In the 1966 sci-fi film Fantastic Voyage, a submarine and its crew are miniaturized so that they could travel through the body of an injured man and attempt to repair damage within his brain. While we can’t shrink surgeons down to the size of a neuron, engineers are rapidly advancing technologies that operate at scale with cells and their even smaller components. Technology at the micro- and nanoscales opens up a new frontier of opportunities when it comes to fighting disease and increasing the quality of human health.
In order to centralize and concentrate research efforts in this space, the University of Pennsylvania has dedicated a $100 million investment to develop new laboratories and hire new faculty, culminating in the Center for Precision Engineering for Health ( CPE4H ). Directed by Daniel A. Hammer, Alfred G. and Meta A. Ennis Professor in Bioengineering and in Chemical and Biomolecular Engineering, CPE4H will enable Penn Engineers to develop technologies that will fight future pandemics, cure incurable diseases and extend healthy life spans around the world.
Daniel A. Hammer
Alfred G. and Meta A. Ennis Professor in Bioengineering and in Chemical and Biomolecular Engineering
Director, Center for Precision Engineering for Health (CPE4H)
“Penn is a unique environment where innovations in healthcare can emerge very rapidly, as we’ve seen with the development of CAR-T cancer immunotherapy, and the design and delivery of m RNA vaccines,” says Hammer. “Engineering plays a central role in making those technologies functional and maximizing their impact, and CPE4H is a golden opportunity to improve these and other novel technologies in a way that actually helps people.”
Engineers in CPE4H , the centerpiece of Penn Engineering’s Signature Initiative on Engineering Health, will focus on innovations in diagnostics and delivery, cellular and tissue engineering, and the development of new devices that integrate novel materials with human tissues. The center will leverage expertise in both biological and non-living materials to increase our under- standing of how cells and tissues operate in order to develop new treatments and medical innovations. “ CPE4H brings together innovators from Penn Engineering and across the University,” says Vijay Kumar, Nemirovsky Family Dean of Penn Engineering. “This further strengthens our existing ties with the Perelman School of Medicine, and focuses our efforts on technologies like biological materials, nanofluidics and biofabrication to solve the biggest health challenges.”
CPE4H is focused on how advances in molecular medicine, such as sequencing and the genome, might give way to personalized treatments. Its efforts will catalyze the ability to move healthcare from providing one-size-fits-all solutions to a system that can recognize the unique state of each individual to provide the best care. With a focus on precision engineering for health, the stories linked below include four examples of Penn Engineering faculty who are at the forefront of developing new technologies based on our increasing understanding of biology and human physiology to create new technologies for healthcare.
Inside the Ko Lab:
Tracking Living Tissues
The Challenge
When scientists create methods to detect disease biomarkers, they give healthcare providers better tools to properly diagnose and treat patients. However, limitations to obtaining this information, especially when using living cells and tissues from patients, prevents a complete picture of what is unique about a case and decreases the chance that the best course of treatment can be identified.
The Status Quo
Several techniques exist for identifying multiple biomarkers in cells, but they are usually not compatible with observing changes over time in living cells or are limited by a set number of biomarkers that can be profiled. The chemicals used to profile multiple (>5) biomarkers are toxic to the cells, preventing live cell monitoring. Due to this limitation, a full understanding of the protein expressions of the living cells could not be obtained and a clear picture of what is actually occurring during the course of cellular changes was out of reach.
The Ko Lab’s Fix
Jina Ko, Assistant Professor in Bioengineering, is working to overcome this limitation with a method known as “scission-accelerated fluorophore exchange” (or SAFE), a new way to detect biomarkers in cells that is highly gentle and allows for high multiplexing via cyclic imaging so that more biomarkers can be identified in a single sample and changes in living cells and tissues can be tracked over time. She first developed this method during her postdoctoral training at Massachusetts General Hospital under the supervision of Jonathan Carlson and Ralph Weissleder.
The method uses “click” chemistry, which is a bioorthogonal, non-toxic and rapid reaction that allows the team to highlight the desired biomarkers in the samples without destroying them each time a microscopy cycle is run.
SAFE can track nearly as many markers as necessary with ultra-fast kinetics because researchers can repeatedly stain cells in a living sample using the developed probes with fluorophores and then release those fluorophores following the imaging, repeating this cycle multiple times to achieve multiplexing. A cycle can profile 3 biomarkers, so if a researcher needs information on 15 markers, they would run the cycle 5 times to create the cell profile that they need within an hour.
Understanding activity in an individual’s living samples over time addresses the issue of subtlety and heterogeneity when identifying a patient’s unique disease response and allows for more tailored treatment approaches.
“You can’t identify a treatment that works for the average person, apply that treatment to everyone and expect the best outcomes,” says Ko. “Using this method, if we want to administer a therapy to a patient, we could remove a sample of their cells and use that sample to try different therapeutic options. After tracking the sample, we could predict if the patient would respond well to therapy A, but not therapy B. Our goal is that this technology will be applied in the clinic to help patients.”
Inside the Miskin Lab:
Cell-Sized Robots
The Challenge
Since their creation, robots and robotic devices have been used to go places and complete tasks that humans have deemed too “dull, dirty or dangerous.” However, there is not a way for humans to observe, explore or interact with the world of cells and cell-sized matter at scale using robotic devices.
The Status Quo
While for fifty years electronics have been getting smaller and smaller, smarts are only half the story; robots also need bodies and parts that move. Until recently, nobody knew exactly how to build the small actuators that are needed to construct a microscale robot.
The Miskin Lab’s Fix
Members of the research team led by Marc Miskin, Assistant Professor in Electrical and Systems Engineering, are harnessing new nanofabrication techniques to create robots that can operate on the same scale as cells and could therefore be used to interact with biology on a cellular level. Their robots can be mass-produced on a silicon wafer using the same techniques used to manufacture microchips, cost less than a cent each and are able to be injected through a syringe.
Measuring 70 microns across, about the width of a human hair or the size of a single-celled paramecium, the devices are too small to be seen with the naked eye, but can be made to move using onboard electronics.
A circuit board serves as the device’s torso and brain, and photovoltaic cells (think solar panels) decorate its surface. To enable movement, the group developed a new class of actuators called surface electrochemical actuators, or SEAs, which are platinum strips with rigid panels that serve as jointed legs. The legs fold at the joints when a charge passes through them because atoms from the surrounding water attach themselves to the surface of the platinum when it’s charged, allowing the robot to move. Put together, these pieces allow for a tiny walking robot: Hit the solar cells with a laser and it passes electricity to the legs, causing them to flex and the robot to walk through its fluidic environment.
In developing and deploying these robots, researchers could unlock a potential treasure trove of diagnostic and treatment capabilities. “We now finally have a match in size between cells and robots that you can communicate with and command,” says Miskin. “Biology is still leaps and bounds more complicated than electronics, but now that there is a foothold in this completely different dimension, what new medicine can you do that you couldn’t before?”
The team continues to improve upon their design, and is currently building more complex circuitry for sensing, computation and control to create robots that could be programmed to carry out specific tasks (like following a temperature gradient) automatically. Future plans include building robots specially designed to operate in the body, figuring out how they can work together as a swarm, or developing new tiny sensors to learn about the world around them.
Inside the Jiang Lab:
An Inventory of Immunity
The Challenge
In order to create personalized immune therapies, researchers need to untangle what is happening between an individual patient’s immune cells and the antigens that they interact with on a molecular level. Immune cell-antigen interactions need to be understood in four different areas in order to create a full picture: the unique genetic sequence of the T cell’s antigen receptors, the antigen specificity of that cell, and both the gene and protein expression of the same cell.
The Status Quo
Prior methods of understanding interactions between T cells and antigens could only get a picture of one or two of these four elements because of technology constraints. Other roadblocks included that cells cultured or engineered in a laboratory setting are not in a natural environment so they won’t express genes or proteins in the way T cells would in the body, and technologies that assess the antigen specificity of T cells were not cost-effective for looking at large numbers of antigens.
The Jiang Lab’s Fix
The lab of Jenny Jiang, J. Peter and Geri Skirkanich Associate Professor of Innovation in Bioengineering, developed a technology called TetTCR-SeqHD, which solves these problems. Using this technology, scientists can now simultaneously profile samples of large numbers of single T cells in the four dimensions using high- throughput screening.
Healthy humans can have hundreds of billions of T cells in their bodies, and these cells are specialized to respond to different antigens. This is further complicated by the fact that the T cells that respond to antigens like those delivered in vaccines are different in different individuals. Two different individuals’ T cells will not have the same set of T cell antigen receptors in their vaccine-responding cells, even though they received the same vaccine.
The Jiang Lab’s technology is essentially a method for getting a “full-body scan” of an individual’s T cells and creates a catalog of the different types of T cells and the antigens they respond (or don’t respond) to, paving the way for the ability to better target immune therapies to an individual patient.
To create this catalog, hundreds of thousands of T cells are mixed with hundreds of antigens in a test tube and allowed to bind. Afterward, those cells are separated inside a machine that has hundreds of thousands of micro- wells that each hold only a single cell. The individual cells are broken down and the genetic material is captured on a barcoded microbead, which is then used for sequencing and amplification so that researchers can identify the types of T cells according to the antigens they responded to and how many of those cells there are.
“Individual T cells are unique, and that’s the challenge of using one treatment to fit all,” says Jiang. “Identifying antigen specificity and creating therapies that target that specificity in an individual’s T cells will be key to truly personalizing immune therapies in the future.”
Crossing Biological Barriers:
Inside the Mitchell Lab
The Challenge
Solid tumors evade the immune system’s ability to attack them in part due to the tumors’ tough, fibrous biological barriers that circulating immune cells can’t cross. Researchers need to identify ways to deliver individualized treatments that can better target these tumors without causing damage to healthy tissues or affecting overall quality of life.
The Status Quo
Current cancer treatments typically involve surgery, radiation or chemo- therapy to eliminate solid tumors. These treatments are invasive and can cause numerous negative downstream effects. Newer treatments involve engineering a patient’s immune system to recognize and fight cancerous cells, but are so far only effective against certain “liquid” cancers, where the mutated cells circulate freely in the blood and bone marrow and are small enough to be picked off by the patient’s upgraded T cells. Additionally, existing methods can also require that the cell engineering take place in a lab rather than directly inside the body.
The Mitchell Lab’s Fix
Members of the lab of Michael Mitchell, J. Peter and Geri Skirkanich Assistant Professor of Innovation in Bioengineering, are looking to utilize nanoparticle delivery technology developed by their lab to engineer a different type of immune cell, the macrophage, in order to fight solid- tumor cancers from the inside.
Thanks to the widely publicized technology behind the m RNA -based COVID vaccines, many people know that you can use lipid nanoparticles ( LNP s) to deliver genetic instructions inside a cell in order to get that cell to change the way it functions. In the case of the vaccines, the nanoparticles smuggled m RNA inside of muscle cells in the upper arm to get those cells to produce the spike proteins of the COVID virus, which immune cells could then see, attack and create memory immune cells to fight against future infection with the actual virus.
The Mitchell lab is using the LNP method to carry mRNA and DNA sequences inside of macrophages, a type of immune cell that can consume tumor cells if engineered correctly. In theory, a patient would receive an injection carrying the LNP payload, and the macrophages, whose name literally means “big eaters,” would take up the genetic sequence, alter their function and be able to recognize a patient’s own unique tumor cells in the body.
Because of the way macrophages operate, they could cross the tumor’s biological barrier and attack the cells, destroying the tumor from the inside. An added benefit of the Mitchell Lab’s technology is that the destroyed tumor cells would then also allow other immune cells to present their antigens to circulating T cells, which could then learn to fight those same cancer cells in the future.
In contrast with other engineered macrophage work, scientists using this method would not need to remove the macrophages and engineer them outside the body. The Mitchell Lab’s technology could mean changing the future of solid- tumor cancer treatment from the status quo to one of receiving an injection.
“One of the longstanding challenges that we face in the context of cancer and immunotherapies is that every tumor has unique antigens that are specific to patients,” says Mitchell. “This is why we’ve had a lot of trouble developing targeted therapies. Personalizing an approach by harnessing an individual’s immune system gives each patient a greater chance of a positive outcome.”
CPE4H Seed Funding
The Penn Center for Precision Engineering for Health (CPE4H) recently announced its inaugural round of seed grants. These projects 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. Judged on technical innovation, potential to attract future resources and ability to address a significant medical problem, the following four projects were selected to receive funding
Evolving and Engineering Thermal Control of Mammalian Cells
Led by Lukasz Bugaj, Assistant Professor in BE, 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.
A Quantum Sensing Platform for Rapid and Accurate Point-of-Care Detection of Respiratory Viral Infections
Combining microfluidics and quantum photonics, Liang Feng, Professor in MSE and ESE, Ritesh Agarwal, Professor in MSE, and Shu Yang, Joseph Bordogna Professor in MSE and CBE, are teaming up with Ping Wang, Professor of Pathology and Laboratory Medicine in Penn Medicine, to design, build and test an ultrasensitive point-of-care detector for respiratory pathogens.
Versatile Coacervating Peptides as Carriers and Synthetic Organelles For Cell Engineering
Amish Patel, Associate Professor in CBE, and Matthew C. Good, Associate Professor of Cell and Developmental Biology in Penn Medicine, will design and create small proteins that self-assemble into droplet-like structures known as coacervates, which can then pass through cell membranes in order to deliver cargo that modulates cell behavior or be maintained as synthetic membraneless organelles.
Towards an Artificial Muscle Replacement for Facial Reanimation
Cynthia Sung, Gabel Family Term Assistant Professor in MEAM and CIS, will lead a research team that includes Flavia Vitale, Assistant Professor in Neurology and BE, and Niv Milbar, Assistant Instructor in Surgery in Penn Medicine. The team will develop and validate an electrically driven actuator to restore basic muscle responses in patients with partial facial paralysis.
Written by Olivia McMahon / Photos by Kevin Monko/ Illustrations by Pete Ryan