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AI tool helps optimize antibody medicines

Machine learning points out why antibodies fail to stay on target, binding to molecules that aren’t markers of disease—and suggests better designs.

BY: DEREK SMITH

Antibody treatments may be able to activate the immune system to fight diseases like Parkinson’s, Alzheimer’s, and colorectal cancer, but they are less effective when they bind with themselves and other molecules that aren’t markers of disease. Now, new machine-learning algorithms can highlight problem areas in antibodies that make them prone to binding non-target molecules.

“We can use the models to pinpoint the positions in antibodies that are causing trouble and change those positions to correct the problem without causing new ones,” said Peter Tessier, the Albert M. Mattocks Professor of Pharmaceutical Sciences, Chemical Engineering, and Biomedical Engineering at the University of Michigan and corresponding author of the study in Nature Biomedical Engineering.

“The models are useful because they can be used on existing antibodies, brand new antibodies in development, and even antibodies that haven’t been made yet,” Tessier added.

Antibodies fight disease by binding specific molecules called antigens on disease-causing agents—such as the spike protein on the virus that causes COVID-19. Once bound, the antibody either directly inactivates the harmful viruses or cells or signals the body’s immune cells to do so.

Unfortunately, antibodies designed to bind their specific antigens very strongly and quickly can also bind non-antigen molecules, which removes the antibodies before they target a disease. Such antibodies are also prone to binding with other antibodies of the same type and, in the process, form thick solutions that don’t flow easily through the needles that deliver antibody drugs.

“The ideal antibody should do three things at once: bind tightly to what they’re supposed to, repel each other and ignore other things in the body,” Tessier said.

An antibody that doesn’t check all three boxes is unlikely to become a successful drug, but many clinical-stage antibodies can’t. In their new study, Tessier’s team measured the activity of 80 clinical-stage antibodies in the lab and found that 75% of the antibodies interacted with the wrong molecules, to one another, or both.

Changing the amino acids that comprise an antibody, and in turn the antibody’s 3D structure, could prevent antibodies from misbehaving because an antibody’s structure determines what it can bind. But, some changes could cause more problems than they fix, and the average antibody has hundreds of different amino acid positions that could be changed.

“Exploring all the changes for a single antibody takes about two workdays with our models, which is substantially shorter compared to experimentally measuring each modified antibody—which would take months, at best,” said Emily Makowski, a recent PhD graduate in pharmaceutical sciences fand the study’s first author.

The team’s models, which are trained on the experimental data they collected from clinical-stage antibodies, can identify how to change antibodies so they check all three of those boxes with 78% to 88% accuracy. This narrows down the number of antibody changes that chemical and biomedical engineers need to manufacture and test in the lab.

Two men wear white lab coats, blue nylon gloves, and safety goggles while standing at a black lab bench. On the bench are several flasks filled with a yellow-brown fluid and test tubes in racks. Tessier, on the left, appears to dispense something into a tube while Tiexin, on the right, holds a centrifuge tube with a blue cap that contains a clear liquid. — Peter Tessier (left) and Tiexin Wang (right), a doctoral student in chemical engineering and study co-author, prepare antibodies to test how they bind to themselves and other molecules. Credit: Hye Jin Lee, Tessier Lab, Pharmaceutical Sciences, University of Michigan.

“Machine learning is key for accelerating drug development,” said Tiexin Wang, a doctoral student in chemical engineering and study co-author.

Biotech companies are already beginning to recognize machine-learning’s potential to optimize the next-generation of therapeutic antibodies.

“Some companies have developed antibodies that they are really excited about because they have a desired biological activity, but they know they are going to have problems when they try to use these antibodies as drugs,” said Tessier. “That’s where we come in and show them the specific spots in their antibodies that need to be fixed, and we are already helping out some companies do this.”

The research was funded by the Biomolecular Interaction Technology Center, the National Institutes of Health, the National Science Foundation and the Albert M. Mattocks Chair and was conducted in collaboration with the Biointerfaces Institute and EpiVax, Inc.

The University of Michigan and Sanofi have filed a patent application for the experimental method that provided the data used to train the algorithm.

Tessier has received honoraria for invited presentations on this research from GlaxoSmithKline, Bristol Myers Squibb, Janssen and Genentech.

Study: Optimization of therapeutic antibodies for reduced self-association and non-specific binding via interpretable machine learning

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.”

BME advisor hosts Code Maize podcast episode

This Code Maize episode, produced by Newnan Advising, features two current students at the University of Michigan Medical School. Piroz Bahar and BME alum Devak Nanua discuss their pathways to medicine, as well as the importance of creating bonds with faculty and fellow students as a meaningful part of defining success as an M1 student. Nanua specifically highlights how his BME grad degree prepared him for Medical School. Rachel Patterson, a BME academic advisor and counselor, hosted this podcast episode.

‘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

A Better Way to Connect Arteries How Coulter’s Newest Licensed Product Is Making Its Way from the Classroom to the Clinic

The Arterial Everter & Synovis Coupler — When reconstructive surgeons repair a breast after mastectomy or a severely injured leg after a car accident, they often move tissue harvested from one part of the body to another using microsurgical techniques. A new device developed at U-M and supported by the Coulter Translational Research Partnership Program will make it possible to connect arteries in the transferred tissue to those at the repair site in just minutes with a few easy steps. The device, called the arterial everter, looks like a thin silicone pen with a flexible steel spine. It was developed as an accessory for the market’s leading product for connecting vessels, the GEM Microvascular Anastomotic Coupler from Synovis Micro Companies Alliance, enabling it to work as well on arteries as it currently does on veins.

When reconstructive surgeons repair a breast after mastectomy or a severely injured leg after a car accident, they often move tissue harvested from one part of the body to another using microsurgical techniques. A new device developed at U-M and supported by the Coulter Translational Research Partnership Program will make it possible to connect arteries in the transferred tissue to those at the repair site in just minutes with a few easy steps. The device, called the arterial everter, looks like a thin silicone pen with a flexible steel spine. It was developed as an accessory for the market’s leading product for connecting vessels, the GEM Microvascular Anastomotic Coupler from Synovis Micro Companies Alliance, enabling it to work as well on arteries as it currently does on veins.

Developing the Everter
The challenge with using the coupler on arteries is that their muscular walls are hard to spread over the device’s rings, often popping off one anchoring pin as the next is attached.

In the class design, a catheter balloon stabilized the artery while a plunger-type tool (yellow) pushed its ends onto the coupler pins all at once. Credit: ENG 490 student team	The next version was a rigid plastic tool with a telescoping dilation mechanism and channels that could accept the coupler’s pins with a single push. Though streamlined, it required precise surgical alignment to avoid bending the pins. Credit: Jeffrey Plott	The latest design is a flexible tool with a tapered silicone tip that can spread the artery onto the coupler’s pins from almost any angle. The pins pierce through the artery and into the silicone without bending, and the tool’s shaft can be angled as needed. Credit: Carolyn McCarthy

$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 Publication: https://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.

Coating method could improve temporary implants that dissolve in the body

A strategy for coating complicated surfaces with biodegradable polymers has been pioneered by a team of researchers led by Joerg Lahann, a professor of chemical engineering and director of the Biointerfaces Institute at U-M. It could enable coatings for implants that dissolve in the body, such as drugs to improve healing.

Permanent polymer coatings are already used on medical equipment that does not biodegrade, such as metal stents that hold blocked arteries open. The drug prevents cells from growing over the webbed metal structure and narrowing the artery again. It can be applied with a technique called chemical vapor deposition – a process that puts the drug into a gas phase and lays it down in an even coating, like fog turning into frost.

“What you couldn’t do until we published this paper is take a suture that biodegrades and coat with a vapor-based coating that would provide similar benefits,” said Lahann. A suture or a biodegradable bone screw might benefit from a coating of growth factors to promote healing, he added.

Other ways of coating include dissolving the drug into a solvent and then spraying it onto the structure. However, the solvents are often toxic, and the spray technique can bridge gaps in open structures or result in one part of a structure blocking the spray from reaching another.

Still, chemical vapor deposition is very tricky with polymers, or chemicals built in a chain – and a biodegradable coating would need to be made out of polymers. Polymers tend to break up when they are vaporized, so they must be built piece by piece onto a surface.

The researchers demonstrated this using two different monomers, or types of links in the polymer chain. By controlling the ratio between the two monomers, and the chemical groups hanging off the sides of the monomers, the team could control how quickly water could get into the polymer and begin breaking up the chain into its nontoxic elements.

In the lab, Lahann’s group is testing out the coating technique with biodegradable scaffolds that they use for implanting stem cells to help heal wounds involving gaps in tissue. They are also beginning a project with the lab of William Giannobile, the Najjar Professor of Dentistry and Biomedical Engineering, to coat biodegradable dental implants with growth factors to speed healing.

Other members of the research team hailed from Northwestern Polytechnical University in Xi’an, China, and the Karlsruhe Institute of Technology in Eggenstein-Leopoldshafen, Germany.

The study was funded the German Science Foundation under the SFB grant 1176 and the Army Research Office (ARO) under Grant W911NF-11-1-0251.

Lahann is also a professor of biomedical engineering, macromolecular science and engineering, and materials science and engineering.

From: Kate McAlpine, Michigan Engineering

Link: http://www.engin.umich.edu/college/about/news/stories/2017/february/coating-method-could-improve-temporary-implants

3-D printed orthotics and prosthetics: A better fit, the same day

3D PRINTED ORTHOTICS

A new way to design and 3D print custom prosthetics and orthotics could give amputees, stroke patients and individuals with cerebral palsy lighter, better-fitting assistive devices in a fraction of the time it takes to get them today.

ANN ARBOR – A new way to design and 3D print custom prosthetics and orthotics could give amputees, stroke patients and individuals with cerebral palsy lighter, better-fitting assistive devices in a fraction of the time it takes to get them today. Developed by the University of Michigan College of Engineering, the system is being implemented at the University of Michigan Orthotics and Prosthetics Center (UMOPC).

The U-M engineers and clinicians who designed the new cyber manufacturing system say that shortening the fabrication time for custom orthotics could make the process easier on custom assistive device users, who today must wait days or weeks to receive essential orthotics and prosthetics. The digital design and manufacturing process can also improve the devices’ precision, fit and function and improve consistency from one provider to the next.

Prostheses are devices used to replace a lost limb, while orthoses are braces used to protect, align or improve function or stability to injured limbs. Currently, the U-M team is focusing on ankle foot orthosis, which are often prescribed to stroke patients to help them regain their ability to walk. More than two-thirds of the 700,000 stroke victims in the United States each year require long-term rehabilitation, and many of them can be helped with custom orthotics. The devices can also help children with cerebral palsy, myelomeningocele and other conditions gain stability and walk more easily.

“Eventually we envision that a patient could come in in the morning for an optical scan, and the clinician could design a high quality orthosis very quickly using the cloud-based software,” said Albert Shih, a professor of mechanical and biomedical engineering at the University of Michigan and the lead on the project. “By that afternoon, they could have a 3-D printed device that’s ready for final evaluation and use.”

The new technique begins with a three-dimensional optical scan of the patient. The orthotist then uploads the scan data to a cloud-based design center and uses specially developed software to design the assistive device. Next, the software creates a set of electronic instructions and transmits them back to the orthotist’s facility, where an on-site 3-D printer produces the actual device in a few hours.

Jeff Wensman, director of clinical and technical services at UMOPC, says the new process is a major departure from current methods, which begin with wrapping fiberglass tapes around the patient’s limb. The tapes harden into a mold, which is then filled with plaster to make a model of the limb. Next, heated plastic is formed around the model in a vacuum forming process to make the actual device. The device is then hand-finished by smoothing the edges and attaching mechanical components like straps. It’s a labor-intensive process that requires a large shop and a highly trained staff. By contrast, the only on-site equipment required by the new process is a optical scanner, a computer and a 3-D printer. In the future, this could give even small clinics in remote areas the ability to provide custom orthotics and prosthetics.

The lighter weight of the 3-D printed devices stems from a technique called “sparse structure,” which can make orthotics that are partially hollow using a wavy internal structure that saves weight without sacrificing strength. Developed by U-M mechanical engineering PhD student Robert Chisena, sparse structure was initially intended as a way to print orthotics more quickly, but researchers quickly realized that it could make them better as well.

“Traditional hand-made orthotics are solid plastic, and they need to be a certain thickness because they have to be wrapped around a physical model during the manufacturing process,” Wensman said. “3-D printing eliminates that limitation. We can design devices that are solid in some places and hollow in others and vary the thickness much more precisely. It gives us a whole new set of tools to work with.”

Because the 3-D manufacturing process uses computer-based models rather than hand fabrication, it’s also more consistent than current methods. Any clinic with a 3-D printer could produce exactly the same device time after time. In addition, computer models of previous orthotics can provide doctors with a valuable record of how a patient’s shape and condition progress over time.

The current 3-D printing device is already turning out orthotics and prosthetics for testing; Shih says the team is working to demonstrate how it can reduce costs and improve service and efficiency. Eventually, they plan to make the system’s software and specifications freely available so that other healthcare providers can roll out similar systems on their own.

“In a sense, we’re building a recipe that others can use to build their own systems,” Shih said.

The project is funded by the National Science Foundation and America Makes, a partnership between industry, academia, government and others that aims to develop advanced manufacturing and 3-D printing capabilities in the United States. Software for the project is being developed by Altair and Standard Cyborg. Stratasys provided the 3-D printer for the project.

“Without America Makes and Manufacturing USA, we would not be able to bring a state-of-the-art 3D-printer to the prosthetics center with the traditional research project,” Shih said. “Without the National Science Foundation’s Partnership for Innovation and cyber manufacturing grants, we would not be able to have PhD engineering students working at UMOPC to develop the system. I am very blessed to have all three projects funded and started at the same time to create this first-of-its-kind demonstration site at UMOPC for the Michigan Difference in advanced manufacturing and patient care.

From: Gabe Cherry, MconneX

Link: http://www.engin.umich.edu/college/about/news/stories/2017/january/3-d-printed-orthotics-and-prosthetics-a-better-fit-the-same-day

U-M research center spurs new approach to musculoskeletal health

ANN ARBOR – A promising new approach to musculoskeletal disease that focuses on the interactions between body systems like bone and muscle is a top priority at the newly established Michigan Integrative Musculoskeletal Health Core Center.

Led by Karl Jepsen, the Henry Ruppenthal Family Professor for Orthopaedic Surgery and Bioengineering and a biomedical engineering professor at the University of Michigan, the center is spearheading a research model that looks at bone, muscle and connective tissue as a single system instead of individual components. It’s funded by a $3.9 million grant from the National Institutes of Health and brings together 60 faculty members from seven schools across the University of Michigan to accelerate new cross-disciplinary research between engineers, doctors and others throughout the university.

Jepsen believes that their efforts could help doctors take action early, enabling more patients to avoid musculoskeletal disease rather than waiting until after disease and injury risk develop. It could also help people avoid maladies like bone fractures and stay more active, improving overall quality of life.

U-M schools involved with center include the School of Medicine, School of Dentistry, Michigan Engineering, School of Kinesiology, Life Sciences Institute, School of Public Health and College of Literature, Science and the Arts.

Jepsen says the new center will provide researchers with access to equipment and other resources, as well as opportunities to collaborate as they study the interactions among the body’s systems. They aim to develop treatments that help patients maintain bone, muscle, tendon, ligament and cartilage health over a lifetime rather than reacting to individual health problems as they occur.

“The field is moving toward a more integrative approach, and we have a diverse group of people at U-M who are doing the world’s best bone and muscle research. Our work with osteoporosis is just one example” Jepsen said. “Our goal is to make sure those departments are talking to each other so that collectively, we can make the maximum impact in these areas.”

The center will help enable interdisciplinary studies across U-M. In Jepsen’s own work with collaborators at the School of Public Health, the team is scouring a database with anonymized medical records dating back decades for thousands of women. Researchers are looking at patients’ entire musculoskeletal systems to identify red flags that lead to osteoarthritis and osteoporosis and bone fractures later in life.

“Ideally, we want to move the diagnostic process for diseases like osteoporosis into people’s 40s, instead of waiting until they’re in their 60s and have already lost much of their muscle mass,” Jepsen said. “We want to change the focus from a reactive to a proactive approach, helping people maintain their bone-muscle system so that it’s prepared to age well.”

Other examples of cross-disciplinary work at the center include research into new three-dimensional imaging techniques for cartilage that could lead to more effective arthritis treatments. Today, cartilage imaging is mostly limited to two-dimensional visual slices; Jepsen believes that improved techniques could help doctors get a better look at how arthritis affects the body.

“Cartilage is mostly water, so it’s very difficult to get good imaging,” Jepsen said. “Three-dimensional imaging would give us a much better picture of how arthritis progresses in a patient; how big the damage is, how deep it is and how it changes the overall bone surface.”

The center will focus on three main goals:

Enabling center investigators to conduct vertically-oriented science from the molecular level to the organ/functional level
Creating new opportunities for collaboration, training and mentorship
Promoting opportunities for novel and emerging science by focusing on research between basic scientists and clinicians, studies on sex-specific differences and interactions among tissues

Three main research cores within the center will focus on histological assessment, structural and compositional assessment and functional assessment. The cores move from molecular mechanisms through functional outcomes.

“This is an exciting time for those of us in musculoskeletal research,” Jepsen says. “Greater interactions between basic scientists and clinicians are important to the future of medicine and the care we will be able to provide to patients in the years to come.”

Source:

By: Gabe Cherry, Michigan Engineering
Original Publication: http://www.engin.umich.edu/college/about/news/stories/2016/october/u-m-research-center-spurs-new-approach-to-musculoskeletal-health

“Kidney on a chip” could lead to safer drug dosing

From: Gabe Cherry
Michigan Engineering

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.

The new technique offers a more accurate way to test medications, closely replicating the environment inside a human kidney. It uses a microfluidic chip device to deliver a precise flow of medication across cultured kidney cells. This is believed to be the first time such a device has been used to study how a medication behaves in the body over time, called its “pharmacokinetic profile.”

“When you administer a drug, its concentration goes up quickly and it’s gradually filtered out as it flows through the kidneys,” said University of Michigan Biomedical Engineering professor Shuichi Takayama, an author on the paper. “A kidney on a chip enables us to simulate that filtering process, providing a much more accurate way to study how medications behave in the body.”

Takayama said the use of an artificial device provides the opportunity to run test after test in a controlled environment. It also enables researchers to alter the flow through the device to simulate varying levels of kidney function.

“Even the same dose of the same drug can have very different effects on the kidneys and other organs, depending on how it’s administered,” said Sejoong Kim, an associate professor at Korea’s Seoul national University Budang Hospital, former U-M researcher and author on the paper. “This device provides a uniform, inexpensive way to capture data that more accurately reflects actual human patients.”

In the study, the team tested their approach by comparing two different dosing regimens for gentamicin, an antibiotic that’s commonly used in intensive care units. They used a microfluidic device that sandwiches a thin, permeable polyester membrane and a layer of cultured kidney cells between top and bottom compartments.

Ryan Oliver, Post-Doctorate Researcher, demonstrates use of a special microchip that can simulate different organs and parts of the body. Photo by: Joseph Xu

They then pumped a gentamicin solution into the top compartment, where it gradually filtered through the cells and the membrane, simulating the flow of medication through a human kidney. One test started with a high concentration that quickly tapered off, mimicking a once-daily drug dose. The other test simulated a slow infusion of the drug, using a lower concentration that stayed constant. Takayama’s team then measured damage to the kidney cells inside the device.

They found that a once-daily dose of the medication is significantly less harmful than a continuous infusion—even though both cases ultimately delivered the same dose of medication. The results of the test could help doctors better optimize dosing regimens for gentamicin in the future. Perhaps most importantly, they showed that a kidney on a chip device can be used to study the flow of medication through human organs.

“We were able to get results that better relate to human physiology, at least in terms of dosing effects, than what’s currently possible to obtain from common animal tests,” Takayama said. “The goal for the future is to improve these devices to the point where we’re able to see exactly how a medication affects the body from moment to moment, in real time.”

Takayama said the techniques used in the study should be generalizable to a wide variety of other organs and medications, enabling researchers to gather detailed information on how medications affect the heart, liver and other organs. In addition to helping researchers fine-tune drug dosing regimens, he believes the technique could also help drug makers test drugs more efficiently, bringing new medications to market faster.

Within a few years, Takayama envisions the creation of integrated devices that can quickly test multiple medication regimens and deliver a wide variety of information on how they affect human organs. PHASIQ, an Ann Arbor-based spinoff company founded by Takayama is commercializing the biomarker readout aspect of this type of technology in conjunction with the University of Michigan Office of Technology Transfer, where Takayama serves as a Faculty Innovation Ambassador.

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.

$3.46M to Combine Supercomputer Simulations with Big Data

A new way of computing could lead to immediate advances in aerodynamics, climate science, cosmology, materials science and cardiovascular research. The National Science Foundation is providing $2.42 million to develop a unique facility for refining complex, physics-based computer models with big data techniques at the University of Michigan, with the university providing an additional $1.04 million.

The focal point of the project will be a new computing resource, called ConFlux, which is designed to enable supercomputer simulations to interface with large datasets while running. This capability will close a gap in the U.S. research computing infrastructure and place U-M at the forefront of the emerging field of data-driven physics. The new Center for Data-Driven Computational Physics will build and manage ConFlux.

Turbulence simulations for a vortex such as a tornado, a galaxy, or the swirls that form at the tips of airplane wings. Courtesy of Karthik Duraisamy, Aerospace Engineering.

The project will add supercomputing nodes designed specifically to enable data-intensive operations. The nodes will be equipped with next-generation central and graphics processing units, large memories and ultra-fast interconnects.

A three petabyte hard drive will seamlessly handle both traditional and big data storage. Advanced Research Computing – Technology Services at University of Michigan provided critical support in defining the technical requirements of ConFlux. The project exemplifies the objectives of President Obama’s new National Strategic Computing Initiative, which has called for the use of vast data sets in addition to increasing brute force computing power.

The common challenge among the five main studies in the grant is a matter of scale. The processes of interest can be traced back to the behaviors of atoms and molecules, billions of times smaller than the human-scale or larger questions that researchers want to answer.

Even the most powerful computer in the world cannot handle these calculations without resorting to approximations, said Karthik Duraisamy, an assistant professor of aerospace engineering and director of the new center. “Such a disparity of scales exists in many problems of interest to scientists and engineers,” he said.

But approximate models often aren’t accurate enough to answer many important questions in science, engineering and medicine. “We need to leverage the availability of past and present data to refine and improve existing models,” Duraisamy explained.

Data from hospital scans, when fed into a computer model of blood flow, can become a powerful predictor of cardiovascular disease. Courtesy of Alberto Figueroa, Biomedical Engineering.

This data could come from accurate simulations with a limited scope, small enough to be practical on existing supercomputers, as well as from experiments and measurements. The new computing nodes will be optimized for operations such as feeding data from the hard drive into algorithms that use the data to make predictions, a technique known as machine learning.

“Big data is typically associated with web analytics, social networks and online advertising. ConFlux will be a unique facility specifically designed for physical modeling using massive volumes of data,” said Barzan Mozafari, an assistant professor of computer science and engineering, who will oversee the implementation of the new computing technology.

The faculty members spearheading this project come from departments across the University, but all are members of the Michigan Institute for Computational Discovery and Engineering (MICDE), which was launched in 2013.

“MICDE is the home at U-M of the so-called third pillar of scientific discovery, computational science, which has taken its place alongside theory and experiment,” said Krishna Garikipati, MICDE’s associate director for research.

The following projects will be the first to utilize the new computing capabilities:

Cardiovascular disease. Noninvasive imaging such as MRI and CT scans could enable doctors to deduce the stiffness of a patient’s arteries, a strong predictor of diseases such as hypertension. By combining the scan results with a physical model of blood flow, doctors could have an estimate for arterial stiffness within an hour of the scan. The study is led by Alberto Figueroa, the Edward B. Diethrich M.D. Research Professor of Biomedical Engineering and Vascular Surgery.
Turbulence. When a flow of air or water breaks up into swirls and eddies, the pure physics equations become too complex to solve. But more accurate turbulence simulation would speed up the development of more efficient airplane designs. It will also improve weather forecasting, climate science and other fields that involve the flow of liquids or gases. Duraisamy leads this project.
Clouds, rainfall and climate. Clouds play a central role in whether the atmosphere retains or releases heat. Wind, temperature, land use and particulates such as smoke, pollen and air pollution all affect cloud formation and precipitation. Derek Posselt, an associate professor of atmospheric, oceanic and space sciences, and his team plan to use computer models to determine how clouds and precipitation respond to changes in the climate in particular regions and seasons.
Dark matter and dark energy. Dark matter and dark energy are estimated to make up about 96 percent of the universe. Galaxies should trace the invisible structure of dark matter that stretches across the universe, but the formation of galaxies plays by additional rules – it’s not as simple as connecting the dots. Simulations of galaxy formation, informed by data from large galaxy-mapping studies, should better represent the roles of dark matter and dark energy in the history of the universe. August Evrard and Christopher Miller, professors of physics and astronomy, lead this study.
Material property prediction. Material scientists would like to be able to predict a material’s properties based on its chemical composition and structure, but supercomputers aren’t powerful enough to scale atom-level interactions up to bulk qualities such as strength, brittleness or chemical stability. An effort led by Garikipati and Vikram Gavini, a professor and an associate professor of mechanical engineering, respectively, will combine existing theories with the help of data on material structure and properties.

“It will enable a fundamentally new description of material behavior—guided by theory, but respectful of the cold facts of the data. Wholly new materials that transcend metals, polymers or ceramics can then be designed with applications ranging from tissue replacement to space travel,” said Garikipati, who is also a professor of mathematics.

Cancer decoy could capture malignant cells and warn of relapse A small, implantable device that researchers are calling a cancer “super-attractor” could eventually give doctors an early warning

A small, implantable device that researchers are calling a cancer “super-attractor” could eventually give doctors an early warning of relapse in breast cancer patients and even slow the disease’s spread to other organs in the body.

The sponge-like device developed at the University of Michigan is designed to attract the cancer cells that emerge in the bloodstream during the early stages of cancer’s recurrence—before tumors form elsewhere in the body. A new study in mice shows that the device attracts detectable numbers of cancer cells before they’re visible elsewhere in the body. It also shows that the cancer cells spread to the lungs 88 percent more slowly in the mice that received the implants. Cancer cells also spread more slowly to the liver and other organs. The team’s findings are reported in a new paper published in the journal Nature Communications.

Researchers envision the super-attractor being implanted just beneath the skin of breast cancer patients. Doctors could monitor it using a non-invasive scan and it could enable them to detect and treat relapse sooner. It also has the potential to be used as a preemptive measure in those who are at high risk for breast cancer.

U-M Researchers construct cancer "super-attractor" scaffolds from mouse tissue, using a tumor as a control in the experimental process at the NCRC. Photo by: Joseph Xu

“Breast cancer is a disease that can recur over a long period in a patient’s life, and a recurrence is often very difficult to detect until the cancer becomes established in another organ,” said Jacqueline Jeruss, an associate professor of surgery in the U-M Comprehensive Cancer Center and an author on the paper. “Something like this could be monitored for years and we could use it as an early indicator of recurrence.”

Jeruss said the idea for the super-attractor was born from the knowledge that cancer cells don’t spread randomly. Instead, they’re attracted to specific areas within the body. So the team worked to design a device that exploited that trait.

“We set out to create a sort of decoy—a device that’s more attractive to cancer cells than other parts of the patient’s body,” explained Lonnie Shea, the William and Valerie Hall Department Chair of Biomedical Engineering at U-M and an author on the paper. “It acts as a canary in the coal mine. And by attracting cancer cells, it steers those cells away from vital organs.”

The device takes advantage of interaction that naturally takes place between cancer and the body’s immune system. Cancer co-opts the immune system, turning a patient’s immune cells into drones that gather in specific organs to prepare them for the arrival of cancer cells. The immune cells then act like a beacon in the body that attracts cancer to that location. In essence, the team has built a brighter beacon.

When the super-attractor was implanted just beneath the skin of the mice in the study, their cancer-compromised immune systems responded as they would to any foreign object, sending out cells to attack the intruder. Cancer cells were then attracted to the immune cells within the device, where they took root in tiny pores designed to be hospitable to them. The study also found that the cells captured by the implant didn’t group together into a secondary tumor, as they normally would.

Grace Bushnell, BME PhD Student, and Shreyas Rao, BME Research Fellow, look at efficacy results of the cancer "super-attractor." Photo by: Joseph Xu

“We were frankly surprised to see that cancer cells appeared to stop growing when they reached the implant,” Shea said. “We saw individual cells in the implant, not a mass of cells as you would see in a tumor, and we didn’t see any evidence of damage to surrounding tissue.

The team is evaluating non-invasive scanning technologies that could be used to monitor the device. They’re looking at ultrasound as well as a light-based technology called optical coherence tomography. Such a technology could enable doctors to detect cancer cells in the implant simply by holding a probe to a patient’s skin.

The device’s spongy structure is particularly attractive to circulating cancer cells. It’s made of an FDA-approved material that’s already widely used in surgical sutures and harmlessly dissolves in the body over time. The device implanted in the mouse study was only a few millimeters in diameter; a human-sized version might be a bit larger than a pencil eraser.

While it’s likely several years away from being used on patients, Shea believes the technology could potentially be used for other types of cancer as well, including pancreatic and prostate cancer. The device could also be an important tool in the emerging field of precision medicine, where cells captured in the device could be analyzed to identify the best therapies for individual patients. The team is now working to gain a better understanding of why cancer cells are attracted to specific areas of the body and why they’re so strongly attracted to the device. Shea believes that this information could lead to new insight into how cancer metastasizes and how to stop it.

“A detailed understanding of why cancer cells are attracted to certain areas in the body opens up all sorts of therapeutic and diagnostic possibilities,” he said. “Maybe there’s something we can do to interrupt that attraction and prevent cancer from colonizing an organ in the first place.”

The paper is titled “In vivo capture and label-free detection of early metastatic cells.” Funding was provided by the National Institutes of Health (grant number R01CA173745) and the Northwestern H Foundation Cancer Research Award. The university is pursuing patent protection for the intellectual property and is seeking commercialization partners to help bring the technology to market.