-M’s Regenerative Medicine Collaborative, comprised of more than 150 faculty across campus. The groundswell recalls BME’s earliest days, when the department was a burgeoning program, its growth and stature fueled by a vision that blurred disciplinary boundaries. The momentum continues, offering clinicians, engineers, and students alike the opportunity to improve lives.

Dr. Parag Patil is a neurosurgeon who works closely with BME’s Cindy Chestek on brain-machine interfaces and welcomes those opportunities. “Engineering helps because when I’m doing my clinical work, I’m always thinking about ways to make things better,” he says.

Zhen Xu, too, is excited by the prospect of opportunity and change. “I hope one day we can tell patients that we can actually remove your blood clots or remove your tumor noninvasively,” she says.

And Dr. Jeruss describes the “renewed sense of optimism about what I can offer to patients. One of the most wonderful things that’s come out of this whole process for me is a new perspective on what’s possible for us to do in our lifetime.”

“One of the most wonderful things that’s come out of this whole process for me is a new perspective on what’s possible for us to do in our lifetime.”Jacqueline Jeruss, M.D., Ph.D.


Empowering Neural Engineering

Some of the earliest neural engineering work in the field was – pun unintended – conducted at U-M, including the invention of the first silicon neural electrode by Kensall Wise, professor emeritus of BME and Electrical Engineering and Computer Science.

Today a cluster of innovative, accomplished faculty is driving the field forward, working side-by-side with clinicians in the U-M Medical School to focus on translational applications to improve the lives of patients.

Brain-machine interfaces and prosthetic hand control

Cynthia Chestek | Assistant Professor | Director, Cortical Neural Prosthetics Laboratory

Chestek’s lab works to restore natural movement to individuals who have lost the use of their hands, whether due to amputation, spinal cord injury or other cause of paralysis. Her work includes improving neural signal control of prosthetics and natural limbs through novel and improved brain-machine interfaces, functional electrical stimulation and assistive exoskeletons.

Cynthia Chestek, BME Professor, and Zachary Irwin, BME PhD Student. Photo: Joseph Xu

Toward that goal, Chestek and collaborators are developing new electrodes. She and Professor Euisik Yoon recently demonstrated an eight-micrometer carbon-fiber probe. Research to date has shown that the probes cause significantly less scarring and immune response than conventional larger electrodes.

Neural control of finger motion

In a collaborative project with Parag Patil, MD, to develop a system for brain controlled functional electrical stimulation, Chestek and her students apply machine learning algorithms to neural signals recorded by 100-channel implanted arrays. Using Kalman filters and regression techniques, the objective is to understand the relationships between hand movements and their respective neuron firing rates.

In collaboration with Paul Cederna, MD, professor of surgery and chief of plastic surgery, Chestek’s lab has been conducting pre-clinical work on hand control using neural signals. One of the barriers to nerve-controlled prosthetic limbs has been the small signal. The team’s work found muscle grafted to the ends of split nerves – a procedure Dr. Cederna performs on patients suffering from painful nerve growths following amputation – can amplify neural signals to the point they can control a prosthetic hand.

Chestek joined the BME faculty in 2012 and jokes that she will be here forever. “At U-M, we have a Top 10 engineering school and a Top 10 medical school — I came here for the very strong collaborations and, because of the doctors, I’ll never leave. I collaborate with a surgeon on every project. There’s a fertile group of clinicians here who are deeply invested in this technology and to bringing it to clinical practice.”

Neurostimulation for chronic pain

Scott Lempka | Assistant Professor |Neuromodulation Laboratory
Scott Lempka, PH.D.

For the 25 million Americans and countless others around the globe who suffer from chronic pain, Lempka’s work holds great promise. Research in his lab focuses on neuromodulation for managing chronic pain and, although such techniques have been used for years, only about 50 percent of patients get relief. In those who do, however, it’s often not enough to make a real impact on their quality of life.

The Neuromodulation Lab develops computer
models of the electric fields generated by the
stimulation and the direct neural response.

To identify and better understand the specific mechanisms by which neurostimulation works, and why it works for some patients and not others, Lempka’s group takes an engineering approach to develop patient-specific computer models. The models are generated from quantitative and qualitative clinical data, obtained from CT, MRI and functional MRI imaging, and how patients respond to different stimulation parameters.

In recently published work, Lempka and colleagues describe a first-in-man clinical trial of deep brain stimulation for post-stroke pain that targets alternate pathways, specifically those related to emotions and behavior, rather than sensation. The areas targeted, the ventral striatum/anterior limb of the internal capsule, have been widely studied and safely used in treatment of obsessive compulsive disorder and refractory depression. Although pain intensity wasn’t significantly reduced in the study, participants’ reports of anxiety and depression related to the pain were.

“This tells us we should consider changing what we consider a success with these neurostimulation therapies. Rather than fixating on pain intensity, we should shift our focus to reducing pain-related suffering or disability,” says Lempka, who joined the BME faculty in January 2017 and is excited about further research. “Working with U-M’s clinical pain research groups and pain management specialists will help us not only better understand how neurostimulation works on pain but also to develop innovative and more effective patient-specific therapies.”

Lempka, S. et al. Randomized clinical trial of deep brain stimulation for poststroke pain. Annals of Neurology, 2017; 81 (5): 653; DOI: 10.1002/ana.24927.

Improving quality of life for the visually impaired

James Weiland | Professor | BioElectronic Vision Lab
James Weiland, Ph.D.

Weiland is co-developer of a bioelectronic retinal prosthesis, or so-called bionic eye, which electrically stimulates the retina and can partially restore vision to individuals who have lost their sight due to inherited retinal disease. The Argus II was approved by the U.S. Food and Drug Administration in 2013 and has since been implanted in over 200 people worldwide, including 10 at the Kellogg Eye Center at U-M.

Weiland’s BioElectronic Vision Lab investigates the fundamental mechanisms underlying the ways in which implantable and wearable electronic systems interact with the natural visual system and other senses. He has demonstrated the feasibility of using MRI and fMRI in patients with the retinal prosthesis to better understand how the visual pathways in the brain respond to sight recovery and also how these pathways adapt to process other sensory input, including tactile input, in a phenomenon known as cross-modal activation.

In addition, Weiland and researchers in his lab are studying how these prosthetic systems affect the anatomy and functioning of the visual system over time in order to optimize existing and future devices. His lab is also developing a wearable, smart camera system that can work with the Argus or as a standalone assistive technology for the visually impaired.

Findings from these studies will lead to further refinements to the Argus II to enhance vision restoration. Involving Argus patients in evaluating design changes is a key aspect to his research program.

Weiland earned his MS and PhD degrees in BME and returned to campus to join the BME faculty in January 2017, after holding faculty appointments at Johns Hopkins University and University of Southern California.

“Ann Arbor has always been a second home for me,” Weiland says. “When an opportunity became available to join the BME department, it was difficult to not explore the possibility. The more I visited and talked with faculty and students in BME and Ophthalmology, the more the move made sense. The excellence of the engineering and medical schools was a strong attraction.


$7.75M for mapping circuits in the brain A new NSF Tech Hub will put tools to rapidly advance our understanding of the brain into the hands of neuroscientists.

The technology exists to stimulate and map circuits in the brain, but neuroscientists have yet to tap this potential.

Now, developers of these technologies are coming together to demonstrate and share them to drive a rapid advance in our understanding of the brain, funded by $7.75 million from the National Science Foundation.

“We want to put our technology into the hands of people who can really use it,” said Euisik Yoon, leader of the project and professor of electrical engineering and computer science at the University of Michigan.

By observing how mice and rats behave when certain neural circuits are stimulated, neuroscientists can better understand the function of those circuits in the brain. Then, after the rodents are euthanized, they can observe the neurons that had been activated and how they are connected. This connects the behavior that they had observed while the rodent was performing a controlled experiment with a detailed map of the relevant brain structure.

We can achieve structural and functional mapping at an unprecedented scale. Euisik Yoon, BME and EECS professor

It could lead to better understanding of disease in the brain as well as more effective treatments. In the nearer term, the details of neural circuitry could also help advance computing technologies that try to mimic the efficiency of the brain.

Over the last decade or so, three tools have emerged that, together, can enable the mapping of circuits within the brain. The most recent, from U-M, is an implant that uses light to stimulate specific neurons in genetically modified mice or rats and then records the response from other neurons with electrodes.

Probes like this one, which stimulate neurons with light and then record activity with electrodes, are just one facet of the technology suite that can help neuroscientists map circuits in the brain. Photo: Fan Wu, Yoon Lab, University of Michigan

Unlike earlier methods to stimulate the brain with light, with relatively large light-emitters that activated many nearby neurons, the new probes can target fewer neurons using microscopic LEDs that are about the same size as the brain cells themselves. This control makes the individual circuits easier to pick out.

The “pyramidal” neurons that cause action—rather than inhibit it—will be genetically modified so that they respond to the light.

“They are just one of the neuron types we are seeking to map,” said John Seymour, one of the co-investigators and U-M assistant research scientist in electrical engineering and computer science. “If you can record from motor cortex pyramidal neurons, you can predict arm movement, for example.”

To visualize the structure of pyramidal cells and other kinds of neurons, researchers need a way to see each tree in the brain’s forest. For this, co-investigator Dawen Cai, U-M assistant professor of cell and developmental biology, has been advancing a promising approach known as Brainbow. Genetically modified brain cells produce fluorescent tags, revealing each cell as a random color.

When it is time to examine the brain, a technique to make the brain transparent will remove all the fatty molecules from a brain and replace them with a clear gel, making it possible to see individual neurons. It was pioneered by another co-investigator, Viviana Gradinaru, who is a professor of biology and biological engineering at the California Institute of Technology.

“Not only may we understand how the signal is processed inside the brain, we can also find out how each neuron is connected together so that we achieve structural and functional mapping at an unprecedented scale,” Yoon said.

While these are the central tools, others at Michigan are working on methods to make the electrodes that record neuron activity even smaller and therefore more precise. In addition, a carbon wire electrode design could even pick up the chemical activity nearby, adding measurements of neurotransmitters as a new dimension of information.

To share these new tools, the team will bring in neuroscientists for annual workshops and then provide them with the hardware and software they need to run experiments in their own labs. For the tools that prove to be most useful, they will seek commercialization opportunities so that they remain available after the project ends.

The project is called Multimodal Integrated Neural Technologies (MINT) and has been awarded as a 5-year National Science Foundation NeuroNex Technology Hub.

Other co-investigators include Cynthia Chestek, U-M assistant professor of biomedical engineering; James Weiland, U-M professor of biomedical engineering; Ken Wise, the William Gould Dow Distinguished University Professor Emeritus of Electrical Engineering and Computer Science at U-M; and György Buzsáki, professor of neuroscience at New York University. Seymour and Yoon are also affiliated with biomedical engineering at U-M. Cai is affiliated with Michigan Medicine.

The neural probes with micro LEDs are made in the Lurie Nanofabrication Facility at U-M.


Original Publicationhttps://news.engin.umich.edu/2017/08/7-75m-for-mapping-circuits-in-the-brain/

Written By: Kate McAlpine, Senior Writer & Assistant News Editor, Michigan Engineering Communications and Marketing

Cover Caption: To follow the long, winding connections among neurons, a technique called “Brainbow” labels each neuron a random color. Credit: Dawen Cai, Cai Lab, University of Michigan

Video Caption: John Seymour explains how the new grant will help neurotechnologists further research to enable a better understanding of the pathways in the brain.


A ‘Communication Breakdown’ During General Anesthesia

May 09, 2016 2:39 PM

When ketamine is used for general anesthesia, two connected parts of the cortex turn to “isolated cognitive islands.”

It’s a topic that has long captivated doctors, scientists and the public — what exactly happens in your brain when you’re oblivious on the operating table?

Some anesthesia drugs work in a straightforward manner by dampening down neurons in the brain. The mechanism of one anesthetic, however, has proved elusive: ketamine.

Certain doses of ketamine induce general anesthesia, though brain activity can still be robust, says Cynthia Chestek, Ph.D., co-senior author of a new study in NeuroImage.

Ketamine is used often in patient care and in laboratory settings. The new paper examines the neurological mechanisms at work during ketamine anesthesia.

Co-senior authors Chestek and anesthesiologist George Mashour, M.D., Ph.D., led the research team, which took precise measurements down to the level of neurons in animal models.

“We found that general anesthesia reflects a communication breakdown in the cortex, even though sensory information is getting processed,” Mashour says. “But the processing appears to occur in isolated cognitive islands.”

Turns out, two adjacent parts of the brain that work together in the waking state simply stop talking to each other under general anesthesia. When awake, communication between the primary somatosensory cortex and the primary motor cortex is critical to normal function.

“This supports the idea that what anesthesia does to cause unconsciousness is interrupt communication between brain areas, stopping the processing of higher-level information,” says first author Karen Schroeder, a doctoral candidate in the U-M Department of Biomedical Engineering. “This was the first time anyone directly observed the interruption between the two areas using individual neurons.”

Different fields collaborating

Chestek’s biomedical engineering lab focuses on brain machine interfaces, recording activity of neurons and reading motor commands and sensory information in real time.

“This turned out to be really useful for the researchers in anesthesiology,” Chestek says. So her team got on board to measure both areas of the brain, which kept firing during anesthesia.

“As soon as we injected ketamine, the sensory information disappeared from the motor cortex. Normally these areas are tightly connected.”

The group plans to continue this work, turning next to investigate the level of anesthesia at which these changes in communication start to occur. They’re also looking into what the groups of neurons are doing under anesthesia when they are still active but no longer communicating with each other.

“These insights could potentially improve our ability to monitor patients’ level of consciousness,” Schroeder says.

Funding for the work came from the National Institutes of Health.