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.

Toward a stem cell model of human nervous system development Human cells could one day show us more about why neural tube birth defects occur and how to prevent them.

Human embryonic stem cells can be guided to become the precursor tissue of the central nervous system, research led by the University of Michigan has demonstrated. The new study also reveals the important role of mechanical signals in the development of the human nervous system.

While studying embryonic development using animal embryos can provide useful insights about what happens during human development, human embryos grow differently even at this early stage.

“There is a critical need to establish embryonic developmental models using human cells. Not only could they advance our fundamental understanding of human development, they are also essential for regenerative medicine and for testing the safety of drugs and chemicals that pregnant women may need or encounter,” said Jianping Fu, an associate professor of mechanical engineering, who has been supervising this research.

“For the first time, we are able to use human embryonic stem cells to develop a synthetic model of neuroectoderm patterning, the embryonic event that begins the formation of the brain and spinal cord in the human embryo.”

There is a critical need to establish embryonic developmental models using human cells.Jianping Fu, associate professor of mechanical engineering.

In humans, the cells that will later differentiate into the central nervous system (including the brain and spinal cord) are known as the neural plate, while those that stand between the neural plate and future skin cells are called the neural plate border. The neural plate folds in on itself about 28 days after conception, becoming the neural tube, and the border on either side of it fuses together along its length. When the neural tube fails to close properly, it typically results in paralysis or death.

“The exact causes of neural tube defects are not clear, and there is currently no cure for them. Environmental factors, such as certain drugs pregnant women take, may play roles in causing neural tube defects,” said Fu.

In the new study, Fu’s research team arranged human embryonic stem cells into circular cell colonies with defined shapes and sizes. The cells were then exposed to chemicals known to coax them to differentiate into neural cells. During the differentiation process, cells in circular colonies organized themselves with neural plate cells in the middle and neural plate border cells in a ring around the outside.

“Since all of the cells in a micropatterned colony are in the same chemical environment, it’s amazing to see the cells autonomously differentiate into different cells and organize themselves into a multicellular pattern that mimics human development,” said Xufeng Xue, a PhD student in mechanical engineering working in Fu’s research group.  Xue is a co-first author of the paper.

Disc-shaped colonies shown with phase contrast (top) and fluorescence (bottom) microscopy. Between day 3 and day 9, cells in the center of the colony grow faster and become much more densely packed. Confined space drives the cells in the center of the colony to become neural plate cells, whereas those cells at the colony border (experiencing less confinement) differentiate into neural plate border cells. Image: Xufeng Xue, Integrated Biosystems and Biomechanics Laboratory, University of Michigan.

 

Fu’s team observed that cells in the circular colony became more densely packed in the middle of the colony, where they became neural plate cells, versus the colony border, where they became neural plate border cells. Suspecting mechanical signals might affect their differentiation, they placed single human embryonic stem cells onto adhesive spots of different sizes.

In the same chemical environment, single human embryonic stem cells grown on larger spots began signaling events within the cells that drove them toward becoming neural plate border cells. These signaling events were inhibited in stem cells confined on smaller spots. The team also developed a system to stretch cells in the middle of a colony. Responding to this mechanical signal, the cells in the middle of a colony differentiated into neural plate border cells, rather than the neural plate cells at the center of an ordinary colony.

“While many current models attribute patterning of embryonic tissues to chemical gradients or cell migration, our results show that these factors may not be the only drivers,” said Yubing Sun (ME PhD ’15), a former doctoral student in Fu’s lab and now an assistant professor of mechanical and industrial engineering at the University of Massachusetts, Amherst. Sun is a co-first author of the paper.

The study, titled, “Mechanics-guided embryonic patterning of neuroectoderm tissue from human pluripotent stem cells,” is published in Nature Materials.

This work was supported by the National Science Foundation (grant numbers CMMI 1129611, CBET 1149401and CMMI 1662835), the American Heart Association (grant number 12SDG12180025) and the U-M Department of Mechanical Engineering.

Fu is also an associate professor of biomedical engineering, cell and developmental biology, and is an associate director of the Michigan Center for Integrative Research in Critical Care.

Credits:

Lab-grown lung tissue could lead to new cancer, asthma treatments A look at how Michigan Engineers created a biomaterial scaffold to help researchers from the U-M Medical School grow mature human lung tissue.

In a breakthrough that could one day lead to new treatments for lung diseases like asthma and lung cancer, researchers have successfully coaxed stem cells—the body’s master cells—to grow into three-dimensional lung tissue. This could be useful in future cell-based therapies that repair damaged lungs by cultivating new, healthy tissue.

University of Michigan researchers grew the tissue by injecting stem cells into a specially developed biodegradable scaffold, then implanting the device in mice, where the cells grew and matured into lung tissue. The team’s findings were published in the Nov. 1 issue of the journal eLife.

Briana Dye, a PhD candidate in Cell & Developmental Biology at the University of Michigan Medical School, demonstrates the process of developing lung organoid tissue samples. This research was conducted partly in the lab of Lonnie Shea, the William and Valerie Hall Department Chair and Professor of Biomedical Engineering. Photo: Evan Dougherty, Michigan Engineering Communications & Marketing

Respiratory diseases account for nearly 1 in 5 deaths worldwide, and lung cancer survival rates remain low despite numerous therapeutic advances during the past 30 years. Cell-based therapies could be a key to improving treatment, helping damaged lungs heal in much the same way as a bone marrow transplant can treat leukemia. But the complexity of lung tissue makes such treatments much more difficult to develop.

“Lung tissue needs to be able to form into specific structures like airways and bronchi, and they all need to be able to work together inside the lung. So we can’t just add in healthy adult cells,” said Lonnie Shea, the William and Valerie Hall Department Chair of Biomedical Engineering and a professor of biomedical engineering at U-M. “Instead, we’re looking at delivering the precursors to these cells, then giving them the cues they need to develop and mature on their own. This project was a step in that direction.”

While previous experiments had successfully grown lung cells, the cells were immature and disorganized. So Shea worked with a U-M medical school team led by Briana Dye, a graduate student in the U-M Department of Cell and Developmental Biology, on a new approach. They developed a three-dimensional, biodegradable scaffold that helped the lung cells mature and begin to develop into structures like those inside an actual lung.

Made of PLG, a spongy, biodegradable material, the scaffold was shaped like a small cylinder approximately five millimeters wide and two millimeters tall. The team injected stem cells into the scaffold, transplanted it into mice, then allowed the cells to mature for eight weeks.

The scaffold provided a stiff structure that supported growth of the mini lungs after transplantation while still allowing the transplanted tissue to become vascularized, growing blood vessels that supplied it with nutrients.

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When the team examined the tissue, they found that it had not only survived, it had developed tube-shaped airway structures similar to the airways in adult lungs. It also developed mucus-producing cells, multiciliated cells and stem cells similar to those found in adult lungs.

“In many ways, the tissue grown in the study was indistinguishable from human adult tissue,” says senior study author Jason Spence, Ph.D., associate professor in the U-M Department of Internal Medicine and the Department of Cell and Developmental Biology at the U-M Medical School.

The researchers caution that they’re far from growing anything like a complete human lung—the tissue grown in the experiment was a mass of lung cells scattered among other types of cells inside the scaffold. But they say it’s an important early step that can yield valuable information about how healthy cells grow and develop. In the future, that could lead to new treatments for lung disease.

Richard Youngblood, a second year PhD student in Biomedical Engineering at the University of Michigan, demonstrates the construction of a lung organoid PLG scaffold. This research was conducted partly in the lab of Lonnie Shea, the William and Valerie Hall Department Chair and Professor of Biomedical Engineering. Photo: Evan Dougherty, Michigan Engineering Communications & Marketing

“What if we could regrow a portion of a damaged lung, like a patch?” Shea said. “Treatments like that, while challenging, may be possible.”

The lung tissue is one of several types of cultured organ tissue, or “organoids” that U-M research teams have developed—other cell types they’ve created include intestines, pancreatic cells and placenta cells. In addition to their uses in developing new cell-based therapy, Shea says the cells can provide a human model for screening drugs, studying gene function, generating transplantable tissue and studying complex human diseases like asthma.

“Organoids enable us to see the development and formation of an organ without having to conduct a test on an entire organism. And once we understand that, we can find new ways of repairing organs that are injured, or that haven’t developed properly.”

The paper is titled “A bioengineered niche promotes in vivo engraftment and maturation of pluripotent stem cell derived human lung organoids.” The research was supported by the National Institutes of Health (grant number R01 HL119215), by the NIH Cellular and Molecular Biology training grant at Michigan and by the U-M Tissue Engineering and Regeneration Training Grant.

Credits:

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).

U-M leads major new regenerative medicine center funded by NIH

ANN ARBOR—A new interdisciplinary health sciences resource center at the University of Michigan has received an $11.7 million award from the National Institutes of Health to advance regenerative medicine.

The center, led by the School of Dentistry, brings together scientists, engineers and clinicians from several U-M departments in collaboration with researchers at the University of Pittsburgh, Harvard University and private companies.

They will investigate new ways to restore dental, oral and craniofacial tissues lost to disease, injury or congenital disorders. Technologies advanced in these areas could lead to tissue engineering applications for other parts of the body as well.

The research, funded by the National Institute of Dental and Craniofacial Research, involves U-M collaborators from the Medical School, School of Public Health, College of Pharmacy, College of Engineering, Office of Technology Transfer and Michigan Institute for Clinical and Health Research. Other co-investigators are from the McGowan Institute at Pittsburgh and the Wyss Institute for Biologically Inspired Engineering at Harvard.

The center is named the Michigan-Pittsburgh-Wyss Resource Center: Supporting Regenerative Medicine in Dental, Oral and Craniofacial Technologies. The three universities have committed financial support in addition to the $11.7 million NIH award to create a project total of about $14 million.

The U-M-based resource center is one of two announced today by the NIDCR. The other is based at the University of California, San Francisco. The combined NIH awards total $24 million over three years.

The collaboration of the Michigan, Pittsburgh and Harvard researchers came out of an initial one-year organizational phase funded with a previous NIDCR planning grant. The new funding supports a second, three-year phase during which investigators will evaluate and select research projects that have the most scientifically sound, clinically applicable and commercially viable strategies for the regeneration of dental, oral and craniofacial tissues.

The resource center will match the projects with engineering, biological, manufacturing, commercial and regulatory expertise from the clinical, academic and private sectors in order to more efficiently translate discoveries into clinical practice.

Regenerative medicine refers to research that integrates engineering and biology, seeking to regenerate damaged cells, tissues or organs to their full function, such as finding ways for the body to heal wounds faster or to repair bone that has been damaged.

Research strategies can be material-based, cell-based and drug delivery, or combinations of those. Some of the current material-based research in the craniofacial area, for example, uses tiny polymer-based scaffolds that are implanted to promote the growth of damaged bone or periodontal tissue that supports teeth or tooth replacement dental implants.

Project directors and principal investigators at the School of Dentistry are David Kohn, professor in the school’s Department of Biologic and Materials Sciences and also professor of biomedical engineering at the College of Engineering, and William Giannobile, the William K. and Mary Anne Najjar Professor of Dentistry and chair of the Department of Periodontics and Oral Medicine, and professor of biomedical engineering at the College of Engineering.

Laurie McCauley, dean of the School of Dentistry, said the resource center has assembled a strong team poised for important breakthroughs in this quickly evolving field.

“Drs. Kohn and Giannobile have established a multidisciplinary group with a robust plan that will build on Michigan’s success in basic tissue engineering and training to achieve transformative approaches in regenerative medicine,” she said.

Kohn said this three-year phase will be a period of investigating many aspects of each project.

“The purpose of the center is to vet technologies,” he said. “And not only vet them scientifically but vet them clinically: Is this scaffold going to solve a compelling clinical problem? Vet them in terms of manufacturing: Can this be manufactured? Can it be manufactured to FDA standards? Vet them in terms of commercialization: Is anyone going to invest and buy this?

“We might prove in a small clinical study that something is effective, but it’s not going to get out to the masses unless a company or investors decide to pursue the technology. So we’re talking about vetting in all those different sectors.”

Giannobile said U-M is uniquely positioned to lead the center. The funding application notes that U-M is the only university in the country with Top 10-ranked dental, medical and engineering schools on the same contiguous campus, which makes it easier for interdisciplinary collaboration in tissue engineering and regenerative medicine.

“There are so many excellent independent investigators here at U-M with individual grants and patents in regenerative medicine,” Giannobile said. “We feel fortunate that we were able to coalesce many different groups from around the university that could really help spearhead regenerative medicine at Michigan with this type of larger, programmatic grant.

“It’s oral, dental and craniofacial research, but certainly this will serve as a bridge to other parts of the body—the musculoskeletal system, bone regeneration, soft tissue, nerve, other structures—because what we learn in the all-important head and neck area will apply to other areas as well.”

Joining Kohn and Giannobile as project directors and principal investigators are Charles Sfeir and William Wagner of the University of Pittsburgh and David Mooney of Harvard.

The project includes two key private-sector contributors—the McGuire Institute of Houston, with extensive experience in practice-based clinical research in regenerative oral and periodontal medicine, and the Avenues Company of Flagstaff, Ariz., a marketing consulting firm focusing on clinical and business development strategies in regenerative dentistry.

NIDCR is one of 27 institutes and centers under the umbrella of the National Institutes of Health. NIH is part of the Department of Health and Human Services.

The new Michigan and California centers are part of the NIDCR’s Dental, Oral, and Craniofacial Tissue Regeneration Consortium, an initiative designed to shepherd new therapies through preclinical studies and into human clinical trials. The ultimate goal is to develop strategies and devices that could help repair or regenerate damaged tissues such as craniofacial bone, muscle and blood vessels, nerves, teeth and salivary glands.

“By establishing this research consortium, NIDCR seeks to lead national efforts to accelerate the translation of promising dental, oral and craniofacial regenerative medicine therapies into the clinic,” said NIDCR Director Martha Somerman. “The consortium is designed as a model for optimizing translation of scientific advances in this field.”

More information:

One Lab, Three Approaches to Restoring Ovarian Function Ariella Shikanov

By Aimee Balfe

BME Assistant Professor Ariella Shikanov has just received an NSF CAREER award to help fund one of the three approaches her lab is taking to help restore ovarian function in women and girls undergoing treatment for cancer and autoimmune disease that is toxic to the ovaries.

While physicians can freeze a woman’s eggs, allowing her to later have a biologically related child, the process isn’t suitable for some patients, including young girls. It also doesn’t address the issue of ovaries’ endocrine function. “Ovaries are not only about making babies,” says Shikanov, “they also produce estrogen, progesterone, and other hormones that are very important for the health of a woman’s bones, cardiovascular system, and skin.”

“Ovaries are not only about making babies…they also produce estrogen, progesterone, and other hormones that are very important for the health of a woman’s bones, cardiovascular system, and skin.” Shikanov

They’re also essential for enabling girls to go through puberty. Girls who’ve lost ovarian function require synthetic hormones, whose long-term use carries a health risk. In addition, the dosage has to be just right. Too little and the girls won’t grow sufficiently. Too much and the bones’ growth plates close prematurely. Without optimal dosing, the girls are at increased risk for various bone, cardiovascular, and metabolic problems like diabetes and obesity.

The Path to U-M

shikanovShikanov would become captivated by this issue and begin down a road that would lead her from the Hebrew University in Jerusalem to U-M via a postdoctoral fellowship in the lab of Lonnie Shea. Then at Northwestern, and now U-M’s William and Valerie Hall Chair and Professor of BME, Shea had been working on ovarian tissue engineering and needed a postdoc with expertise in polymer synthesis and hydrogel development. Shikanov, a medicinal chemist by training, had the right skill set.

“He told me, ‘Don’t worry; you’ll learn about reproduction,’” she says. Over the next four years, she found herself doing surgeries in mice, looking for ways to make ovarian tissue transplantation more successful, and developing synthetic culture environments for ovarian follicles – the structures that contain immature eggs and are essential to endocrine function.

The latter offered an intriguing engineering challenge. “We had to design a hydrogel that would be soft enough not to kill an ovarian follicle, but rigid enough to support its 3D structure as it matures and expands 100 times in volume,” she says. “It also had to be physiologic, allowing the diffusion of nutrients and oxygen.”

“We had to design a hydrogel that would be soft enough not to kill an ovarian follicle, but rigid enough to support its 3D structure as it matures and expands 100 times in volume” Shikanov

She was deep in this work when U-M announced a cluster-hire position in reproductive biomaterials that precisely matched her expertise. She was hired in 2012, launching a lab that would address ovarian function through three distinct but mutually reinforcing projects.

The Projects

Restoring endocrine function in girls

Shikanov’s first project aims to restore endocrine function in girls with damaged ovaries, allowing them to undergo physiologic puberty. She is developing an implant that encapsulates donor ovarian tissue in an immunoisolating hydrogel. Injected under the skin, it won’t restore fertility but would stimulate the production of estrogen at this critical time.

“Puberty starts in the brain,” says Shikanov. “The hypothalamus secretes a hormone, which stimulates the pituitary gland to secrete follicular stimulating hormone, which tells the ovarian tissue to secrete estrogen. Then the estrogen goes back to the brain, controlling things through a finely tuned loop. This is what allows us to go through puberty, and this why it is so important to have a healthy and functioning ovarian tissue that we aim to engineer.”

With a grant from The Hartwell Foundation, her lab has already demonstrated in mice that the process works and that its longevity is determined by the number of follicles implanted. She plans to move to larger animal models before testing the product in humans.

Understanding how ovarian follicles develop

Shikanov’s second project, for which she won her CAREER award, aims to understand the cell signaling involved in the development of ovarian follicles so she can design better culture systems for harvested tissue.

Harvesting of immature ovarian follicles holds promise for restoring fertility when a woman can’t freeze her eggs – either because she doesn’t have time to undergo ovarian stimulation prior to starting treatment or because she has a hormone-driven cancer where stimulation would be inappropriate. The problem has been getting follicles to survive and mature in culture.

The reason for this, says Shikanov, is that follicles’ essential signaling networks are poorly understood. “Right now, we know that follicles grow best when they’re co-cultured with other follicles and stem cells, but we don’t know why.”

She hopes to remedy this through mechanistic studies of folliculogenesis. Using transcription factor reporters, metabolomics, and systems biology, she aims to reveal the identity, timing and activity pattern of secreted growth factors and transcription factors that allow follicles to grow.

During the project, she plans to continue collaborating with Lonnie Shea, as well as with BME computational modeling expert David Sept, new faculty member Kelly Arnold, and U-M’s metabolomics core, MRC2.

She will start the experimental work in mice, but hopes to move to human tissue in a matter of years. “I want to get to the point where I can take one follicle and say, if I add this list of factors at these concentrations in this timing sequence, I will be able to grow the follicle without adding other follicles or cells,” she says.

Designing an artificial ovary
engineering-ovary
Her final project is the design of an artificial ovary. This involves encapsulating the smallest, primordial follicles in a synthetic polymer that mimics the ovaries’ natural environment with the goal of restoring both fertility and endocrine function. She expects that her mechanistic studies will offer substantial insights to this work.

Shikanov says her research is extremely gratifying, and she enjoys introducing it to young people, especially women, through camps and programs for middle and high schoolers. In addition, her lab is always seeking talented postdocs interested in learning more about biomaterials in reproductive sciences. She can be contacted at shikanov@umich.edu.

New Michigan Regenerative Medicine Center Formed

 
The University of Michigan School of Dentistry is one of 10 institutions in the country that has been selected by the National Institute of Dental and Craniofacial Research (NIDCR) to establish a center that will develop clinical applications in tissue engineering and regenerative medicine that have dental, oral and craniofacial tests.

The Michigan Regenerative Medicine Resource Center, as it’s official known, will be led by Drs. William Giannobile and David Kohn.  Their education and expertise complement each other – Giannobile’s as a clinician/life scientist; Kohn’s as an engineer.  Giannobile chairs the school’s Department of Periodontics and Oral Medicine.  Kohn is a professor in the school’s Department of Biologic and Materials Sciences and a professor in the Department of Biomedical Engineering at the College of Engineering.

“The center will transform how clinicians in the not-too-distant future repair, reconstruct and regenerate dental, oral and craniofacial anomalies in patients due to injury or disease,” Giannobile says.  “In recent years there have been major discoveries and advances in dentistry, medicine, biology, materials science, technology and other fields, and NIDCR wants the Michigan Center and similar centers around the country to find ways to use those advances so clinicians can then apply those discoveries to help their patients.”

Above are three-dimensional printed polymer scaffolds designed to promote bone and periodontal repair in the oral cavity. The design offers the potential to regenerate the different tissues teeth needed to treat teeth that have lost support due to the periodontal disease process. Photo by Jerry Mastey

Above are three-dimensional printed polymer scaffolds designed to promote bone and periodontal repair in the oral cavity. The design offers the potential to regenerate the different tissues teeth needed to treat teeth that have lost support due to the periodontal disease process. Photo by Jerry Mastey

Above are three-dimensional printed polymer scaffolds designed to promote bone and periodontal repair in the oral cavity. The design offers the potential to regenerate the different tissues teeth needed to treat teeth that have lost support due to the periodontal disease process. Photo by Jerry Mastey

Above are three-dimensional printed polymer scaffolds designed to promote bone and periodontal repair in the oral cavity. The design offers the potential to regenerate the different tissues teeth needed to treat teeth that have lost support due to the periodontal disease process. Photo by Jerry Mastey

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Crucial to achieving that objective, Kohn says, will be establishing teams of multidisciplinary and interdisciplinary specialists from across the University of Michigan, industry and private practice.  “These teams will be dedicated to selecting the most scientifically sound, clinically and commercially applicable strategies to regenerate oral tissues,” he says.

Historically, Kohn says, discoveries in a laboratory have progressed in a linear fashion, that is, they move forward one step at a time before being commercialized and used clinically.  “We want to change that approach,” Kohn adds.  “Our teams will take discoveries that show promise and provide the resources to advance the technologies to apply them more quickly than in the past.”  This approach, he adds, is uniquely suited to Michigan’s broad scientific, clinical and engineering strengths, and interdisciplinary culture.

Giannobile says clinical teams will work with technical advisory groups and data centers to assess what might be feasible clinically.  In the past, he says, scientists and clinicians have not always communicated to take advantages of scientific advances that can be used by dentists in a patient care setting.

Among the groups that will help the Michigan Regenerative Medicine Resource Center will be the Wyss Institute at Harvard, a multidisciplinary research institute that focuses on developing new materials with applications in health care, manufacturing and other areas, and the McGuire Institute in Houston which focuses on delivering clinical applications based on research using new or improved technologies.

The center was established with a $125,000 grant from NIDCR, the first step in what will be a two-step process.  The next step involves submitting a proposal that could possibly lead to funding for as much as $10 million, sometime next summer.

- See more at: http://dent.umich.edu/news/2015/10/14/new-michigan-regenerative-medicine-center-formed#sthash.1i4hOOSf.dpuf