A group of bioengineers from Chan Zuckerberg Biohub Chicago and Northwestern University announced a significant advancement in sensors inserted beneath the skin and monitoring protein alterations in living animals as they occur. The new technology measured protein biomarkers of inflammation in diabetic rats with high accuracy and sensitivity in proof-of-concept tests published in the journal Science.
Close-up image of the implantable microdevice. Image Credit: Hossein Zargartalebi
Since proteins are the building blocks of life, variations in their levels can be a sign of inflammation or indicate that health is improving. Although periodic blood or urine tests can measure protein levels, it has proven difficult to determine how to continuously and in real-time monitor protein levels in the human body.
The study represents a major advancement in the knowledge of inflammation, one of the body's most intricate and significant processes. Inflammation-related illnesses, such as cancer and heart disease, are thought to be responsible for half of all fatalities.
The new technology sets the stage for tools that will be used to track, monitor, and even prevent inflammation in people. Similar to how continuous glucose monitors transformed the treatment of diabetes by improving patient outcomes and reducing overall healthcare costs, such a capability could fundamentally alter the way inflammation-related illnesses are treated.
This is a completely new capability to be able to watch inflammation in real-time. We hope one day this technology will benefit many people and provide a means to prevent advanced disease.
Shana Kelley, Study Senior Author and Professor, Northwestern University
Kelley is the President of Chan Zuckerberg Biohub Chicago.
Shake It Off
When it opened in 2023, the team at CZ Biohub Chicago set out to monitor inflammation by integrating bioelectronic sensors into tissues. The team first needed a method to quantify the amounts of protein cytokines, immune system-produced chemical messengers that attach to cells and cause inflammation.
However, there was an issue. Although many sensors can continuously detect small molecules, like glucose or electrolytes, it has proven more difficult to find protein sensors because they are larger and more complex than small molecules.
Scientists use molecules or proteins that firmly bind to proteins to extract them from fluids and detect proteins in biological fluids. However, because of the strength of that Velcro-like attachment, the receptors remain attached for over 20 hours, making it impossible to measure changes in protein levels in real time.
We recognized this fundamental obstacle and developed the idea that maybe we can shake the proteins right off of the sensors. And the first time we tried it, it worked beautifully.
Shana Kelley, Study Senior Author and Professor, Northwestern University
To bind a desired protein, the team created nanoscale sensors that resemble rows of bulbous pendulums. Each sensor comprises a DNA cord with a larger DNA fragment. Target proteins are “caught” by those sticky pendulums, which then shake back and forth to release the proteins and catch others in a minute.
The team then created an implantable microdevice with sensors built into a thin, three-hair-wide microneedle, resembling the microneedles found in continuous glucose monitors that diabetics use to check their blood sugar levels. The researchers inserted the gadget under the skin of diabetic rats. Inflammation and diabetes are closely related, with inflammation being the cause of many of the complications associated with diabetes.
In the fluid immediately beneath the rats' skin, the sensors were able to detect variations in the concentrations of two cytokine proteins, which are indicators of inflammation. The sensors saw the cytokine levels dwindling when the rats were fasting and their blood sugar levels were under control.
On the other hand, the sensors detected a sharp increase in inflammatory cytokine levels after the rats received an injection of an immune-stimulating drug.
“The Sky’s the Limit”
Kelley and the Chan Zuckerberg Biohub Chicago team are currently integrating the sensors into various tissue models of inflammation and using them to investigate inflammation in rats under various circumstances.
To identify strategies for guiding the immune system away from the “tipping points” that result in inflammatory disorders, Biohub's collaborative team of scientists, engineers, technologists, and physicians is embedding tissues with thousands of sensors and sampling probes to track immune cell activity in real-time.
The ultimate objective is to determine how to use this technology to track people's health. Researchers may be able to prevent and even treat inflammation-related diseases in the future, revolutionizing healthcare and saving lives if they can better understand and track inflammation in the human body in real time.
Like continuous glucose monitoring opened up the ability to monitor patients with diabetes in real-time, this has the same potential to allow us to monitor, and even prevent, many diseases. With inflammation, the sky's the limit with what you could do for your health by keeping a handle on it.
Shana Kelley, Study Senior Author and Professor, Northwestern University
The project is a major advancement in CZ Biohub Chicago's goal to develop technology that will enable accurate, molecular-level measurements of biological processes in human tissues.
The collaborative scientific research model of the CZ Biohub Network is directly responsible for these preliminary findings. The Chan Zuckerberg Biohub Network consists of four institutes, including CZ Biohub Chicago.
Journal Reference:
Zargartalebi, H., et al. (2024) Active-reset protein sensors enable continuous in vivo monitoring of inflammation. Science. doi.org/10.1126/science.adn2600.