June 25, 2012
Dan Huh recognizes great engineering when he sees it. The precision workings of everything from engines to insects to the tiniest portion of an organ in the body, give him inspiration for solving bioengineering conundrums.
It started with automobiles. For his undergraduate thesis, 2012 SLAS Innovation Award winner and 2012 SLAS Asia Conference and Exhibition speaker Dan Dongeun Huh, Ph.D., studied car engines. After receiving a bachelor's degree in mechanical engineering from Seoul National University, Seoul, South Korea, in 2000, Huh worked as a research assistant on a glaucoma project and gained an introduction to biomedical engineering, which set the course for his current work.
"A doctor in the university hospital noticed that the density of epithelial cells lining corneal tissue was reduced dramatically in patients who received a surgically implanted shunt to relieve pressure in the eye chamber caused by glaucoma," Huh explains. "The research team suspected that the reduction in pressure during the drainage of fluid from the eye chamber was related to the reduction in the cells, but they didn't have a good model system for testing their hypothesis." Huh used a computational simulation tool to figure out what was happening. He developed an interest in microfluidics while working in these small areas of the body. This interest eventually led Huh to the University of Michigan, Ann Arbor, MI, where he began conducting research on microfluidics. While at UM, Huh earned master's degrees in biomedical engineering and mechanical engineering in 2001 and 2003, respectively, and a Ph.D. in biomedical engineering in 2007.
"When I came to the U.S., I joined the research laboratory directed by Shuichi Takayama in the Department of Biomedical Engineering at the University of Michigan. Takayama had been trained by George M. Whitesides at Harvard University, Boston, MA. Working in his lab, I was introduced to these microtechnologies and microengineering tools for cell biology," Huh continues. Not only did he enjoy his increased knowledge in biomedical engineering, he was fueled by the collaboration of the many scientific disciplines that the work required.
In 2007, Huh became a postdoctoral research fellow in the lab of Donald E. Ingber, M.D., Ph.D. in Harvard Medical School and Children's Hospital Boston. Ingber is a founding director of the Wyss Institute for Biologically Inspired Engineering. "When I came on board there was a joint project between our lab and George Whitesides' lab," Huh says. In this joint project, Huh was challenged to microengineer a system that would allow researchers to look at the toxicity of nanoparticles in the environment or in commercial products on human lungs. To meet this challenge, Huh devised a simple device containing transparent microscopic channels lined with human lung cells and capillary cells to mimic the functional units of the living human lung called alveoli. Huh continued this work as a Research Associate at the Wyss Institute where he further improved and refined the microdevice into a human breathing lung-on-a-chip system that Huh presented at SLAS2012.
For Huh, meeting challenges requires one of two approaches: perseverance or taking a purposeful pause. "It depends on your situation," he reasons. "While perseverance is good for tackling challenges, it sometimes helps to step away from a problem to get some perspective."
Taking a walk and pondering the situation is what works for Huh. "I constantly think about problems that I am working on in my research. Sometimes I do need some time away, but I cannot help thinking about them. Exercise helps! It gives you time to refresh your brain," he says.
The arrival of his son, Joshua, however, has cut short some of his free time for the past two years. "Actually, I don't have any free time!" he laughs. "My free time is spent taking care of my son and playing with him."
Even at this tender age, Joshua, seems to be following in his father's footsteps with an intense interest in mechanical things. "I guess it runs in the blood," he says. "He really loves wheels, cars, trains. He gets really excited looking out the car window at other cars and trucks we pass." Huh said that his parents recount similar stories from his own youth, sharing that once, while still very young, he took apart the family's stereo system.
The magic of design continues to captivate his attention. "I look for solutions using unconventional approaches, such as how the body or nature works. That's one approach that really inspires for me. Also talking with clinicians, biologists and people from diverse backgrounds gives me solutions, as well. The institution in which I work gives me a very multidisciplinary, collaborative environment. I think companies and universities are realizing that creating this kind of environment is crucial for fostering collaboration between people with different backgrounds."
One of his collaborators is 2010 SLAS Innovation Award winner Ali Khademhoessini, a good friend and colleague at Wyss Institute. Huh described him as one of the leaders in the field. "He has done a lot of interesting work and is one of the pioneers in applying microtechnologies to tissue engineering and cell biology," he says.
The work at Wyss Institute requires scientists to turn to natural design for inspiration. "The idea is to learn from nature and its basic design principles to build and control living biological systems," Huh explains. "We use this new knowledge to develop new devices and materials for biomedicine." He frequently browses the Internet and the local book sellers for information on plant and insect design.
One book he read last year was Biomimicry: Innovation Inspired by Nature by Janine Benyus. The book examines how science is studying nature's best ideas to solve the 21st-century's toughest problems. Photosynthesis, brain power and shells are just a few of evolution's discoveries that the text reveals may help the human race. These natural designs, according to the author, impact how we invent, heal, harnesses energy, repair the environment and feed the world.
"A lot of intriguing biological systems are out there. We can learn from them to develop new and better engineering systems. This is something that I started studying in the free time that I do have," Huh says.
"Design principles found in nature or books describing such examples are very helpful in designing innovative engineering systems for a variety of applications, especially for biomedical applications. Some of those ‘smart' systems in nature give me new and creative ideas on how to design and build new types of engineering systems," Huh explains. He offers capturing and clearing environmental particulates in large airways or enabling efficient blood oxygenation deep in the lung as examples. "I think nature provides us with remarkable examples of clever engineering designs and sustainable solutions to many problems we are facing today," he states.
During his Ph.D. studies, Huh and his colleagues created a microchip to model small areas in the lung that mimicked what happens in the body. "We used the system to look at the mechanical injury of lung cells under pathological conditions such as asthma or pulmonary edema," Huh explains. "Clinical observation reveals that small liquid plugs form to block the airway tube. Under normal conditions, air flows in and out of the tube, but when these plugs form, the airways get blocked. When you breathe, these liquid plugs move and gradually become shorter and rupture, reopening the closed area. During this process, people thought that there were high levels of mechanical stress being generated by the fluids from the rupture of these small liquid plugs," he continues.
Huh further developed the microsystem using human cells to model the alveolar-capillary interface of the human lung and then exposed it to cyclic mechanical strain and fluid dynamic forces that mimic breathing and blood flow. Huh shares that the research team was inspired by how breathing actually works in the body. "When you breathe in, your chest cavity becomes large and as a result the pressure in the chest cavity is reduced to subatmospheric pressure. Because of this pressure difference, the alveolar air sacs expand and air is sucked into the lungs," he explains. "This mechanism inspired us. We stretched the two layers we form in the microfluidic channel using a vacuum. I was trying to achieve dynamic cell stretching using different methods." "We can also flow different test materials over the surface of cells to mimic stress in blood vessels and exposure of lung cells to different environmental particulates or toxins," Huh explains. The resulting system led to his 2012 SLAS Innovation Award-winning podium presentation, A Human Breathing Lung-on-a-Chip for Drug Screening and Nanotoxicology Applications.
The device reproduces complex integrated organ-level responses to bacteria and inflammatory cytokines introduced into the alveolar space by inducing expression of intercellular adhesion molecule-1 (ICAM-1) on the microvascular endothelium surface, adhesion of circulating blood-borne neutrophils, their transmigration across the capillary-alveolar interface and phagocytosis of the infectious pathogens, which can be visualized using real-time, high-resolution microscopy.
Using this approach, Huh and the research team developed novel nanotoxicology models and revealed that physiological cyclic mechanical strain greatly accentuates toxic and inflammatory responses of the lung to silica nanoparticles by promoting rapid release of reactive oxygen species by alveolar epithelial cells and upregulating endothelial ICAM-1 expression. Mechanical strain also enhances nanoparticle uptake by the epithelial cells and stimulates their transport into the underlying microvasculature.
Huh faced a very different challenge while developing the device. He had to consider how these microsystems could be used in biomedical applications. The desire to use the system for broader applications led Huh to talk with clinicians, biologists and chemists engaged in biomedical work.
"Talking with clinicians really helped," Huh observes. "They provided me with insights as to how these microengineered systems could be useful for biomedical applications. Now we are at a stage where we hope to leverage this technology for drug development and toxicology screening applications. We're trying to improve and modify the Lung-on-a-Chip system to make human disease models."
Huh reports that the presentation at SLAS2012 resulted in many inquiries. "Major pharmaceutical companies asked about potential opportunities to work with us. It was a pleasant surprise. I didn't think they would be interested in advanced technologies," he reports. "The bottom line is, these companies are in dire need of drug-testing technology that will allow for more accurate, inexpensive and rapid screening of drug compounds."
Many preclinical drug studies depend on simple-cell culture models in which human cells are cultured in a plastic dish, drug compounds are introduced and scientists review what happens to the cells. Other studies use animal models.
"The conventional models have many limitations for drug-testing purposes and animal models are not very predictive of human responses. These companies have been looking for a new drug-testing platform for many years," says Huh. When he made his presentation, many in the industry saw the potential in Lung-on-a-Chip.
The announcement of the SLAS Innovation Award for Huh's podium presentation came just after the closing keynote session of SLAS2012.
"I was thrilled to hear the announcement of the award, but it was not something I expected," he says. In fact, at that particular moment he was lost in thought about Robert Ballard's preceding keynote address on deep sea science and exploration.
"I enjoyed Ballard's talk so much, and I was just sitting there, still thinking about it," Huh explains. "I was shocked to hear the announcement that I had won the award. I am so glad that the presentation was well received. It created some excitement and a lot of people gave me new ideas and new directions, which I really appreciate. This is what I enjoy most about going to conferences and meetings, particularly SLAS. They understand the technical challenges I experienced during the course of the research, and also they can see the potential and the future direction we can pursue with this technology. It was a great opportunity to talk with people and get feedback."
Huh concluded that through these interactions at the conference, the most important lesson he learned is that the pharmaceutical companies have already started exploring advanced drug testing technology like the ones he is trying to develop. "It's gratifying to know," he says. "I feel that bioengineers working on organ mimics will have a lot to offer in realizing the goals the pharma companies are trying to accomplish. We have a bright future."
The road to the 2013 SLAS Innovation Award lies ahead! SLAS2013 podium presentation abstracts are accepted until Monday, July 30. Authors should opt-in for Innovation Award consideration by checking the appropriate box on the submission form. Check the SLAS2013 Innovation Award website for complete details.
SLAS2013, the Second Annual SLAS Conference and Exhibition, is set for January 12-16, Orlando, FL.
Dan Huh Describes the Benefits of Organs-on-a-Chip
How Human Breathing Lung-on-a-Chip Works