Surgeon uses academic development time to collaborate with Biomedical Engineering

Drew Braet is a fourth-year resident in Vascular Surgery and is taking his two-year academic development time to work with C. Alberto Figueroa, the Edward B Diethrich M.D. Research Professor of Biomedical Engineering and Vascular Surgery, professor of surgery, Medical School and professor of biomedical engineering, Medical School and College of Engineering. Dr. Braet’s goal from this collaboration is to gain a better understanding of determining which patients are most likely to benefit from surgical intervention. 

“I sought to work with Biomedical Engineering, and Dr. Figueroa, specifically, by choice,” Dr. Braet said. “Early in my training, I became frustrated with the lack of information we often have about vascular disease, particularly when looking at which patients we should or should not offer surgery to. It’s pretty typical in medicine that things aren’t black and white, and that there are many gray areas. We’re really lacking clear data in a lot of different realms that can help us with decision making.”

“It is not typical that a surgeon would do research in an engineering laboratory like ours,” said Dr. Figueroa. “To have someone who goes from operating on patients to then spending two years learning analytical tools–imaging tools, modeling tools and computational tools–is somewhat unique.” A two-year research period is mandatory at U-M, but most people in the training program do not end up focusing on Engineering. “Historically, most trainees do time working in a basic science wet laboratory,” he added. 

Dr. Braet was researching information in his quest to learn more ways data analysis can inform surgical interventions, and through a Google search, came upon Dr. Figueroa’s lab. 

“I thought what he was doing in using computational methods in advanced imaging analysis would really help me,” Dr. Braet said. “I wanted to learn a tool set to be able to explore some of the questions I had. I ultimately want to improve our understanding and to provide better patient care. We met early on in my intern year. I heard about some of the work they were doing in the lab and explained some of the things I was interested in. In my intern year, we started doing a smaller project. Dr. Nick Burris, a radiologist, and I worked on that for a year, and we were able to publish a paper. From there, we started thinking about a bigger project that we could do during my dedicated time, and that led us to do my current project and current NIH F32 fellowship, where I’m looking at patients with high-grade asymptomatic carotid artery disease.”

The carotid artery is the artery in your neck that goes to your brain. “Patients who have narrowings in that artery have buildup of cholesterol plaque, the same kind of plaque that can lead to heart attacks,” Dr. Braet said. “That plaque can break off, and cause a stroke. The way that we think about these plaques in medicine is based on historical studies which suggest that the percentage of narrowing of the carotid artery is related to the risk of having a stroke. When I think about that from a biophysical and biomechanical standpoint, it doesn’t make sense. Not to discredit the studies that were previously done, this is what science has shown and we have helped a lot of people by thinking that way. But when you really boil it down to the biophysics of blood flow, that doesn’t make sense, because plaques rupture when the forces exerted on them exceed the strength of the tissue. We’re doing a computational modeling study by looking at the pressure differences, the velocity differences and the wall shear stress on carotid artery plaques to try to get a better understanding of the hemodynamic strains and stresses of the plaque and thus the risk of stroke. This could potentially lead to an entirely new way of looking at the way patients present with this particular issue. In a perfect world, 20 years from now, it would be great if the medical field could be using some of the things that we’re studying today. These kinds of engineering, imaging and modeling analyses, I think, will help us do a much better job with risk stratification that ultimately will determine whether to perform surgery or to watch a patient more conservatively.”

Dr. Braet noted that it is “refreshing” to learn to examine problems in a different way. ”In the big picture, if more surgeons and more doctors learned to look at challenges differently, we might be able to be more creative in the treatments that we can offer,” Dr. Braet said. The analysis of big data and the use of technological innovations are playing increasingly important roles in medicine, and Dr. Braet wants to understand how Engineering can assist the profession.

Dr. Figueroa noted the value of this type of mentorship for the mentor as well as the mentee. “It’s interesting because someone like Drew has a very different background and very different ways of seeing a problem than someone from a traditional engineering background,” he said. “Everybody talks about translation and reaching out, and when you are in engineering, you want to have your tools applied, but it’s actually quite difficult to do because of how distant the training and the day-to-day professional thought processes these two groups have. In engineering, you typically say you want to talk to clinicians because at the end, they are your customers for developing a new device or a new diagnostic procedure. Eventually, they’re going to have to use it and understand it, right?”

The fact that the University of Michigan has a Biomedical Engineering Department that is jointly in both the Medical School and in the College of Engineering enhances these opportunities for collaboration. There are a lot of institutions out there where perhaps they have a biomedical engineering department, but they don’t have a medical school,” Dr. Figueroa said. “In those institutions, this understanding is much harder to achieve because the engineering folks are kind of isolated and they don’t have ready access to clinical peers.”

Dr. Figueroa added that the opportunity to serve as a mentor is a rewarding experience, professionally and personally. “To me, it’s important that when I one day finish my career, I will have contributed to training a small group of clinicians who have an engineering thought process,” he said.

Histotripsy researchers receive Distinguished University Innovator Award

Histotripsy, a term coined by University of Michigan researchers, is a technique that uses sound waves to break down diseased tissue. Designed as a noninvasive alternative to surgical procedures, the novel technology uses focused ultrasound to mechanically disrupt target tissue, as opposed to thermal ablation.

The technology holds promise to permit patients with diseased tissue, such as cancerous tumors, to obtain treatment with less discomfort and faster recovery times than traditional surgery.

A team led by researchers from the College of Engineering and the Medical School invented and developed histotripsy, and their efforts to bring it to the clinic to address human disease has earned them this year’s Distinguished University Innovator Award. The team members are:

  • Zhen Xu, professor of biomedical engineering.
  • Timothy Hall, research scientist in biomedical engineering.
  • Jonathan Sukovich, assistant research scientist in biomedical engineering.
  • J. Brian Fowlkes, professor of radiology and of biomedical engineering.
  • William Woodruff Roberts, professor of urology and of biomedical engineering.

The Distinguished University Innovator Award is the highest honor for U-M faculty members who have developed transformative ideas, processes or technologies and shepherded them to market for broad societal impact. It was established in 2007 and is supported by endowments from the Office of the Vice President for Research and the Stephen and Rosamund Forrest Family Foundation.

“What distinguishes the University of Michigan as a leading public research university is our shared perpetual pursuit of innovative solutions to the greatest challenges impacting communities across the globe,” said Rebecca Cunningham, vice president for research and the William G. Barsan Collegiate Professor of Emergency Medicine.

“Together, we are persistent in our mission to serve the people of Michigan and the world, and as part of this collective commitment, we will continue to support our research discoveries and help translate them into real-world tools and services. What the histotripsy team has developed is a prime example of innovative research that needs to be shared broadly with the world.”

OVPR selected this year’s award recipients based on the recommendation of a diverse faculty selection committee that reviews a pool of nominees. The histotripsy team will receive the award Sept. 14 at the annual Celebrate Invention event at the Michigan Union.

Changing the landscape of surgical treatment

“This highly collaborative team has developed a breakthrough idea with innovative hardware and software to enable the histotripsy process,” said Mary-Ann Mycek, professor of biomedical engineering and interim chair of the department, which is jointly housed in CoE and the Medical School.

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“They’ve published a tremendous amount of data showing histotripsy’s disruptive and transformational potential, created a new subfield and formed a company that is making outstanding progress toward clinical translation and commercialization. The contributions they’ve made are substantial, and I look forward to seeing the team’s future innovations.”

A startup company based on histotripsy, HistoSonics, was launched in 2010 with support from Innovation Partnerships, a unit based in OVPR that serves as a central hub to lead U-M research commercialization efforts.

While minimally invasive and noninvasive technologies are routinely used in the clinic, they have limitations such as bleeding, infection, radiation and heat induced complications. HistoSonics has developed the Edison System, the first noninvasive, non-ionizing and non-thermal procedure to destroy targeted tissues that is guided by real-time imaging, alleviating the limitations of earlier versions. It has accomplished what has been out of reach for others — successfully using sound wave energy to mechanically obliterate diseased tissue.

“We are grateful for the support we received from the University of Michigan on our journey to invent histotripsy and develop it into a platform that can be leveraged broadly to treat patients,” Xu said.

“We would not have accomplished all that we have and come as far as we have without Innovation Partnerships. They have been with us every step of the way to go from an inventor mindset to commercialization.”

HistoSonics now employs more than 100 people and has raised more than $200 million. With a presence in Ann Arbor, HistoSonics embodies what the university strives for in its research commercialization efforts — it not only delivers a product or service that positively impacts patients, it also generates a significant economic impact.

“One of the best parts about science is turning the impossible to possible,” Xu said. “What our team has accomplished by providing an incisionless, non-toxic, painless way to destroy disease tissue via sound wave energy is incredible. I’m excited about the potential of histotripsy to change the field of medicine and cancer treatment, and eventually extend to treat many other disease types beyond cancer, such as stroke, neurological diseases, cardiovascular diseases and skin diseases.”

‘IMAGING AND THERAPY IN VISION RESEARCH 2023’ COMING THIS WEEK

The BME Summer Workshop @ Michigan, titled “Imaging and Therapy in Vision Research 2023,” is happening August 11-12, 2023, at the NCRC Building 10, South Atrium. 

This event, which is co-hosted by U-M BME and Ophthalmology and Visual Sciences, will provide a platform for discussing common research interests in diagnosis and treatment of pathologic conditions associated with the eye and the brain.

Featured guest speakers will include Dr. Joseph Izatt, the Michael J. Fitzpatrick Distinguished Professor of Engineering and Chair, Biomedical Engineering Department, Duke University; Dr. Xincheng Yao, the Richard and Loan Hill Professor from the University of Illinois at Chicago; Dr. Juliette E. McGregor, Assistant Professor at the University of Rochester, and Dr. Salavat Aglyamov, Research Assistant Professor from the University of Houston.

Here is the agenda for the event:

2-2:15 p.m. Opening Remarks 

Mary-Ann Mycek, Interim Chair, Biomedical Engineering, Professor, Biomedical Engineering, University of Michigan

David Antonetti, Roger W. Kittendorf Research Professor of Ophthalmology and Visual Sciences, Professor, Ophthalmology and Visual Sciences, Professor, Molecular & Integrative Physiology, Scientific Director, Ophthalmology and Visual Sciences, University of Michigan

SESSION 1

Moderator: Guan Xu, Assistant Professor, Ophthalmology and Visual Sciences; Assistant Professor, Biomedical Engineering, University of Michigan

2:15-2:45 p.m. 

Joseph Izatt, the Michael J. Fitzpatrick Distinguished Professor of Engineering, and Chair, Biomedical Engineering Department, Duke University: “New technologies for intra-operative and hand-held OCT” (joseph.izatt@duke.edu)

2:45-3 p.m. 

Luis Hernandez-Garcia, Research Professor, Biomedical Engineering Research Professor, Functional MRI Laboratory: “Engineering Functional MRI at Michigan” (hernan@umich.edu)

3-3:15 p.m. 

Mingyang Wang, PhD Student, U-M Biomedical Engineering: “Photo-mediated ultrasound therapy on the fundus of the eye—with real-time SD-OCT guidance” (mingyanw@umich.edu)

3:15-3:30 p.m. 

Zhongming Liu, Associate Professor, Biomedical Engineering, Associate Professor, Electrical Engineering and Computer Science, U- M: “Imaging and decoding human visual cortex during natural vision” (zmliu@umich.edu)

3:30-3:45 p.m.

Valeria Caruso, Research Area Specialist Senior in the Kovelman Lab, U-M: “Shining Light on Child Brain Development: fNIRS studies of child language, literacy, and cognition” (vcaruso@umich.edu)

3:45-4 p.m. 

Zhen Xu, Professor, Biomedical Engineering, U-M: “Transcranial histotripsy for neurological applications” (zhenx@umich.edu) 

4-4:30 p.m. Break

SESSION 2

Moderator: Xueding Wang, Jonathan Rubin Collegiate Professor, Biomedical Engineering; Professor, Radiology, University of Michigan

4:30-5 p.m.

Xincheng Yao, the Richard and Loan Hill Professor, University of Illinois at Chicago: Wide field fundus photography (xcy@uic.edu)

5-5:15 p.m.

Mark Draelos, Assistant Professor, Robotics, Assistant Professor, Ophthalmology and Visual Sciences, U-M: “Robotic OCT for Unstabilized Ophthalmic Imaging” (mdraelos@umich.edu)

5:15-5:30 p.m.

Van Phuc Nguyen, Postdoctoral Research Fellow, Paulus Lab, U-M: “Molecular and Cellular Imaging of the Retina” (vanphucn@med.umich.edu)

5:30-5:45 p.m.

Dongshan Yang, Research Assistant Professor, Internal Medicine, Medical School, U-M: “Genetically Engineered Rabbit Models of Inherited Retinal Disease” (doyang@med.umich.edu)

5:45-6 p.m. 

Hao Su, Associate Professor, Department of Mechanical and Aerospace Engineering; Director, Lab of Biomechatronics and Intelligent Robotics, North Carolina State University: “Design, Learning, and Control for Snake-like Robotic Microsurgery” (hao.su796@ncsu.edu)

6-6:15 p.m.

Yannis Paulus, Helmut F Stern Career Development Professor, Associate Professor of Ophthalmology and Visual Sciences, Associate Professor of Biomedical Engineering and Medical Director, Grand Blanc Ophthalmology, Medical School: “Biodegradable silicon nanoneedles for sustained treatment of ocular angiogenesis” (ypaulus@med.umich.edu)

6:15-6:30 p.m.

Kwoon Wong, Associate Professor, Ophthalmology and Visual Sciences Associate Professor, Molecular, Cellular & Developmental Biology, & Guan Xu, Assistant Professor, Ophthalmology and Visual Sciences, Assistant Professor, Biomedical Engineering: “Imaging Visually-Evoked Hemodynamic Responses in the Mouse Brain Using Photoacoustic Computed Tomography” (kwoon@umich.edu, guanx@umich.edu)

Dinner Reception 6:30-8:30 p.m.

Saturday, August 12

SESSION 3

Moderator: Jim Weiland, Associate Chair for Research, Biomedical Engineering;

Professor, Biomedical Engineering; Professor, Ophthalmology and Visual Sciences, University of Michigan

8:30-9 a.m.

Salavat Aglyamov, Research Assistant Professor from the University of Houston: “Elastography of ocular tissues using optical methods” (saglyamo@Central.UH.EDU)

9-9:15 a.m.

Linyu Ni, PhD Student, U-M Biomedical Engineering: “Role of aqueous veins and perilimbal sclera in the regulation of intra ocular pressure” (nilinyu@umich.edu)

9:15-9:30 a.m.

Yanhui Ma, Research Scientist, The Ohio State University: “Retinal Biomarkers of Hypertensive Effects on Cognitive Function” (ma.1634@osu.edu)

9:30-9:45 a.m.

Tianqu Zhai, PhD Candidate, U-M: “Multi-modality Imaging of Retinal and

Cerebral Biomarkers in Mice with Alzheimer’s Disease” (tianquzh@umich.edu)

9:45-10 a.m.

Kevin Chang, PhD Candidate, Biomedical Engineering, U-M: “Photoacoustic Imaging of Hemodynamic Responses in Squirrel Monkey Brain Induced by Peripheral Electrical and Mechanical Stimulation” (kaiweic@umich.edu)

10-10:30 a.m. Break

SESSION 4

Moderator: Yannis Paulus, Helmut F Stern Career Development Professor, Associate Professor, Ophthalmology and Visual Sciences; Associate Professor, Biomedical Engineering, University of Michigan

10:30-11 a.m. 

Juliette McGregor, Assistant Professor at the University of Rochester: “Advancing vision restoration therapies using calcium imaging ophthalmoscopy” 

(jmcgrego@ur.rochester.edu)

11-11:15 a.m.

Jim Weiland, Associate Chair for Research in Biomedical Engineering (Medical School), Professor, Biomedical Engineering, Professor, Ophthalmology and Visual Sciences, U-M: “Calcium Imaging of Electrically Elicited Responses in the Retina” (weiland@med.umich.edu)

11:15-11:30 a.m.

Yujia Hu, Research Investigator, Life Sciences Institute, Ye Lab (Bing group): “LabGym 2: versatile and efficient automated analysis of complex behaviors” (henryhu@umich.edu)

11:30-11:45 a.m.

Maria do Carmo Pereira da Costa, Research Assistant Professor, Neurology: “Altered retinal structure and function in Spinocerebellar ataxia type 3” (mariadoc@med.umich.edu)

11:45-Noon 

Ye Li, Research Fellow, Cai Lab (Dawen group): “Novel transgenic tools for studying the functional connectome of the Drosophila visual projection circuitry” (cnliye@umich.edu)

Noon-12:30 p.m. Box Lunch

Thank you to our special guest speakers: 

Salavat Aglyamov, Research Assistant Professor, University of Houston 

Joseph Izatt, the Michael J. Fitzpatrick Distinguished Professor of Engineering, and Chair of Biomedical Engineering, Duke University

Juliette E. McGregor, Assistant Professor, University of Rochester

Xincheng Yao, the Richard and Loan Hill Professor, University of Illinois at Chicago

New kind of superresolution explores cell division

by Kate McAlpine

A new way to see details smaller than half the wavelength of light has revealed how nanoscale scaffolding inside cells bridges to the macroscale during cell division. Unlike earlier superresolution techniques, the one developed and tested at the University of Michigan doesn’t rely on molecules that wear out with prolonged use.

Superresolution can reveal structures down to 10 nanometers, or about the same breadth as 100 atoms. It opened a whole new world in biology, and the techniques that first made it possible received a Nobel Prize in 2014. However, its weakness has been that it can only take snapshots over tens of seconds. This makes it impossible to observe the evolution of the machinery of a cell over long periods of time.

“We were wondering—when the system as a whole is dividing, how do nanometer-scale structures interact with their neighbors at the nanometer scale, and how does this interaction scale up to the whole cell?” said Somin Lee, an assistant professor of electrical and computer engineering at U-M, who led the study in Nature Communications. Co-authors of the study include BME Professor David Sept and BME PhD student Di Zu.

To answer that question, they needed a new kind of superresolution. Using their new method, they were able to continuously monitor a cell for 250 hours.

“The living cell is a busy place with proteins bustling here and there. Our superresolution is very attractive for viewing these dynamic activities,” said Guangjie Cui, a PhD student in electrical and computer engineering and co-first author of the study with Yunbo Liu, a PhD graduate in electrical and computer engineering.

Like the original method, the new technique uses probes near the nanoscale objects of interest to shed light on them. Superresolution 1.0 used fluorophores for this, fluorescent molecules that would send out an answering light after being illuminated. If the fluorophores were closer together than the size of whatever was being imaged, the image could be reconstructed from the bursts of light produced by the fluorophores. 

The new technique uses gold nanorods, which don’t break down with repeated exposure to light, but making use of the light that interacts with them is more challenging. Nanorods respond to the phase of the light, or where it is in the up-and-down oscillation of the electric and magnetic fields that compose it. This interaction depends on how the nanorod is angled to the incoming light. 

Like the fluorophores, the nanorods can attach to particular cell structures with targeting molecules on their surfaces. In this case, the nanorods sought out actin, a protein that adds structure to soft cells. Actin is shaped like branching filaments, each about 7 nanometers (millionths of a millimeter) in diameter, though they link together to span thousands of nanometers. Even though the nanorods are often more than twice the diameter of the actin, the data they provide as a group can illuminate its tiny details.

To locate the nanorods, the team built filters made of thin layers of polymers and liquid crystals. These filters enabled the detection of light with a particular phase, enabling the team to pick out nanorods with particular angles to the incoming light. By taking 10-30 images—each looking at a different subset of nanorods—and merging them into a single image, the team was able to deduce the nanometer-scale details of the filaments inside the cells. These details would be blurred out in conventional microscopes.

Using the technique, the team discovered three rules governing the way that actin self-organizes during cell division:

  • Actin expands to reach its neighbors when actin filaments are far apart.
  • Actin will draw nearer to its neighbors to increase connections, although this tendency is tempered by the drive to expand and reach more neighbors.
  • As a result, the actin network tends to contract when it is more connected, and it will expand when it is less connected.

The behavior of the actin is connected to the behavior of the cell—but the cell contracts when the actin expands, and it expands when the actin contracts. The team wants to explore this further, discovering why the motions are opposite at different scales. They also want to investigate the consequences of dysregulating this molecular process: Is this at the root of some diseases?

More broadly, they hope to use superresolution to understand how self-organization is built into biological structures, without the need for central control.

“Our genetic code doesn’t actually include enough information to encode every detail of the organization process. We want to explore the mechanisms of collective behaviors without central coordination that are like birds flying in formation—in which the system is driven by interactions between individual parts,” said Lee.

The study was supported by the Air Force Office of Scientific Research, grant nos. FA9550-16-1-0272, FA9550-19-1-0186, and FA9550-22-1-0285; and the National Science Foundation grant no. 1454188.

Study: Phase intensity nanoscope (PINE) opens long-time investigation windows of living matter (DOI: 10.1038/s41467-023-39624-w)

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.

M-HEAL + Mentors = Design Progress

by Kim Roth

The student-run organization M-HEAL, Michigan Health Engineered for All Lives, has a laudable, and ambitious, mission: to design healthcare solutions in collaboration with international partners to positively impact global health.

Today, with over 100 members on more than nine teams working on projects for communities worldwide, it’s no surprise M-HEAL has grown significantly over the past decade.

With growth has come increased interest among members to pursue the College’s Multidisciplinary Design Minor, which enables M-HEAL students to pursue academic credit for their project work. The trend has highlighted the need for additional mentorship to help students take their projects and products to the next level, so designs can be finalized, manufactured, and adopted by end users.

“Given the large number of design teams and students interested in the Multidisciplinary Design minor and the diversity of M-HEAL projects, students are best served if they can reach out to industry experts to help them navigate many of the key aspects of solution development – ideation, design, quality, risk management, and even business development,” says Aileen Huang-Saad, M-HEAL faculty advisor since 2007, assistant professor in biomedical engineering, entrepreneurship and engineering education.

The need has led to a budding mentorship program with medical device manufacturer Stryker Corporation. Following a successful pilot with Stryker Principal Engineer, Bill Hassler, and U-M mechanical engineering and design science graduate student, Michael Deininger, in the Winter 2016 semester, the program expanded quickly.

In Fall 2016, six Stryker engineering mentors – Bruce Henniges, Mitch Baldwin, CliffLambarth, Brian VanderWoude, SteveCarusillo and Dan McCombs – began working with several M-HEAL teams, offering dozens of students access to experts with industry experience and technical skills demanded by the complex design process. With the success of the program, M-Heal students added a local business mentor, Randy Schwemmin, in Winter 2017.

Teams typically meet with mentors via Skype every two weeks to discuss progress, challenges, and next steps. Both mentors and mentees are benefiting in big ways, and the model program is expanding to other industry participants as well.

“It’s so critically important our students have this input,” says Huang-Saad. “The more resources they can draw upon to help them design better products, the better they’re able to meet the needs of their intended end users. The teams’ mentors have helped them make great progress toward their respective goals.”

Stryker mentor Bill Hassler worked with Project MESA, a portable gynecological exam table for use in Nicaragua.

“Working with bright, motivated students who are doing good work for people who need help was an honor, and it was gratifying to see that my experience could have a positive impact and help them become even more knowledgeable and enthusiastic about their project,” – Bill Hassler

“Working with bright, motivated students who are doing good work for people who need help was an honor, and it was gratifying to see that my experience could have a positive impact and help them become even more knowledgeable and enthusiastic about their project,” says Hassler.

Getting to know those motivated, bright students also introduces the company to promising talent and aids recruitment efforts. “It’s a real win-win-win,” he adds. “The program has a very good vibe around here.”

 

Team: PeriOperative

Mission: To provide low-resource settings with a sustainable, user-friendly warming device to keep patients at a stable core body temperature during surgery while also reducing the risk of infection.

Mentor:  Bruce Henniges

Next stop: Dominican Republic, May 2018

Members of team PeriOperative, Elizabeth Seeley, Estefania Rios, Hannah Soifer, Adam Burdo, Brian Qian, and Tejaswini Hardas, (left – right) with their Stryker mentor Bruce Henniges (center).

The team is currently prototyping and finishing the design of its second iteration warming device. Using input from clinical partners in the Dominican Republic, the team has been testing new ideas for the next prototype. The team’s regulatory group is investigating CE Mark designation and performing risk analysis, according to PeriOperative team member Hannah Soifer, rising senior and former M-HEAL secretary.

Team PeriOperative worked with Stryker mentor Bruce Henniges, senior director of advanced development, who helped with the risk analysis. “This was new territory for the team this semester, and Bruce spent a lot of time explaining the best way to go about conducting it,” says Soifer. He also helped the team with schematics to make a constant current source, “something we hadn’t known how to do before,” she adds.

Working with its Stryker mentor, the team “made faster progress because we were guided in the right direction from the get-go and our potential mistakes were caught early,” Soifer says. “Bruce brought an incredible knowledge base in all areas of design and development, and he always gave us advice or resources we hadn’t known about.”

 

Team: Project MESA

Mission: To design a portable gynecological exam table to help improve cancer screening and better monitor pregnancies in women at high risk of complications

Mentors:  Dan McCombs, Cliff Lambarth, Randy Schwemmin

Next stop: Nicaragua, May 2017

Four members of M-HEAL’s Project MESA help a nurse try on their gamma prototype of a portable gynecological examination table at their partner clinic of Santa Lastenia in Nicaragua. Credit: Jennifer Lee

The team is currently working on its sixth prototype. Members will return to Nicaragua this spring to meet with its clinical partners and get additional feedback on two prototypes, each with different features, so it can solidify the design. Members will also get feedback on two prototype tables it previously delivered, which have been in use with patients in-clinic, according to team member Samantha Fox, a rising junior.

During the 2016-’17 academic year, Stryker mentor Cliff Lambarth, senior principle engineering product manager, helped the team uncover some key design flaws and find solutions.

“He really forced us to think about design decisions we’d made and their justification. He analyzed our design – and pushed us to analyze it – and opened our eyes to changes we needed to make,” Fox says.

“His experience and technical knowledge made him able to immediately see things we didn’t, and he also emphasized justifying our decisions. We have really good documentation now of the decisions we made and why, and that’s going to help us move forward,” she adds.

 

Team: Solar Fridge

Mission: To design an absorption refrigerator that uses solar energy to help rural health clinics and traveling health workers keep vaccines at a consistent, desired temperature.

Mentor:  Steve Carusillo

Next stop: Dominican Republic, August 2017

Team Solar Fridge with their prototype design. From left to right: Ayana Dambaeva, Adam Racette, Michelle Ruffino, Austin Friedant, Christine Hathaway , Aidan Connolly, Saswat Sahoo, and Daniel Bruni.

The team has been designing and building a prototype that could be built by users on site and running evaporation tests. Members will travel to the Dominican Republic this summer to conduct a needs assessment in a local community, recommended by M-HEAL alum Hope Tambala (Chemistry, ’15), now serving as a Peace Corps volunteer in the country.

The team worked with Stryker mentor Steve Carusillo, vice president of research and development technology, who has been helping the technical team test components and develop ideas for redesigning the device for the new stakeholder community, according to team member Michelle Ruffino, rising senior.

“It’s been a very valuable interaction,” Ruffino says. “About two weeks ago I was telling Steve about issues a sub-team was having – we’re not getting enough heat transfer from the copper pipe to the condenser – and he told us to try thermal epoxy. We bought some, tested it, and we’re very likely going to implement it. It’s inexpensive and easy to use. It’s that kind of real-world expertise and experience that helps us so much,” she adds.

 

Team:  The Initiative

Mission: To reduce infant mortality with a low-cost warmer that combines kangaroo care with an infant incubator.

Mentors:  Brian VanderWoude, Mitch Baldwin

Next stop:  Ethiopia, August 2017

 

Members of The Initiative, (left to right) Elizabeth Zwier, Elizabeth Zwier, Meghna Menon, David Chang, and Connor Yako, show Stryker mentor Brian VanderWoude (right) how to properly wear the kangaroo mother component of their hybrid infant incubator.

The team recently completed its third prototype, which includes a heated mattress, a bassinet, and a wearable wrap to hold the infant against the parent. Members plan to travel to Ethiopia this summer to further evaluate the hospital environment, conduct usability studies, and meet with its community partners.

Working with Stryker mentors “definitely helped speed up our project timelines,” said team lead Connor Yako. Mentors provided technical expertise, including feedback on materials and manufacturability, as well as big-picture input. “Having that industry experience helped us avoid power consumption and other problems we might have encountered down the line; it helped us pick the right paths early on.”

Excited by the opportunity to improve access to healthcare in a developing area of the world, Brian Vanderwoude, principal engineer with Stryker, said the team’s “creativity and resourcefulness were apparent” despite limited resources. “They weren’t intimidated by challenges, and they were really open to learning.”

Improving medical devices Collaboration by design

Image caption: Clare Donohue at Medical Device Sandbox redesign session. Credit: Lauren Stuart.

by Kim Roth

The design of health-related and medical devices directly impacts patient safety, and engineers and clinicians designing, and using, medical devices depend upon each other’s expertise.

A new experiential learning opportunity at U-M, the Medical Device Sandbox (MDS), helps both BME students and health care learners, including medical students, residents, nurses, and other health providers, collaborate across disciplines to improve device design and, ultimately, patient safety.

“Interprofessional collaboration and shared learning between BME students and health care learners is absolutely critical to designing and using medical devices in the clinic that are effective and safe for patients,” says John Gosbee, MD, a lecturer in the Departments of Biomedical Engineering and Internal Medicine and a human factors engineering and patient safety consultant.

“Interprofessional collaboration and shared learning between BME students and health care learners is absolutely critical to designing and using medical devices in the clinic that are effective and safe for patients,” -John Gosbee

Gosbee conceived of the MDS and, working closely with colleagues, BME Professor Jan Stegemann and BME Lecturer Rachael Schmedlen, has held more than two dozen MDS sessions to date.

The guided, structured, and interdisciplinary sessions begin in a simulated patient examination or hospital room at either the U-M Center for Experiential Learning and Assessment or the Clinical Simulation Center. Gosbee presents the group – typically four to six BME students and four to six medical learners – with a realistic scenario that involves the use of a medical device.

Guided by the instructor, the students identify potential design flaws, use errors, and safety issues.

During a recent session, Gosbee asked a participant to climb on and off the examination table, just as doctors routinely ask patients to do. The other students observed. Gosbee continued to prompt students with probable scenarios – the patient has a twisted ankle, the patient is short, the patient’s hands slip on the paper as they try to climb on.

BME students and health care learners constructing prototypes of their redesign ideas. Credit: John Gosbee and Jennifer Lee.

Next, the group brainstorms possible solutions. In the case of the exam table, students suggested moving the step to the side of the table, adding an extra step, and adding handrails.

Interactivity is key. Instead of simply talking about or sketching the changes they would make, students use prototyping materials – items such as foam core, scrap fabric, glue, and tape – to build a three-dimensional representation of their ideas. Participants then share their ideas with the group, and Gosbee helps them synthesize takeaway lessons.

Sessions have included a range of devices and scenarios, including layperson use of an automated external defibrillator, a pulse oximeter found in a first responder’s medical bag, and a medication organizer a patient would use at home.

Students also have brought course projects to the sessions, for example, a liver biopsy simulator from BME 450 and an existing and redesigned EKG device, brought by internal medicine residents.

The MDS name, fittingly, refers to sandbox mode in gaming, where players are freed from the usual rules and constraints.

“Bringing learners from these two disciplines together has transformative potential,” says Gosbee. “Having a creative physical and intellectual space where this kind of interaction can take place brings everyone closer to their shared goal of safer, more effective devices.”

To date, about 100 medical learners and 136 BME students – from BME 450, 452, 499, 599, and M-HEAL – have participated. BME undergraduate Jennifer Lee (’17) played an important role in organizing and running sessions and ensuring as many BME students as possible participated.

BME students who have taken part in the MDS have said it’s helped them think more about patient safety and usability testing as a crucial part of the design process – and that working with health care learners was a key way to better incorporate their expertise.

Other students said they no longer felt resigned to work with products as they currently exist and felt empowered by the redesign process.

In the words of one participant, “Redesign is an outlet for change.”

The MDS has been supported by the Third Century Initiative at U-M and by the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health under Award Number R25-EB019898.

Collaboration between Project MESA and Washtenaw Community College’s Advanced Fabrication Program

M-HEAL’s Project MESA has been finalizing its design of a portable gynecological examination table for use in rural mobile clinics in Nicaragua. In addition to improving the design’s comfort, durability, and clinical features, they have been working to simplify manufacturing of their product. The group connected with Amanda Scheffler, a welding instructor at Washtenaw Community College (WCC). She donated her time to weld the team’s fifth iteration of their prototype, and after hearing their mission to reduce cervical cancer morbidity in low-resource settings, she wanted her students to get involved. She teaches the Advanced Fabrication course at WCC, and she wanted her students to have the chance to apply their manufacturing skills from the classroom in a meaningful way. Her students have been designing and building three welding fixtures for Project MESA’s portable table, which can be used for quicker and simpler assembly of the devices. This partnership has provided both the WCC and UM students with the unique opportunity for cross-collaboration between engineers and manufacturers, with both groups learning from each other while working on a project geared towards improving global healthcare. In the future, they hope to continue this relationship in optimizing the manufacturing of the tables so that more of MESA’s devices can reach their target communities.

From: Erik Thomas (erikmich@umich.edu), M-HEAL, Project MESA Lead.

Image: Amanda Scheffler and one of her students welding Project MESA’s fifth prototype of their portable gynecological examination table in December 2016.

U-M Schools and Colleges Form Regenerative Medicine Collaborative

March 31, 2017

ANN ARBOR, MI –A Regenerative Medicine Collaborative, formed with support from U-M Office of Research, College of Engineering, and School of Medicine, aims to foster connections and enable new initiatives among investigators at the major U-M schools and colleges, including: U-M Engineering, Medical School, Dentistry, LSA, Public Health, and Pharmacy.

The University of Michigan Office of Research charged a planning task force to evaluate The University of Michigan’s strength in regenerative medicine. U-M ranks #5 in the world for regenerative medicine related citations and the stakeholder group has received nearly $320 million from NIH over the last five years for related research. We are among the leaders in the number of patents awarded, with faculty interested in regenerative and restorative medicine submitting over 320 invention disclosures resulting in greater than 120 patent filings in the past five years.

A web site (http://regenerativemedicine.umich.edu) and monthly highlights aim to communicate the breadth and depth of regenerative medicine work being done at U-M. Furthermore, the regenerative medicine collaborative will solicit a call for themes to identify areas in which U-M can grow or lead an area. The initiative will, also, facilitate the assembly of teams to be competitive for large-scale initiatives and projects across disciplines.

In addition to the website and monthly highlights, a launch symposium is being planned for the summer of 2017 to welcome the stakeholders. If you are interested in receiving the newsletters or attending the symposium, please send an email request to Amalia DiRita (amdirita@umich.edu).

‘5-D protein fingerprinting’ could give insights into Alzheimer’s, Parkinson’s

ANN ARBOR—In research that could one day lead to advances against neurodegenerative diseases like Alzheimer’s and Parkinson’s, University of Michigan engineering researchers have demonstrated a technique for precisely measuring the properties of individual protein molecules floating in a liquid.

Proteins are essential to the function of every cell. Measuring their properties in blood and other body fluids could unlock valuable information, as the molecules are a vital building block in the body. The body manufactures them in a variety of complex shapes that can transmit messages between cells, carry oxygen and perform other important functions.

Sometimes, however, proteins don’t form properly. Scientists believe that some types of these misshapen proteins, called amyloids, can clump together into masses in the brain. The sticky tangles block normal cell function, leading to brain cell degeneration and disease.

But the processes of how amyloids form and clump together are not well understood. This is due in part to the fact that there’s currently not a good way to study them. Researchers say current methods are expensive, time-consuming and difficult to interpret, and can only provide a broad picture of the overall level of amyloids in a patient’s system.

The University of Michigan and University of Fribourg researchers who developed the new technique believe that it could help solve the problem by measuring an individual molecule’s shape, volume, electrical charge, rotation speed and propensity for binding to other molecules.

They call this information a “5-D fingerprint” and believe that it could uncover new information that may one day help doctors track the status of patients with neurodegenerative diseases and possibly even develop new treatments. Their work is detailed in a paper published in Nature Nanotechnology.

“Imagine the challenge of identifying a specific person based only on their height and weight,” said David Sept, a U-M biomedical engineering professor who worked on the project. “That’s essentially the challenge we face with current techniques. Imagine how much easier it would be with additional descriptors like gender, hair color and clothing. That’s the kind of new information 5-D fingerprinting provides, making it much easier to identify specific proteins.”

Michael Mayer, the lead author on the study and a former U-M researcher who’s now a biophysics professor at Switzerland’s Adolphe Merkle Institute, says identifying individual proteins could help doctors keep better tabs on the status of a patient’s disease, and it could also help researchers gain a better understanding of exactly how amyloid proteins are involved with neurodegenerative disease.

This illustration depicts the device used to measure individual protein. The inset shows proteins (in red) flowing through a nanopore.

To take the detailed measurements, the research team uses a nanopore 10-30 nanometers wide—so small that only one protein molecule can fit through at a time. The researchers filled the nanopore with a salt solution and passed an electric current through the solution.

As a protein molecule tumbles through the nanopore, its movement causes tiny, measurable fluctuations in the electric current. By carefully measuring this current, the researchers can determine the protein’s unique five-dimensional signature and identify it nearly instantaneously.

“Amyloid molecules not only vary widely in size, but they tend to clump together into masses that are even more difficult to study,” Mayer said. “Because it can analyze each particle one by one, this new method gives us a much better window to how amyloids behave inside the body.”

Ultimately, the team aims to develop a device that doctors and researchers could use to quickly measure proteins in a sample of blood or other body fluid. This goal is likely several years off; in the meantime, they are working to improve the technique’s accuracy, honing it in order to get a better approximation of each protein’s shape. They believe that in the future, the technology could also be useful for measuring proteins associated with heart disease and in a variety of other applications as well.

“I think the possibilities are pretty vast,” Sept said. “Antibodies, larger hormones, perhaps pathogens could all be detected. Synthetic nanoparticles could also be easily characterized to see how uniform they are.”

The study is titled “Real-time shape approximation and fingerprinting of single proteins using a nanopore.” Funding for the project was provided by the Miller Faculty Scholar Award, Air Force Office of Scientific Research, National Institutes of Health, National Human Genome Research Institute, a Rackham Pre-Doctoral Fellowship from U-M and the Microfluidics in Biomedical Sciences Training Program from the National Institutes of Health and National Institute of Biomedical Imaging and Bioengineering.

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