OCTOPUS, an Optimized Device for Growing Mini-Organs in a Dish

by Devorah Fischler

With OCTOPUS, Dan Huh’s team has significantly advanced the frontiers of organoid research, providing a platform superior to conventional gel droplets. OCTOPUS splits the soft hydrogel culture material into a tentacled geometry. The thin, radial culture chambers sit on a circular disk the size of a U.S. quarter, allowing organoids to advance to an unprecedented degree of maturity.

When it comes to human bodies, there is no such thing as typical. Variation is the rule. In recent years, the biological sciences have increased their focus on exploring the poignant lack of norms between individuals, and medical and pharmaceutical researchers are asking questions about translating insights concerning biological variation into more precise and compassionate care.

What if therapies could be tailored to each patient? What would happen if we could predict an individual body’s response to a drug before trial-and-error treatment? Is it possible to understand the way a person’s disease begins and develops so we can know exactly how to cure it?

Dan Huh, Associate Professor in the Department of Bioengineering at the University of Pennsylvania’s School of Engineering and Applied Science, seeks answers to these questions by replicating biological systems outside of the body. These external copies of internal systems promise to boost drug efficacy while providing new levels of knowledge about patient health.

An innovator of organ-on-a-chip technology, or miniature copies of bodily systems stored in plastic devices no larger than a thumb drive, Huh has broadened his attention to engineering mini-organs in a dish using a patient’s own cells.

A recent study published in Nature Methods helmed by Huh introduces OCTOPUS, a device that nurtures organs-in-a-dish to unmatched levels of maturity. The study leaders include Estelle Park, doctoral student in Bioengineering, Tatiana Karakasheva, Associate Director of the Gastrointestinal Epithelium Modeling Program at Children’s Hospital of Philadelphia (CHOP), and Kathryn Hamilton, Assistant Professor of Pediatrics in Penn’s Perelman School of Medicine and Co-Director of the Gastrointestinal Epithelial Modeling Program at CHOP.

Read the full story in Penn Engineering Today.

‘Organ-on-a-Chip’ Device Provides New Insights into Early-Stage Pregnancy

by Scott Harris

Dan Huh’s BIOLines Lab develops several different kinds of organ-on-a-chip systems, such as this blinking-eye-on-a-chip.

If you’d read about it in a science fiction novel, you might not have believed it. Human organs and organ systems — from lungs to blood vessels to blinking eyes — bio-miniaturized and stored on a plastic chip no larger than a matchbook.

But that’s the breathing, blinking reality at the Biologically Inspired Engineering Systems (BIOLines) Laboratory in the Department of Bioengineering in the School of Engineering and Applied Sciences at the University of Pennsylvania, a bona fide pioneer of what is now widely known as “organ-on-a-chip” technology. Proponents hope these devices can one day help scientists around the world learn more about the body’s inner workings and ultimately improve disease prevention and treatment.

“The century-old practice of cell culture is to grow living cells isolated from the human body in hard plastic dishes and keep them bathed in copious amounts of culture media under static conditions, and that is drastically different than the complex, dynamic environment of native tissues in which these cell reside,” said Dan Dongeun Huh, Ph.D., BIOLines’ principal investigator and an associate professor of Bioengineering in Penn’s School of Engineering and Applied Science. “What makes this organ-on-a-chip technology so unique and powerful is that it enables us to reverse-engineer living human tissues using microengineered devices and mimic their intricate biological interactions and physiological functions in ways that have not been possible using traditional cell culture techniques. This represents a major advance in our ability to model and understand the inner workings of complex physiological systems in the human body.”

Generally speaking, organ-on-a-chip devices are made of clear silicone rubber — the same material used to make contact lenses — and can vary in size and design. Embedded within are microfabricated three-dimensional chambers lined with different human cell types, arranged and propagated to ultimately form a structure complex enough to actually mimic the essential elements of a functioning organ.

With partners at the Perelman School of Medicine, BIOLines recently developed a newer variation of the organ-on-a-chip: one that replicates the interface between maternal tissue and the cells of the placenta at the critical moments in early pregnancy when the embryo is implanting in the uterus. Huh and Penn Medicine physicians led a study using the “implantation-on-a-chip” to observe things that would otherwise have been virtually unobservable.

The study findings appeared this spring in the journal Nature Communications.

Continue reading at Penn Medicine News.

Microbes That Cause Cavities Can Form Superorganisms Able to ‘Crawl’ and Spread On Teeth

by Katherine Unger Baillie

Hyun (Michel) Koo

A cross-kingdom partnership between bacteria and fungi can result in the two joining to form a “superorganism” with unusual strength and resilience. It may sound like the stuff of science fiction, but these microbial groupings are very much part of the here and now.

Found in the saliva of toddlers with severe childhood tooth decay, these assemblages can effectively colonize teeth. They were stickier, more resistant to antimicrobials, and more difficult to remove from teeth than either the bacteria or the fungi alone, according to the research team, led by University of Pennsylvania School of Dental Medicine scientists.

What’s more, the assemblages unexpectedly sprout “limbs” that propel them to “walk” and “leap” to quickly spread on the tooth surface, despite each microbe on its own being non-motile, the team reported in the journal Proceedings of the National Academy of Sciences

“This started with a very simple, almost accidental discovery, while looking at saliva samples from toddlers who develop aggressive tooth decay,” says Hyun (Michel) Koo, a professor at Penn Dental Medicine and a co-corresponding author on the paper. “Looking under the microscope, we noticed the bacteria and fungi forming these assemblages and developing motions we never thought they would possess: a ‘walking-like’ and ‘leaping-like’ mobility. They have a lot of what we call ‘emergent functions’ that bring new benefits to this assemblage that they could not achieve on their own. It’s almost like a new organism—a superorganism—with new functions.”

Read the full story in Penn Today.

Hyun (Michel) Koo is a professor in the Department of Orthodontics and the divisions of Community Oral Health and Pediatric Dentistry in the School of Dental Medicine, co-founder of the Center for Innovation & Precision Dentistry (CiPD) at the University of Pennsylvania, and member of the Penn Bioengineering Graduate Group.

A Robot Made of Sticks

Kristina García

Devin Carroll, a doctoral candidate in the School of Engineering and Applied Sciences, is designing a modular robot called StickBot, which may be adapted for rehabilitation use in global public health settings.

Stickbot, a small robot composed of sticks, circuitry, actuators, a microcontroller, and a motor driver, lashed together with string.
StickBot in walking mode, using the sticks as legs to propel itself across the table.

In late summer, just as the leaves were starting to crisp and curl in the heat, Devin Carroll walked out of his apartment, looked on the ground, and picked up a couple of sticks that he thought might work for his robot. About half an inch thick and the length of an adult hand, he stripped the three sticks of their bark and lashed them with string to StickBot, a modular robot composed of circuitry, actuators, a microcontroller, and a motor driver.

Powered by four AA batteries, connected by a maze of wires and blinking lights, StickBot’s wooden arms now thump up and over, powering the robot across the table at Penn’s General Robotics, Automation, Sensing & Perception (GRASP) Lab, where Carroll is a Ph.D. candidate in the School of Engineering and Applied Sciences.

Controlling the robot using an app he designed, Carroll shows how StickBot can pivot from using the sticks as legs in “crawler mode,” to using them as arms. In “grasper mode,” the sticks are attached to a controller plate on one side to form a hinge joint while moving with their free end to hold a cup upright.

Rather than a static, singular invention, StickBot is an idea, a flexible system that can be reconfigured in a variety of ways. A modular robot, StickBot’s components can be added, adjusted, and discarded as needed.

Read the full story in Penn Engineering Today.

This article features quotes from Michelle Johnson, Associate Professor in Physical Medicine and Rehabilitation in the Perelman School of Medicine and in Bioengineering in the School of Engineering and Applied Sciences, and Director of the Rehabilitation Robotics Lab.

 

Defining Neural “Representation”

by Marilyn Perkins

Neuroscientists frequently say that neural activity ‘represents’ certain phenomena, PIK Professor Konrad Kording and postdoc Ben Baker led a study that took a philosophical approach to tease out what the term means.

Monitors Show EEG Reading and Graphical Brain Model. In the Background Laboratory Man Wearing Brainwave Scanning Headset Sits in a Chair with Closed Eyes. In the Modern Brain Study Research Laboratory
Neuroscientists use the word “represent” to encompass multifaceted relationships between brain activity, behavior, and the environment.

One of neuroscience’s greatest challenges is to bridge the gaps between the external environment, the brain’s internal electrical activity, and the abstract workings of behavior and cognition. Many neuroscientists rely on the word “representation” to connect these phenomena: A burst of neural activity in the visual cortex may represent the face of a friend or neurons in the brain’s memory centers may represent a childhood memory.

But with the many complex relationships between mind, brain, and environment, it’s not always clear what neuroscientists mean when they say neural activity “represents” something. Lack of clarity around this concept can lead to miscommunication, flawed conclusions, and unnecessary disagreements.

To tackle this issue, an interdisciplinary paper takes a philosophical approach to delineating the many aspects of the word “representation” in neuroscience. The work, published in Trends in Cognitive Sciences, comes from the lab of Konrad Kording, a Penn Integrates Knowledge University Professor and senior author on the study whose research lies at the intersection of neuroscience and machine learning.

“The term ‘representation’ is probably one of the most common words in all of neuroscience,” says Kording, who has appointments in the Perelman School of Medicine and School of Engineering and Applied Science. “But it might mean something very different from one professor to another.”

Read the full story in Penn Today.

Konrad Kording is a Penn Integrates Knowledge University Professor with joint appointments in the Department of Neuroscience the Perelman School of Medicine and in the Department of Bioengineering in the School of Engineering and Applied Science.

Ben Baker is a postdoctoral researcher in the Kording lab and a Provost Postdoctoral Fellow. Baker received his Ph.D. in philosophy from Penn.

Also coauthor on the paper is Benjamin Lansdell, a data scientist in the Department of Developmental Neurobiology at St. Jude Children’s Hospital and former postdoctoral researcher in the Kording lab.

Funding for this study came from the National Institutes of Health (awards 1-R01-EB028162-01 and R01EY021579) and the University of Pennsylvania Office of the Vice Provost for Research.

CEMB Researchers Find that Disease Can Change the Physical Structure of Cells

by Ebonee Johnson

In these super-resolution images of tendon cell nuclei, the color coding represents chromatin density map, from low density in blue to high density in red. Comparing a healthy human tendon cell nucleus (left) to one diagnosed with tendinosis (right) shows that disease alters the spatial localization and compaction of chromatin.

Researchers from Penn’s Center for Engineering Mechanobiology (CEMB) have discovered that cells change the physical structure of their genome when they’re affected by disease.

In a recent study published in Nature Biomedical Engineering, the team detailed what they found when they closely observed the nucleus of cells inside connective tissues deteriorating as a result of tendinosis, which is the chronic condition that results from a tendon repeatedly suffering small injuries that don’t heal correctly. Using the latest super-resolution imaging techniques, they found that the tendon cells involved in maintaining the tissue’s structure in a diseased microenvironment improperly reorder their chromatin — the DNA-containing material that chromosomes are composed of — when attempting to repair.

This and other findings highlighted in the report point to the possibility of new treatments, such as small-molecule therapies, that could restore order to the affected cells.

“Interestingly, we were able to explain the role of mechanical forces on the 3-D organization of chromatin by developing a theory that integrates fundamental thermodynamic principles (physics) with the kinetics of epigenetic regulation (biology),” said study co-author and CEMB Director Vivek Shenoy in a news release from Penn Medicine News.

The CEMB, one of 18 active interdisciplinary research centers funded by the National Science Foundation’s Science and Technology Center (STC) program, brings together dozens of researchers from Penn Engineering and the Perelman School of Medicine, as well as others spread across campus and at partner institutions around the world.

With its funding recently renewed for another five years, the CEMB has entered  into a new phase of its mission, centered on the nascent concept of “mechanointelligence,” which is exemplified by studies like this one. While mechanobiology is the study of the physical forces that govern the behavior of cells and their communication with their neighbors, mechanointelligence adds another layer of complexity: attempting to understand the forces that allow cells to sense, remember and adapt to their environments.

Ultimately, harnessing these forces would allow researchers to help multicellular organisms — plants, animals and humans — better adapt to their environments as well.

Read “Aberrant chromatin reorganization in cells from diseased fibrous connective tissue in response to altered chemomechanical cues” at Nature Biomedical Engineering.

Read “The Locked Library: Disease Causes Cells to Reorder Their DNA Incorrectly” at Penn Medicine News.

This story originally appeared in Penn Engineering Today.

Vivek Shenoy is Eduardo D. Glandt President’s Distinguished Professor in Materials Science and Engineering, Bioengineering, and in Mechanical Engineering and Applied Mechanics.

2022 Career Award Recipient: Michael Mitchell

by Melissa Pappas

Michael Mitchell (Illustration by Melissa Pappas)

Michael Mitchell, J. Peter and Geri Skirkanich Assistant Professor of Innovation in the Department of Bioengineering, is one of this year’s recipients of the National Science Foundation’s CAREER Award. The award is given to early-career faculty researchers who demonstrate the potential to be role models in their field and invest in the outreach and education of their work.

Mitchell’s award will fund research on techniques for “immunoengineering” macrophages. By providing new instructions to these cells via nanoparticles laden with mRNA and DNA sequences, the immune system could be trained to target and eliminate solid tumors. The award will also support graduate students and postdoctoral fellows in his lab over the next five years.

The project aligns with Mitchell’s larger research goals and the current explosion of interest in therapies that use mRNA, thanks to the technological breakthroughs that enabled the development of COVID-19 vaccines.

“The development of the COVID vaccine using mRNA has opened doors for other cell therapies,” says Mitchell. “The high-priority area of research that we are focusing on is oncological therapies, and there are multiple applications for mRNA engineering in the fight against cancer.”

A new wave of remarkably effective cancer treatments incorporates chimeric antigen receptor T-cell (CAR-T) therapy. There, a patient’s T-cells, a type of white blood cell that fights infections, are genetically engineered to identify, target and kill individual cancer cells that accumulate in the circulatory system.

However, despite CART-T therapy’s success in treating certain blood cancers, the approach is not effective against cancers that form solid tumors. Because T-cells are not able to penetrate tumors’ fibrous barriers, Mitchell and his colleagues have turned to another part of the immune system for help.

Read the full story in Penn Engineering Today.

Training the Next Generation of Scientists on Soft Materials, Machine Learning and Science Policy

by Melissa Pappas

Developing new soft materials requires new data-driven research techniques, such as autonomous experimentation. Data regarding nanometer-scale material structure, taken by X-ray measurements at a synchrotron, can be fed into an algorithm that identifies the most relevant features, represented here as red dots. The algorithm then determines the optimum conditions for the next set of measurements and directs their execution without human intervention. Brookhaven National Laboratory’s Kevin Yager, who helped develop this technique, will co-teach a course on it as part of a new Penn project on Data Driven Soft Materials Research.

The National Science Foundation’s Research Traineeship Program aims to support graduate students, educate the STEM leaders of tomorrow and strengthen the national research infrastructure. The program’s latest series of grants are going toward university programs focused on artificial intelligence and quantum information science and engineering – two areas of high priority in academia, industry and government.

Chinedum Osuji, Eduardo D. Glandt Presidential Professor and Chair of the Department of Chemical and Biomolecular Engineering (CBE), has received one of these grants to apply data science and machine learning to the field of soft materials. The grant will provide five years of support and a total of $3 million for a new Penn project on Data Driven Soft Materials Research.

Osuji will work with co-PIs Russell Composto, Professor and Howell Family Faculty Fellow in Materials Science and Engineering, Bioengineering, and in CBE, Zahra Fakhraai, Associate Professor of Chemistry in Penn’s School of Arts & Sciences (SAS) with a secondary appointment in CBE, Paris Perdikaris, Assistant Professor in Mechanical Engineering and Applied Mechanics, and Andrea Liu, Hepburn Professor of Physics and Astronomy in SAS, all of whom will help run the program and provide the connections between the multiple fields of study where its students will train.

These and other affiliated faculty members will work closely with co-PI Kristin Field, who will serve as Program Coordinator and Director of Education.

Read the full story in Penn Engineering Today.

The Penn Center for Precision Engineering for Health Announces First Round of Seed Funding

by Melissa Pappas

CPE4H is one of the focal points of Penn Engineering signature initiative on Engineering Health.

The Penn Center for Precision Engineering for Health (CPE4H) was established late last year to accelerate engineering solutions to significant problems in healthcare. The center is one of the signature initiatives for Penn’s School of Engineering and Applied Science and is supported by a $100 million commitment to hire faculty and support new research on innovative approaches to those problems.

Acting on that commitment, CPE4H solicited proposals during the spring of 2022 for seed grants of $80K per year for two years for research projects that address healthcare challenges in several key areas of strategic importance to Penn: synthetic biology and tissue engineering, diagnosis and drug delivery, and the development of innovative devices. While the primary investigators (PIs) for the proposed projects were required to have a primary faculty appointment within Penn Engineering, teams involving co-PIs and collaborators from other schools were eligible for support. The seed program is expected to continue for the next four years.

“It was a delight to read so many novel and creative proposals,” says Daniel A. Hammer, Alfred G. and Meta A. Ennis Professor in Bioengineering and the Inaugural Director of CPE4H. “It was very hard to make the final selection from a pool of such promising projects.”

Judged on technical innovation, potential to attract future resources, and ability to address a significant medical problem, the following research projects were selected to receive funding.

Evolving and Engineering Thermal Control of Mammalian Cells

Led by Lukasz Bugaj, Assistant Professor in Bioengineering, this project will engineer molecular switches that can be toggled on and off inside mammalian cells at near-physiological temperatures. Successful development of these switches will provide new ways to communicate with cells, an advance that could be used to make safer and more effective cellular therapies.  The project will use directed evolution to generate and find candidate molecular tools with the desired properties. Separately, the research will also develop new technology for manipulating cellular temperature in a rapid and programmable way. Such devices will enhance the speed and sophistication of studies of biological temperature regulation.

A Quantum Sensing Platform for Rapid and Accurate Point-of-Care Detection of Respiratory Viral Infections

Combining microfluidics and quantum photonics, PI Liang Feng, Professor in Materials Science and Engineering and Electrical and Systems Engineering, Ritesh Agarwal, Professor in Materials Science Engineering, and Shu Yang, Joseph Bordogna Professor in Materials Science and Engineering and Chemical and Biomolecular Engineering, are teaming up with Ping Wang, Professor of Pathology and Laboratory Medicine in Penn’s Perelman School of Medicine, to design, build and test an ultrasensitive point-of-care detector for respiratory pathogens. In light of the COVID-19 pandemic, a generalizable platform for rapid and accurate detection of viral pathogenesis would be extremely important and timely.

Versatile Coacervating Peptides as Carriers and Synthetic Organelles for Cell Engineering

PI Amish Patel, Associate Professor in Chemical and Biomolecular Engineering, and Matthew C. Good, Associate Professor of Cell and Developmental Biology in the Perelman School of Medicine and in Bioengineering, will design and create small proteins that self-assemble into droplet-like structures known as coacervates, which can then pass through the membranes of biological cells. Upon cellular entry, these protein coacervates can disassemble to deliver cargo that modulates cell behavior or be maintained as synthetic membraneless organelles. The team will design new chemistries that will facilitate passage across cell membranes, and molecular switches to sequester and release protein therapeutics. If successful, this approach could be used to deliver a wide range of macromolecule drugs to cells.

Towards an Artificial Muscle Replacement for Facial Reanimation

Cynthia Sung, Gabel Family Term Assistant Professor in Mechanical Engineering and Applied Mechanics and Computer Information Science, will lead a research team including Flavia Vitale, Assistant Professor of Neurology and Bioengineering, and Niv Milbar, Assistant Instructor in Surgery in the Perelman School of Medicine. The team will develop and validate an electrically driven actuator to restore basic muscle responses in patients with partial facial paralysis, which can occur after a stroke or injury. The research will combine elements of robotics and biology, and aims to produce a device that can be clinically tested.

“These novel ideas are a great way to kick off the activities of the center,” says Hammer. “We look forward to soliciting other exciting seed proposals over the next several years.”

This article originally appeared in Penn Engineering Today.

Applying Microrobotics in Endodontic Treatment and Diagnostics

by Beth Adams

Controlled and actuated by magnetic fields, these mircrorobots are capable of precisely targeting the apical region — the opening where blood vessels and nerve enter the tooth — in a root canal.

With its irregularities and anatomical complexities, the root canal system is one of the most clinically challenging spaces in the oral cavity. As a result, biofilm not fully cleared from the nooks and crannies of the canals remains a leading cause of treatment failure and persistent endodontic infections, and there are limited means to diagnose or assess the efficacy of disinfection. One day, clinicians may have a new tool to overcome these challenges in the form of microrobots.

In a proof-of-concept study, researchers from Penn Dental Medicine and its Center for Innovation & Precision Dentistry (CiPD), have shown that microrobots can access the difficult to reach surfaces of the root canal with controlled precision, treating and disrupting biofilms and even retrieving samples for diagnostics, enabling a more personalized treatment plan. The Penn team shared their findings on the use of two different microrobotic platforms for endodontic therapy in the August issue of the Journal of Dental Research; the work was selected for the issue’s cover.

“The technology could enable multimodal functionalities to achieve controlled, precision targeting of biofilms in hard-to-reach spaces, obtain microbiological samples, and perform targeted drug delivery, ” says Dr. Alaa Babeer, lead author of the study and a Penn Dental Medicine Doctor of Science in Dentistry (DScD) and endodontics graduate, who is now within the lab of Dr. Michel Koo, co-director of the CiPD .

In both platforms, the building blocks for the microrobots are iron oxide nanoparticles (NPs) that have both catalytic and magnetic activity and have been FDA approved for other uses. In the first platform, a magnetic field is used to concentrate the NPs in aggregated microswarms and magnetically control them to the apical area of the tooth to disrupt and retrieve biofilms through a catalytic reaction. The second platform uses 3D printing to create miniaturized helix-shaped robots embedded with iron oxide NPs. These helicoids are guided by magnetic fields to move within the root canal, transporting bioactives or drugs that can be released on site.

“This technology offers the potential to advance clinical care on a variety of levels,” says Dr. Koo, co-corresponding author of the study with Dr. Edward Steager, a senior research investigator in Penn’s School of Engineering and Applied Science. “One important aspect is the ability to have diagnostic as well as therapeutic applications. In the microswarm platform, we can not only remove the biofilm, but also retrieve it, enabling us identify what microorganisms caused the infection. In addition, the ability to conform to the narrow and difficult-to-reach spaces within the root canal allows for a more effective disinfection in comparison to the files and instrumentation techniques presently used.”

Continue reading at Penn Dental Medicine News

Michel Koo is a professor in the Department of Orthodontics and divisions of Community Oral Health and Pediatric Dentistry in Penn Dental Medicine and co-director of the Center for Innovation & Precision Dentistry. He is a member of the Penn Bioengineering Graduate Group.