Week in BioE (August 16, 2019)

by Sophie Burkholder

Electrode Arrays and Star Wars Help to Inspire a New Prosthetic Arm

Brain-controlled prosthetic arm, Wikimedia commons

After nearly fifteen years of work, a new high-tech prosthetic arm from researchers at the University of Utah allows hand amputees to pluck grapes, pick up eggs without breaking them, and even put on their wedding rings. Named after Luke Skywalker’s robotic hand in the Star Wars saga, the LUKE Arm includes sensors that better mimic the way the human body sends information to the brain, allowing users to distinguish between soft and hard surfaces and to perform more complicated tasks. The arm relies heavily on an electrode array invented by University of Utah biomedical engineering professor Richard A. Normann, Ph.D., which is a bundle of microelectrodes that enable a computer to read signals from connected nerves in the user’s forearm.

But the biggest innovation in the use of these electrode arrays for the LUKE Arm is in the way they allow the prosthetic to mimic the sense of feeling on the surface of an object that indicates how much pressure should be applied when handling it. Gregory Clark, Ph.D., an associate professor of biomedical engineering at the University of Utah and the leader of the LUKE Arm project, says the key to improving these functions in the prosthetic was by more closely mimicking the path that this information takes to the brain, as opposed to merely what comprises that sensory information. In the future, Clark hopes to improve upon the LUKE Arm by including more inputs, like one for temperature data, and on making them more portable by eliminating the device’s need for computer connection.

Philly Voice Recognizes the Cremins Lab’s Innovations in Light-Activated Gene-Folding

While technological advancements over the past few decades have opened doors to understanding the topological structures of DNA, we still have far more to learn about how these structures impact and contribute to genome function. But here at Penn, the Cremins Laboratory in 3D Epigenomes and Systems Neurobiology hopes to fix that. Led by Jennifer E. Phillips-Cremins, Ph.D., members of the lab use light-activated dynamic looping (LADL) to better understand the way that genome topological properties and folding can affect protein translation. Cremins and her lab use this technique to force specific genome folds to interact with each other, and create temporary DNA loops that can then be bound together in the presence of blue light for certain proteins in the Arabidopsis plant. Using the data from these tests, researchers can better understand the genome structure-function relationships, and hopefully open the door to new treatments for diseases in which expression or mis-expression of certain genes is the cause.

Artificial Cells Can Deliver Molecules Better than the Real Thing

From pills to vaccines, ways to deliver drugs into the body have been constantly evolving since the early days of medicine.

Now, a new study from an interdisciplinary team led by researchers at the University of Pennsylvania provides a new platform for how drugs could be delivered to their targets in the future. Their work was published in the Proceedings of the National Academy of Sciences.

The research focuses on a dendrimersome, a compartment with a lamellar structure and size that mimic a living cell. It can be thought of as the shipping box of the cellular world that carries an assortment of molecules as cargo.

The scientists found that these dendrimersomes, which have a multilayered, onion-like structure, were able to “carry” high concentrations of molecules that don’t like water, which is common in pharmaceutical drugs. They were also able to carry these molecules more efficiently than other commercially available vessels. Additionally, the building block of the cell-like compartment, a janus dendrimer, is classified as an amphiphile, meaning it contains molecules that don’t like water and also molecules that are soluble in water, like lipids, that make up natural membranes.

“This is a different amphiphile that makes really cool self-assembled onions into which we were able to load a bunch of molecular cargos,” says co-author Matthew Good.

Read the rest of the story on Penn Today.

A Warm Evening Bath Could Improve Sleep Quality

In a recent review of over 5,000 sleep studies, biomedical engineering researchers at the University of Texas at Austin found a connection between water-based passive body heating and sleep onset latency, efficiency, and quality. Using meta-analytical tools to compare all of the studies and patient data, lead author and Ph.D. candidate Shahab Haghayegh and his team found that a warm bath in the temperature range of 104-109 degrees Fahrenheit taken 1-2 hours before bed has the ability to improve all three considered sleep categories. This makes sense considering that our body’s Circadian rhythms govern both our sleep cycles and temperature, bringing us to a higher temperature during the day and a lower one at night during sleep. In fact, this lowering of body temperature before sleep is what helps to trigger the onset of sleep, so taking a warm bath and allowing your body to cool down from it before going to sleep enhances the body’s own efforts of naturally cooling down before we go to bed. With this new and comprehensive review, those who suffer from poor sleep quality may soon find solace in temperature regulation therapy systems.

People & Places

With the recent 50th anniversary of the first moon landing by Americans Neil Armstrong, Buzz Aldrin, and Michael Collins in 1969, ABC News looked back at one of the women involved in the project. Judy Sullivan was a biomedical engineer at the time of the project, and served as the lead engineer of the biomedical system for Apollo 11. In this role, she led studies on the astronauts’ breathing rates and sensor capabilities for the devices being sent into space to help the astronauts monitor their health. For the Apollo 11 mission and a lot of Sullivan’s early work at NASA, she worked on teams of all men, as women were often encouraged to become teachers, secretaries, or homemakers over other professions. Today, Sullivan says she’s thrilled that women have more career options to choose from, and wants to continue seeing more women getting involved in math and science.

We would like to congratulate Sanjay Kumar, M.D., Ph.D., on his appointment as the new Department Chair of Bioengineering at the University of California, Berkeley. Since joining the faculty in 2005, Kumar has received several prestigious awards including the NSF Career Award, the NIH Director’s New Innovator Award, the Presidential Early Career Award for Scientists and Engineers, and the Berkeley student-voted Outstanding Teacher Award.

 

Penn Bioengineering Faculty Member Paul Ducheyne Receives the European Society for Biomaterials’ International Award

Ducheyne
Paul Ducheyne, Ph.D.

by Sophie Burkholder

We would like to congratulate Paul Ducheyne, Ph.D., a Professor in the Bioengineering Department and a Professor of Orthopaedic Surgery Research at Penn, on being selected for the International Award by the European Society for Biomaterials (ESB). The International Award is one of the ESB’s highest honors, recognizing scientists who have spent the majority of their careers outside of Europe. They are internationally recognized, have a high scientific profile, and have made  major contributions to the field of biomaterials. Those nominated for the award typically also have had strong collaborations with the scientific community in Europe throughout their careers.

Beyond being a professor at Penn, Ducheyne is also the founder of XeroThera, a spin-out from Penn that develops novel concepts for tissue engineering and drug delivery based on his group’s twenty years of fundamental studies of sol gel-processed, nanoporous, oxide-based materials. XeroThera’s first product formulations focus on prophylaxis and treatment of surgical infections. A pipeline is being developed building from his group’s breakthrough data   that demonstrate the utility of sol-gel synthesized silica-based nanoporous materials for therapeutic use. These materials may well represent a next generation of agents for delivery of drugs, including antibiotics, analgesics, and osteogenic and anti-inflammatory molecules.

In being selected for the International Award, Ducheyne joins only five previous recipients of it so far, a group of scientists that represents those at the top of the field in biomaterials worldwide. Ducheyne will give a presentation and award lecture for the ESB at its next annual meeting this September in Dresden, Germany. Read more about the ESB’s awards here and see the full list of 2019 awardees here.

Bioengineering Welcomes New Faculty Member Cesar de la Fuente

Cesar de la Fuente, PhD

by Sophie Burkholder

The Department of Bioengineering at the University of Pennsylvania is excited to welcome César de la Fuente, Ph.D., as an Assistant Professor of Bioengineering. De la Fuente, who is also an Assistant Professor in the Department of Psychiatry and Microbiology in the Perelman School of Medicine and was recently named a Penn Presidential Professor, is the principal investigator of the de la Fuente Lab with current projects including the development of computer-made antibiotics, microbiome engineering technologies, and synthetic neuromicrobiology tools.

Dr. de la Fuente has wanted to learn the mysteries of the world around him from a young age, from the origins of life and human consciousness to how diseases can affect the body. His dream of understanding the building blocks of life began to take shape when he enrolled as a graduate student at the University of British Columbia to study microbiology, immunology, and protein engineering. After earning his Ph.D. in these subjects, de la Fuente went on to complete a post doctorate in synthetic biology and computer science at the Massachusetts Institute of Technology (MIT).

Recently, MIT recognized Dr. de la Fuente on its “35 Innovators Under 35” list, which honored de la Fuente as one of the world’s top 35 innovators and as a pioneer for his use of technology to improve antibiotics. Furthermore, GEN recently listed Dr. de la Fuente on its “Top 10 Under 40” list of young leaders in the life sciences, noting his development of transformative biotechnologies as a potential solution to antibiotic resistance. De la Fuente refers to this latest research as “Machine Biology,” a crossover of life and technology that “brings together elements of machines in order to computerize biological systems.”

His creativity in the merging of so many domains of science echoes throughout de la Fuente’s general approach to research and academia as well. While he emphasizes a thinking-from-the-ground-up approach, he also feels that “heterogeneous groups make better ideas,” and thus strives to maintain diversity in his lab — currently his entire lab is made up of international students and postdocs. In the future, de la Fuente hopes to extend his love of mentorship to the classroom in a course exploring the intersection of microbiology and synthetic biology, overlapping in a way similar to his research. We can’t wait for all of the innovation and creativity in engineering that de la Fuente will undoubtedly bring to our department.

Penn Engineering’s Blinking Eye-on-a-Chip Used for Disease Modeling and Drug Testing

By Lauren Salig

Rachel Young, a graduate student in Huh’s lab, holds up the new eye-on-a-chip device. The latest iteration of the lab’s eye-on-a-chip has a mechanical eyelid to simulate blinking, and was used to test an experimental drug for dry eye disease. By incorporating human cells into an engineered scaffolding, the eye-on-a-chip has many of the benefits of testing on living subjects, while minimizing risks and ethical concerns.

People who spend eight or more hours a day staring at a computer screen may notice their eyes becoming tired or dry, and, if those conditions are severe enough, they may eventually develop dry eye disease (DED). DED is a common disease with shockingly few FDA-approved drug options, partially because of the difficulties of modeling the complex pathophysiology in human eyes. Enter the blinking eye-on-a-chip: an artificial human eye replica constructed in the laboratory of Penn Engineering researchers.

This eye-on-a-chip, complete with a blinking eyelid, is helping scientists and drug developers to improve their understanding and treatment of DED, among other potential uses. The research, published in Nature Medicine, outlines the accuracy of the eye-on-a-chip as an organ stand-in and demonstrates its utility as a drug testing platform.

Dan Huh and Jeongyun Seo

The study was led by Dan Huh, associate professor in the Department of Bioengineering, and graduate student Jeongyun Seo.

They collaborated with Vivian Lee, Vatinee Bunya and Mina Massaro-Giordano from the Department of Ophthalmology in Penn’s Perelman School of Medicine, as well as with Vivek Shenoy, Eduardo D. Glandt President’s Distinguished Professor in Penn Engineering’s Department of Materials Science and Engineering. Other collaborators included Woo Byun, Andrei Georgescu and Yoon-suk Yi, members of Huh’s lab, and Farid Alisafaei, a member of Shenoy’s lab.

Huh’s lab specializes in creating organs-on-a-chip that provide microengineered in vitro platforms to mimic their in vivo counterparts, including lung and bone marrow proxies launched into space this May to study astronaut illness. The lab has spent years fine-tuning its eye-on-a-chip, which earned them the 2018 Lush Prize for its promise in animal-free testing of drugs, chemicals, and cosmetics.

In this study, Huh and Seo focused on engineering an eye model that could imitate a healthy eye and an eye with DED, allowing them to test an experimental drug without risk of human harm.

The Huh lab’s eye-on-a-chip attached to a motorized, gelatin-based eyelid. Blinking spreads tears over the corneal surface, and so was a critical aspect to replicate in the researchers’ model of dry eye disease. cells. The cells of the cornea grow on the inner circle of scaffolding, dyed yellow, and the cells of the conjunctiva grow on the surrounding red circle. Artificial tears are supplied by a tear duct, dyed blue.

To construct their eye-on-a-chip, Huh’s team starts with a porous scaffold engineered with 3D printing, about the size of a dime and the shape of a contact lens, on which they grow human eye cells. The cells of the cornea grow on the inner circle of scaffolding, dyed yellow, and the cells of the conjunctiva, the specialized tissue covering the white part of human eyes, grow on the surrounding red circle. A slab of gelatin acts as the eyelid, mechanically sliding over the eye at the same rate as human blinking. Fed by a tear duct, dyed blue, the eyelid spreads artificial tear secretions over the eye to form what is called a tear film.

“From an engineering standpoint, we found it interesting to think about the possibility of mimicking the dynamic environment of a blinking human eye. Blinking serves to spread tears and generate a thin film that keeps the ocular surface hydrated. It also helps form a smooth refractive surface for light transmission. This was a key feature of the ocular surface that we wanted to recapitulate in our device,” says Huh.

For people with DED, that tear film evaporates faster than it’s replenished, resulting in inflammation and irritation. A common cause of DED is the reduced blinking that occurs during excessive computer usage, but people can develop the disease for other reasons as well. DED affects about 14 percent of the world’s population but has been notably difficult to develop new treatments for, with 200 failed clinical drug trials since 2010 and only two currently available FDA-approved drugs for treatment.

Huh’s lab has been considering the drug-testing potential of organs-on-a-chip since their initial conceptualization, and, because of its surface-level area of impact, DED seemed the perfect place to start putting their eye model to the test. But before they started a drug trial, the team had to ensure their model could really imitate the conditions of DED.

“Initially, we thought modeling DED would be as simple as just keeping the culture environment dry. But as it turns out, it’s an incredibly complex multifactorial disease with a variety of sub-types,” Huh says. “Regardless of type, however, there are two core mechanisms that underlie the development and progression of DED. First, as water evaporates from the tear film, salt concentration increases dramatically, resulting in hyperosmolarity of tears. And second, with increased tear evaporation, the tear film becomes thinner more rapidly and often ruptures prematurely, which is referred to as tear film instability. The question was: Is our model capable of modeling these core mechanisms of dry eye?”

The answer, after much experimentation, was yes. The team evoked DED conditions in their eye-on-a-chip by cutting their device’s artificial blinking in half and carefully creating an enclosed environment that simulated the humidity of real-life conditions. When put to the test against real human eyes, both healthy and with DED, the corresponding eye-on-a-chip models proved their similarity to the actual organ on multiple clinical measures. The eyes-on-a-chip mimicked actual eyes’ performance in a Schirmer strip, which tests liquid production; in an osmolarity test, which looks at tear film salt content; and in a keratography test, which evaluates the time it takes for a tear film to break up.

Having confirmed their eye-on-a-chip’s ability to mirror the performance of a human eye in normal and DED-inducing settings, Huh’s team turned to the pharmaceutical industry to find a promising DED drug candidate to test-drive their model. They landed on an upcoming drug based on lubricin, a protein primarily found in the lubricating fluid that protects joints.

“When people think of DED, they normally treat it as a chronic disease driven by inflammation,” says Huh, “but there’s now increasing evidence suggesting that mechanical forces are important for understanding the pathophysiology of DED. As the tear film becomes thinner and more unstable, friction between the eyelids and the ocular surface increases, and this can damage the epithelial surface and also trigger adverse biological responses such as inflammation. Based on these observations, there is emerging interest in developing ophthalmic lubricants as a topical treatment for dry eye. In our study, we used an lubricin-based drug that is currently undergoing clinical trials. When we tested this drug in our device, we were able to demonstrate its friction-lowering effects, but, more importantly, using this model we discovered its previously unknown capacity to suppress inflammation of the ocular surface.”

By comparing the testing results of their models of a healthy eye, an eye with DED, and an eye with DED plus lubricin, Huh and Seo were able to further scientists’ understanding of how lubricin works and show the drug’s promise as a DED treatment.

Similarly, the process of building a blinking eye-on-a-chip pushed forward scientists’ understanding of the eye itself, providing insights into the role of mechanics in biology. Collaborating with Shenoy, director of the Center for Engineering MechanoBiology, the team’s attention was drawn to how the physical blinking action was affecting the cells they cultivated to engineer an artificial eye on top of their scaffolding.

“Initially, the corneal cells start off as a single layer, but they become stratified and form multiple layers as a result of differentiation, which happens when these cells are cultured at the air-liquid interface. They also form tight cell-cell junctions and express a set of markers during differentiation,” Huh says. “Interestingly, we found out that mechanical forces due to blinking actually help the cells differentiate more rapidly and more efficiently. When the corneal cells were cultured under air in the presence of blinking, the rate and extent of differentiation increased significantly in comparison to static models without blinking. Based on this result, we speculate that blink-induced physiological forces may contribute to differentiation and maintenance of the cornea.”

In other words, human cornea cells growing on the scientists’ scaffold more quickly became specialized and efficient at their particular jobs when the artificial eyelid was blinking on top of them, suggesting that mechanical forces like blinking contribute significantly to how cells function. These types of conceptual advances, coupled with drug discovery applications, highlight the multifaceted value that engineered organs-on-a-chip can contribute to science.

Huh and Seo’s eye-on-a-chip is still just dipping its toes into the field of drug testing, but this first step is a victory that represents years of work refining their artificial eye to reach this level of accuracy and utility.

“Although we have just demonstrated proof-of-concept,” says Seo, “I hope our eye-on-a-chip platform is further advanced and used for a variety of applications besides drug screening, such as testing of contact lenses and eye surgeries in the future.”

“We are particularly proud of the fact that our work offers a great and rare example of interdisciplinary efforts encompassing a broad spectrum of research activities from design and fabrication of novel bioengineering systems to in vitro modeling of complex human disease to drug testing,” says Huh. “I think this is what makes our study unique and representative of innovation that can be brought about by organ-on-a-chip technology.”

This work was supported by the National Institutes of Health through grants 1DP2HL127720–0, R01EY026972 and K08EY025742–01, the National Science Foundation through grants CMMI:15–48571, and Research to Prevent Blindness.

Originally posted on the Penn Engineering Medium blog.

Six Penn Engineers Receive Tenure

Brian Chow, David Issadore, Dongeun (Dan) Huh, Linh Thi Xuan Phan, Amish Patel and Aleksandra Vojvodic

The School of Engineering and Applied Science has granted tenure to six faculty members, including three from the Department of Bioengineering.

Tenured faculty at Penn Engineering demonstrate teaching excellence and international leadership in their fields of study and research collaborations.

Brian Chow
Associate Professor in Bioengineering
Chow’s research focuses on the discovery and engineering of photoreceptors and sensory proteins for manipulating and monitoring the physiology of genetically targeted cells, and the application of these tools to reveal principles of cellular dynamics. His work has advanced the rational design of light activated proteins and the use of optogenetic reagents to study cell signaling.

David Issadore
Associate Professor in Bioengineering
Issadore’s research combines microelectronics, microfluidics, and nanomaterials to create miniaturized platforms for the diagnosis of disease. His work has the potential to radically change the way we diagnose and treat diseases by bringing the technologies out of the lab and directly to the point of care.

Dongeun (Dan) Huh
Associate Professor in Bioengineering
Huh’s research aims to develop innovative bioengineering tools and technologies using biologically inspired design principles and micro- and nano-scale engineering techniques to create systems that mimic the structure and function of human physiological systems.

Linh Thi Xuan Phan
Associate Professor in Computer and Information Science
Phan’s work focuses on making cyber-physical systems (CPS) safer, faster, and more secure, both by strengthening the theoretical foundations and by developing practical solutions. Her recent projects include a cloud platform with real-time capabilities, a new diagnosis technique for timing-related faults, and new ways to defend CPS against attacks from insiders and/or external attackers.

Amish Patel
Associate Professor in Chemical and Biomolecular Engineering
Patel’s research strives to achieve a molecular-level understanding of solvation and transport in aqueous and polymeric systems, with applications ranging from the prediction of protein interactions to the design of advanced materials for water purification and energy storage. His group combines principles of statistical mechanics and liquid state theory with state-of-the-art molecular modeling and atomistic simulation techniques to study these biological, nanoscopic and polymeric systems.

Aleksandra Vojvodic
Associate Professor in Chemical and Biomolecular Engineering
Vojvodic’s research focuses on theory and computation-driven materials design. Her lab uses computational frameworks to obtain fundamental understanding of surface and interface properties of complex materials that can be used to develop theoretical models for chemical transformations and energy conversion. These models have been used to predict new catalyst materials for several chemical reactions which have been experimentally synthesized and tested, validating the desired properties of the computationally predicted catalyst material.

Originally posted on the Penn Engineering Medium blog.