According to the American Cancer Society, brain cancer impacts over 24,000 people in the United States each year, and more than 18,000 American will die of some type of brain cancer in 2023.

When a patient receives a diagnosis of a cancerous brain tumor, the typical plan of action is to remove the tumor surgically. Then chemotherapy is used to clean up the remaining cancer cells that are left behind. Unfortunately, brain cancers resist chemotherapy because the blood vessel lining stops large molecules that might harm the brain from passing through. This also stops chemo drugs and other therapeutics from destroying brain cancer cells and treating other brain diseases.

One way to breach the blood-brain barrier is using ultrasound to “shake” cells enough to open pores large enough to permit the medicine to pass. Getting ultrasound through the thick human skull, however, needs multiple, powerful ultrasound devices strategically placed around the skull and focused on the tumor site with an MRI machine right after chemo is given in the hospital. The process takes five or six hours and the powerful ultrasound can damage tissue; it’s rarely done more than once despite aggressive brain cancers requiring chemo treatment for months.

Using ultrasound each time the patient gets chemo would be more effective, but because the process is so cumbersome, it’s rarely done.

In response to this clinical need, University of Connecticut researchers built a new, biodegradable ultrasound implant far more powerful than past devices. The researchers reported their work in the June 14 issue of Science Advances.¹

“We can avoid all of that by using an implanted device within the brain itself,” biomedical engineer Thanh Nguyen told UConn Today. “We can repeatedly use it, allowing chemo to penetrate the brain and kill off tumor cells.”

Nguyen, along with graduate students Thinh T. Le and Meysam Chorsi—who is co-advised by Engineering Professor Horea Ilies and Engineering Dean Kazem Kazerounian—along with postdoc Feng Lin, devised a totally novel technique to build a biodegradable polymer ultrasound that’s as powerful as those made from ceramics, which can potentially be toxic and must be surgically removed before the treatment is done. The team has previously built a safe, biodegradable piezoelectric ultrasound brain implant before this, but it wasn’t as powerful as the traditional piezoelectric ceramics.

The plan was to use crystal of glycine, an amino acid that is common in the body and has been recently discovered to be strongly piezoelectric. Piezoelectric means the material vibrates when a small electrical current is run through it. These “smart” materials can convert mechanical force into electricity and vice versa, and are the core of many medical devices, including pressure sensors, actuators, and ultrasonic transducers. These devices are implanted in the body for many applications: generating ultrasound to facilitate drug delivery, ablating diseased tissues, and/or stimulating tissue healing.

Glycine is both safe and biodegradable, but perhaps too much so—it dissolves quickly in water. According to the researchers, glycine piezoelectric crystals are also brittle and shatter easily, making handling the material and shaping it into a useful ultrasound device quite difficult.

In order to address this challenge, the researchers grew glycine crystals, then purposely shattered them into pieces that are only a few hundred nanometers in size. The shattered crystals were then electrospun with the biodegradable polymer polycaprolactone (PCL) to create piezoelectric films made of nanofibers of glycine and PCL. Under voltage of about 0.15 Vrms, the film can reportedly generate ultrasound at 334 kilo-Pascals—the same as a ceramic ultrasound brain implant. The glycine-PCL film was then coated in other biodegradable polymers for protection. One possible coating, Poly-L-Lactide (PLLA), takes about six weeks to break down.

The UConn researchers then tested the device in mice with brain cancer. The mice were treated with paclitaxel (PTX), a very strong chemotherapy chemical that’s effective against brain cancer but challenging to get through the blood-brain barrier.

The glycine-PCL ultrasound allowed the PTX to successfully breach the blood-brain barrier, even reaching the deep brain regions. The tumors reduced in size and the treatment reportedly doubled the lifetime of mice afflicted with brain cancer compared to the mice that received no therapy at all. The combined glycine-PCL ultrasound and PTX treatment also proved to be vastly more effective for the mice than using PTX alone, or PTX and ultrasound from the original, weaker version of the researchers’ biodegradable ultrasound device, based on PLLA.

The UConn team has already completed a six-month safety analysis of the device implanted in the brain. They found it didn’t have adverse effects on the mices’ health, and reported that they will begin testing safety and efficacy in large animals. 

Reference

1. bit.ly/mpomusings0723