Tag: publication

Posted on

RNA Lipid Nanoparticle Engineering Stops Liver Fibrosis in its Tracks, Reverses Damage

by Melissa Pappas

Members of the research team include (from left to right) Xuexiang Han, Michael J. Mitchell, Ningqiang Gong, Lulu Xue, Sarah J. Shepherd, and Rakan El-Mayta.
Members of the research team include (from left to right) Xuexiang Han, Michael J. Mitchell, Ningqiang Gong, Lulu Xue, Sarah J. Shepherd, and Rakan El-Mayta.

Since the success of the COVID-19 vaccine, RNA therapies have been the object of increasing interest in the biotech world. These therapies work with your body to target the genetic root of diseases and infections, a promising alternative treatment method to that of traditional pharmaceutical drugs.

Lipid nanoparticles (LNPs) have been successfully used in drug delivery for decades. FDA-approved therapies use them as vehicles for delivering messenger RNA (mRNA), which prompts the cell to make new proteins, and small interfering RNA (siRNA), which instruct the cell to silence or inhibit the expression of certain proteins.

The biggest challenge in developing a successful RNA therapy is its targeted delivery. Research is now confronting the current limitations of LNPs, which have left many diseases without an effective RNA therapy.

Liver fibrosis occurs when the liver is repeatedly damaged and the healing process results in the accumulation of scar tissue, impeding healthy liver function. It is a chronic disease characterized by the buildup of excessive collagen-rich extracellular matrix (ECM). Liver fibrosis has remained challenging to treat using RNA therapies due to a lack of delivery systems for targeting activated liver-resident fibroblasts. Both the solid fibroblast structure and the lack of specificity or affinity to target these fibroblasts has impeded current LNPs from entering activated liver-resident fibroblasts, and thus they are unable to deliver RNA therapeutics.

To tackle this issue and help provide a treatment for the millions of people who suffer from this chronic disease, Michael Mitchell, J. Peter and Geri Skirkanich Assistant Professor of Innovation in the Department of Bioengineering, and postdoctoral fellows Xuexiang Han and Ningqiang Gong, found a new way to synthesize ligand-tethered LNPs, increasing their selectivity and allowing them to target liver fibroblasts.

Lulu Xue, Margaret Billingsley, Rakan El-Mayta, Sarah J. Shepherd, Mohamad-Gabriel Alameh and Drew Weissman, Roberts Family Professor in Vaccine Research and Director of the Penn Institute for RNA Innovation at the Perelman School of Medicine, also contributed to this work.

Read the full story in Penn Engineering Today.

Posted on

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.

Posted on

‘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.

Posted on

Listen: ‘Curious Minds’ on NPR’s ‘Detroit Today’

by Ebonee Johnson

Twin siblings and scholars Dani S. Bassett of Penn and Perry Zurn of American University collaborated over half a dozen years to write “Curious Minds: The Power of Connection.” (Image: Tony and Tracy Wood Photography)

Twin academics Dani S. Basset, J. Peter Skirkanich Professor and director of the Complex Systems Lab, and Perry Zurn, a professor of philosophy at American University, were recently featured as guests on NPR radio show “Detroit Today” to discuss their new book, “Curious Mind: The Power of Connection.”

In their book, Basset and Zurn draw on their previous research, as well as an expansive network of ideas from philosophy, history, education and art to explore how and why people experience curiosity, as well as the different types it can take.

Basset, who holds appointments in the Departments of Bioengineering and Electrical and Systems Engineering, as well as the Department of Physics and Astronomy in Penn Arts & Science, and the Departments of Neuroscience and Psychiatry in Penn Perelman’s School of Medicine, and Zurn spoke with “Detroit Today” producer Sam Corey about what types of things make people curious, and how to stimulate more curiosity in our everyday lives.

According to the twin experts, curiosity is not a standalone facet of one’s personality. Basset and Zurn’s work has shown that a person’s capacity for inquiry is very much tied to the overall state of their health.

“There’s a lot of scientific research focusing on intellectual humility and also openness to ideas,” says Bassett. “And there are really interesting relationships between someone’s openness to ideas, someone’s intellectual humility and their curiosity and also their wellbeing or flourishing,”

Listen to “What makes people curious and how to encourage the act” at “Detroit Today.”

Register for a book signing event for “Curious Minds: The Power of Connection,” on Friday, December 9th at the Penn Bookstore.

This story originally appeared in Penn Engineering Today.

Posted on

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.

Posted on

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.

Posted on

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.

Posted on

‘Curious Minds: The Power of Connection’

Twin siblings and scholars Dani S. Bassett of Penn and Perry Zurn of American University collaborated over half a dozen years to write “Curious Minds: The Power of Connection.” (Image: Tony and Tracy Wood Photography)

With appointments in the Departments of Bioengineering and Electrical and Systems Engineering, as well as the Department of Physics and Astronomy in Penn Arts & Science, and the Departments of Neuroscience and Psychiatry in Penn Perelman’s School of Medicine, Dani S. Bassett is no stranger to following the thread of an idea, no matter where it might lead.

Curious Minds book cover

Those wide-ranging fields and disciplines orbit around an appropriate central question: how does the tangle of neurons in our brains wire itself up to learn new things? Bassett, J. Peter Skirkanich Professor and director of the Complex Systems Lab, studies the relationship between the shape of those networks of neurons and the brain’s abilities, especially the way the shape of the network grows and changes with the addition of new knowledge.

 

To get at the fundamentals of the question of curiosity, Bassett needed to draw on even more disciplines. Fortunately, they didn’t have to look far; Bassett’s identical twin is Perry Zurn, a professor of philosophy at American University, and the two have investigated the many different ways a person can exhibit curiosity.

Bassett and Zurn have now published a new book on the subject. In Curious Minds: The Power of Connection, the twins draw on their previous research, as well as an expansive network of ideas from philosophy, history, education and art.

In an interview with The Guardian, Bassett explains how these threads wove together:

“It wasn’t clear at the beginning of our careers that we would even ever have a chance to write a book together because our areas were so wildly different,” Bassett says – but then, as postgraduates, Zurn was studying the philosophy of curiosity while Bassett was working on the neuroscience of learning. “And so that’s when we started talking. That talking led to seven years of doing research together,” Bassett says. “This book is a culmination of that.”

How exactly do philosophy and neuroscience complement each other? It all starts with the book’s first, and most deceptively simple question: what is curiosity? “Several investigators in science have underscored that perhaps the field isn’t even ready to define curiosity and how it’s different from other cognitive processes,” says Bassett. The ambiguity in the neuroscience literature motivated Bassett to turn to philosophy, “where there are really rich historical definitions and styles and subtypes that we can then put back into neuroscience and ask: ‘Can we see these in the brain?’”

Curious Minds: The Power of Connection is available now. Read Amelia Tait’s review “Are you a busybody, a hunter or a dancer? A new book about curiosity reveals all,” in The Guardian. 

This story originally appeared in Penn Engineering Today.

Posted on

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.

Posted on

A Novel Method for Monitoring the ‘Engine’ of Pregnancy

Combining optical measurements with ultrasound, an interdisciplinary team from the School of Arts & Sciences, Perelman School of Medicine, and CHOP developed a device to better measure blood flow and oxygenation in the placenta. (Image: Lin Wang)

A study published in Nature Biomedical Engineering details a novel method for imaging the placenta in pregnant patients as well as the results of a pilot clinical study. By combining optical measurements with ultrasound, the findings show how oxygen levels can be monitored noninvasively and provides a new way to generate a better understanding of this complex, crucial organ. This research was the result of a collaboration of the groups of the University of Pennsylvania’s Arjun Yodh and Nadav Schwartz with colleagues from the Children’s Hospital of Philadelphia (CHOP) and was led by postdoc Lin Wang.

Schwartz describes the placenta as the “engine” of pregnancy, an organ that plays a crucial role in delivering nutrients and oxygen to the fetus. Placental dysfunction can lead to complications such as fetal growth restriction, preeclampsia, and stillbirth. To increase knowledge about this crucial organ, the National Institute of Child Health and Human Development launched the Human Placenta Project in 2014. One focus of the program is to develop tools to assess human placental structure and function in real time, including optical devices.

For three years, the researchers optimized the design of their instrument and tested it in preclinical settings. The process involved integrating optical fibers with ultrasound probes, exploring various ultrasound transducers, and improving the multimodal technology so that measurements were stable, accurate, and reproducible while collecting data at the bedside. The resulting instrumentation now enables researchers to study the anatomy of the placenta while also collecting detailed functional information about placenta blood flow and oxygenation, capabilities that existing commercially devices do not have, the researchers say.

Because the placenta is located far below the body’s surface, one of the key technical challenges addressed by Wang, a postdoc in Yodh’s lab, was reducing background noise in the opto-electronic system. Light is scattered and absorbed when it travels through thick tissues, Yodh says, and the key for success was to reduce background interference so that the small amount of light that penetrates deep into the placenta and then returns is still large enough for a high-quality measurement.

“We’re sending a light signal that goes through the same deep tissues as the ultrasound. The extremely small amount of light that returns to the surface probe is then used to accurately assess tissue properties, which is only possible with very stable lasers, optics, and detectors,” says Yodh. “Lin had to overcome many barriers to improve the signal-to-noise ratio to the point where we trusted our data.”

Read the full story in Penn Today.

The authors are Lin Wang, Jeffrey M. Cochran, Kenneth Abramson, Lian He, Venki Kavuri, Samuel Parry, Arjun G. Yodh, and Nadav Schwartz from Penn; Tiffany Ko, Wesley B. Baker, and Rebecca L. Linn from the Children’s Hospital of Philadelphia, and David R. Busch, previously a research associate at Penn and now at the University of Texas Southwestern Medical School.

Arjun Yodh is the James M. Skinner Professor of Science in the Department of Physics and Astronomy in the School of Arts & Sciences at the University of Pennsylvania. He is a member of the Penn Bioengineering Graduate Group.

Nadav Schwartz is an Associate Professor in the Department of Obstetrics and Gynecology in Penn’s Perelman School of Medicine.

Lin Wang is a postdoc in the Department of Physics and Astronomy in Penn’s School of Arts & Sciences.

This research was supported by National Institutes of Health grants F31HD085731, R01NS113945, R01NS060653, P41EB015893, P41EB015893, T32HL007915, and U01HD087180.