MEDx Bridging the Gap

Monday, May 14, 2018
By Mara Shurgot

LISTENING TO BLOOD: ADAPTING TECHNOLOGY TO IMAGE BLOOD VESSELS IN SKIN DISEASE

Adela Rambi G. CardonesSmall vessel vasculitis—inflammation of the small blood vessels—appears as a stain of tiny, red dots covering the skin that, depending on the severity, can evolve into painful pustules or ulcers.  In some patients, it may even reflect inflammation in internal organs.

Diagnosis usually requites a skin biopsy, which involves cutting a small piece of skin.  This can usually be done as an easy bedside procedure, although certain sites, such as areas around the nails and the tips of fingers and toes, or certain patients may be more prone to poor wound healing and complications from the procedure. 

Adela Rambi G. Cardones, MD, HS’06-‘09, associate professor of dermatology, wanted to create a device that could capture an image of at least a centimeter of skin area through a quick, non-invasive process. She wanted to detect the speed, color, and amount of blood flowing through the small blood vessels in order to make a fast, painless, accurate diagnosis. 

Junjie Yao, PhD, assistant professor of biomedical engineering, develops photoacoustic imaging: the conversion of light beamed through tissue into ultrasound waves that are then analyzed to create high-resolution images. Photoacoustic imaging can reveal a tissue’s anatomical, functional, and metabolic properties, with specificity at the molecular and neuronal level.

Cardones and Yao teamed up to create a handheld device that could provide high-resolution imaging of the tiny blood vessels in the skin to diagnose vasculitis. One of the key design inspirations came from, of all places, the supermarket.

“We were inspired by the handheld devices that scan bar codes in grocery stores,” says Yao. “The devices use a polygon mirror and a laser diode to quickly ‘read’ the product information, and we adapted this concept to build a prototype handheld photoacoustic device to ‘read’ the skin. We printed a 3D polygon mirror, added a laser and an ultrasound transducer, and then put everything in waterproof frame to detect the emitting ultrasound signals.”

The lightweight, handheld prototype is about the size of a flashlight. With their photoacoustic imaging device, Cardones and Yao can provide functional sampling of the skin—a photoacoustic biopsy—that clearly identifies the organization and oxygenation of tiny blood vessels in the tissue.

With functional imaging of up to 13 mm across and 5 mm in depth, there are numerous other potential applications of their device, such as the study of skin tumors, brain disorders, and eye diseases. 

Cardones and Yao hope to win IRB approval and begin clinical testing of their device. Beyond that, they see potential for commercialization and will be working with MEDx and the FDA to navigate the process of safety testing and bringing the device to market.

 

MIMICKING THE HUMAN PLACENTAL BARRIER

The United States has one of the highest rates of preterm birth—up to 10 percent of all pregnancies—in the world. And many pregnancy complications, such as pre-eclampsia, which contributes to preterm birth, are associated with abnormal placenta development.

“One of the reasons we don’t understand pregnancy well is that we don’t understand the human placenta, which is extremely complex,” says Liping Feng, MD, assistant professor of obstetrics and gynecology, who studies pregnancy complications and improving pregnancy outcomes. “The placenta is one of the most under-studied organs because we lack a model for research.”

Nutrients, oxygen, immunoglobulins, and waste all pass through the placenta.  

Researchers have been stymied by the absence of an effective placental research model. Attempts to develop an in vitro model of the placenta that mimics its unique cellular properties have been unsuccessful, and ethical considerations prevent researchers from using the placenta in vivo. And because it’s a dynamic organ, developing throughout gestation, placentas collected after birth can’t be used to model placental dynamics.

To address this challenge, Feng aimed to create a novel placenta model that would enable researchers to better understand the organ, the cellular interface, and the transport of nutrients and foreign components from the mother to the fetus.  Sallie Permar, MD, PhD, professor of Pediatrics, was also interested in the idea for her research in the transfer of both protective maternal antibodies and harmful pathogens to the fetus.

Permar’s team researches maternal and infant immune systems and strategies to prevent the transmission of viral and environmental pathogens between mother and child.

Feng approached George Truskey, MD, PhD, the R. Eugene and Susie E. Goodson Professor of Biomedical Engineering, because of his expertise in microfluidics—the manipulation of small amounts of fluid—and his pioneering research in engineering model tissues and blood vessels.

Truskey’s lab has developed a polycarbonate membrane that is seeded with placental cells drawn from patients who have had a C-section and given consent for a research donation of the placenta.  A channel above and below the membrane allows the researchers to draw fluid across at a very low rate, mimicking blood flow through an active placenta. Ultimately, they wish to dissect the route that molecules and virus particles take as they travel between mother and fetus.

A placenta model would serve multiple purposes. Researchers could study both normal function and disease states; better understand the mechanism of viral transmission, such as Zika, cytomegalovirus (CMV), and HIV; study immune regulation and nutrient transfer; and environmental toxicology.  “A system such as this “microfluidic placenta on a chip” is critical for researchers to understand how to optimally protect and nurture a developing fetus, and the design of strategies to avoid some of the perils of pregnancy, including congenital infections, adverse exposures, and preterm birth” says Permar.

 

BUILDING A BETTER BRAIN

Like a team in a science fiction movie, the six-lab squad funded by a 2017 MEDx Biomedical research grant is striking in its combination of diverse skills and duties.

The project is led by Kafui Dzirasa, MD’09, PhD’07, HS’10-’16, associate professor of psychiatry and behavioral sciences and assistant professor in neurobiology and neurosurgery; and Nenad Bursac, PhD, professor of biomedical engineering and associate professor in medicine. Their team includes: Marc Caron, PhD, James B. Duke Professor of Cell Biology, professor in neurobiology and medicine; Fan Wang, PhD, professor of neurobiology; Christopher Kontos, MD, HS’93-’97, professor of medicine and associate professor of pharmacology and cancer biology—all at Duke University School of Medicine—and Jennie Leach, PhD, associate professor of chemical, biochemical, and environmental engineering at the University of Maryland Baltimore County, along with a cadre of committed graduate students, postdocs, and technicians.

Dzirasa’s background in engineering informs his approach to the study of neuropsychiatric illness and disease. In the summer of 2016, he and members of his lab were discussing the challenge of precisely monitoring brain activity.

“We do not have the technology to monitor individual neurons interacting with each other on a large scale in real-time,” says Dzirasa. “All of our existing tools have limitations. We wanted to fundamentally change the paradigm of how information is taken out of—and put back into—the brain.”  

Their question was: what is the best type of sensor to more accurately assess brain activity? Their answer: the brain. Their quest: build a biological brain that can monitor, activate, and potentially repair or enhance cell function in various parts of the brain.

“What we imagine is a framework made of biological material that’s powered by blood, nutrients, and oxygen, and this framework will connect to the brain and to the outside world,” Dzirasa says. “It will be like a brain connection patch.”

Bursac’s experience using proteins to transfer electricity from one cell to another will inform the creation of the base, or “substrate” of the brain. “How cells electrically communicate within this system will be very important,” says Bursac.

Wang has experience in calcium imaging, which allows visualization of a large number of cells simultaneously, and Caron’s experience altering genes informs the understanding of neuronal communication. Kontos studies how blood vessels create new extensions, and his job is to explore how to vascularize the brain sensor to keep it alive. Last but not least, Leach was brought in for her expertise in building biomaterial frameworks that can keep cells that sense electricity alive. 

Elizabeth Ransey, PhD, a postdoc with a background in biochemistry, coordinates the teams’ efforts.

Dzirasa imagines their project primarily in the context of understanding and treating disease and injury. Patients with psychiatric disorders and neurological illnesses such as depression and Alzheimer’s would be ideal candidates.   

But another possibility involves the question of how human brains interface with computers.

“As it stands now, our brains interact with computers all the time, but we’re limited by pressing the buttons on our cell phone or typing on a keyboard,” Dzirasa says. “What if we could speed up the information transfer so that information can go directly into the brain, bypassing the eyes and ears? That’s a little bit more on the sci-fi side, but that future is not far off.”

The hope is to have a fully functioning prototype within the next two to three years. What will it look like? 

“We haven’t figured that part out yet,” Dzirsa admits. “We’re bringing in the designers next. Nobody wants two heads.”

 

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