Drill to the brain

May 07, 2022

(News from Nanowerk) Traumatic brain injury may have disappeared from the headlines since the NFL reached a $765 million settlement for concussion-related brain injuries, but professional football players aren’t the only ones affected by these wounds. Every year, between 2 and 3 million Americans suffer from traumatic brain injuries, whether they are elderly people who fall and hit their heads, teenagers who play sports or fall from a tree, or even of people who are victims of road accidents.

There is currently no treatment to stop the long-term effects of traumatic brain injury (TBI), and an accurate diagnosis requires a visit to a medical center for a CT scan or MRI, both of which involve large equipment and expensive.

Ester Kwon, a professor of bioengineering at UC San Diego who directs the Nanoscale Bioengineering Research Lab at the Jacobs School of Engineering, aims to change that. Kwon’s team is developing nanomaterials – materials with nanoscale dimensions – that could be used to diagnose traumatic brain injury on the spot, whether it’s a sports field, a car accident or a car crash. a clinical environment. They are also developing nanoparticles that could target the part of the patient’s brain that has been injured, providing specific treatments to treat the injury and improve the patient’s long-term quality of life.

“It’s really a dire condition for these patients, and TBI is unfortunately quite common,” Kwon said.

“Patients with head trauma will often experience changes in their motor function, cognitive abilities, and psychosocial behavior, such as depression.”

Crossing the blood-brain barrier

The diagnosis and treatment of brain damage has long hampered scientists and doctors for several reasons, the first of which is the blood-brain barrier. The barrier is a semi-permeable layer of cells intended to prevent potentially harmful toxins circulating in the blood from entering the brain. This barrier makes it difficult to introduce diagnostic or therapeutic particles into the brain.

To overcome the challenge of bypassing the blood-brain barrier, Kwon’s lab is taking advantage of recent insight into the field of cancer research.

“Nanomedicine has always been applied to the field of cancer,” Kwon said. “My lab has thought about how there are parallels in disease physiology between brain damage and cancer. For example, there are changes in the vasculature of a cancer patient – ​​the blood vessels of “a tumor aren’t normal, they have holes – and people have exploited that to get nanomaterials into the tumor through those holes. Similarly, in TBI, there are holes in the vasculature created by the injury that can be exploited to bring nanomaterials into the brain.

Diagnose a TBI

Kwon’s research group aims to diagnose TBI using biomarkers from a simple urine or blood sample. While scientists have known for decades that a class of enzymes called proteases show increased activity in injured parts of the brain, introducing a sensor into the brain to measure the activity of these proteases has remained elusive. Taking advantage of the vascular holes caused by TBI, Kwon’s team was able to develop a nanomaterial capable of detecting this protease activity and releasing a fluorescent signal at the exact location where the activity is increased.

Their studies, published in February 2020 (ACS sensors, “An activity-based nanosensor for traumatic brain injury”) and December 2021 (ACS Nano, “Targeting the extracellular matrix in traumatic brain injury increases signal generation from an activity-based nanosensor”), were the first demonstration of a sensor capable of detecting protease activity to identify and localize TBI in mice.

Follow-up studies in mice showed that levels of this protease activity detected by their nanosensors, which were administered intravenously, could be measured in blood and urine samples.

While researchers have yet to perfect the measurement of these protease signals from urine or blood samples before the TBI diagnostic tool can be used in humans, promising advances from a similar concept used for hepatic fibrosis are encouraging.

“A very similar type of material has already been used in humans to detect liver disease, which is exciting for us in terms of the approach being established as safe,” Kwon said.

Treat TBI

In addition to diagnosing TBI, Kwon’s lab is working to design nanoparticles that could be engineered to reach the specific part of the brain that has been affected, carrying a therapeutic payload to reduce inflammation or provide pro-regenerative therapies. These two components would work in tandem, with the diagnostic tool generating information about the exact type and location of the injury, to indicate which specific therapy would work best and where it should be administered.

“Our big dream is to create a precision medicine approach,” Kwon said. “Which is essentially understanding the molecular basis of disease and applying therapeutics specific to that molecular basis. Because the patient population is heterogeneous, if we know more precisely what is happening at the molecular level, we can potentially match therapeutics to their condition and hopefully mitigate side effects.

The nanoparticles his lab is developing are roughly the size of a virus. They consist of a polymer core that carries the desired payload, covered with an outer layer of peptides that give it a location to move to, like a GPS.

RNA charged nanoparticle

In addition to filling the core of these nanoparticles with therapeutic drugs, Kwon’s lab is also working to design a nanoparticle that could be used to transport RNA material to the brain for a variety of purposes, from reducing inflammation to stimulation of the growth of damaged cells. These particular nanoparticles are made from lipids that protect the RNA cargo and ensure that it can be released and activated when needed. This type of lipid nanoparticle carrying RNA cargo is similar to what is used in mRNA vaccines for COVID-19.

To date, there have been no targeted lipid nanoparticles that can reach specific cell types in humans that would be needed for use in the brain. Engineering these particles to target specific cell types in the brain is one of Kwon’s main areas of research.

For Kwon, all the possibilities and experimentation are part of the excitement of working at the heart of the two burgeoning fields of biological nanomaterials and neuroscience.

“In general, the field of brain nanomaterials is a few decades behind our brothers and sisters in cancer treatment,” she said. “There have been a lot of rapid developments in neuroscience – our knowledge of the basic biology of the brain – that have only happened in the last decade or so. And that’s setting the stage for engineers to start understanding how to design materials to interact with the brain in more sophisticated ways.

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