Implantable device uses ultrasound to improve drug delivery to the brain

Patients with glioblastoma, an aggressive type of brain tumor, usually undergo surgery to remove the tumor. However, it’s difficult for surgeons to remove all of the cancer cells, and the tumor often recurs.MIT researchers have now designed an implantable drug-delivery device that they hope could help prevent recurrence of glioblastoma. Their device contains a reservoir that can release drugs over an extended period, along with ultrasound transducers that use sound waves to help drugs spread farther through the brain and bypass the blood-brain barrier.Such a device could be implanted in the brain during surgery, then gradually release drugs that would help kill the remaining tumor cells. After implantation, a wireless controller can be used to program the exact ultrasound dosages to be delivered, enhancing the reach of the delivered therapy.“We have 24 transducers in one ultrasound array, which can help a given drug bypass the blood-brain barrier and enhance the drug infusion. The device also gives doctors options in terms of the size, the length, and the number of infusions,” says Canan Dagdeviren, an associate professor of media arts and sciences at MIT and the senior author of the study.In a paper appearing today in the journal Device, the researchers showed that their ultrasound device allowed molecules to spread further after being released, in tissue models and in a mouse study. MIT graduate student Sarah Ornellas and Jason Hou PhD ’26 are the lead authors of the study.Enhanced by ultrasoundGlioblastoma is a rare but deadly cancer, with a little more than 10,000 cases diagnosed in the United States per year. On average, patients survive 12 to 15 months after diagnosis. Patients typically undergo surgery to remove as much of the tumor as possible, followed by radiation and chemotherapy.Chemotherapy drugs are usually given either as pills or an intravenous infusion, but in recent years, scientists have developed drug-delivery wafers and hydrogels that can be implanted directly in the skull. That can help to eliminate the side effects of chemotherapy and ensure that a higher concentration of the drug reaches the brain.Those devices work by passive diffusion of drugs, but the MIT team wanted to design a new device that would allow for greater control of the timing of drug release. They also wanted to incorporate ultrasound arrays to enhance the distribution of drug molecules. Previous research has shown that ultrasound helps drug molecules to disperse more widely, by creating convective flows that help travel them longer distances. The mechanical oscillations generated by ultrasound waves also temporarily increase the permeability of the blood-brain barrier, helping drug molecules get into the brain.Dagdeviren had previously designed a tiny cannula, about as thin as a human hair, that could be implanted in the brain to deliver drugs. She also built an implant called ImPULS, which uses tiny ultrasound transducers to deliver deep brain stimulation.In the new study, her lab combined these technologies to create LUCID (Long-term Ultrasound-enhanced Convective Injection Device) — a flexible implant as thin as a sheet of cardstock. A drug-delivery cannula is 3D-printed directly onto an array of 24 miniature ultrasound transducers. These transducers generate ultrasound waves right at the tip of the needle, helping drug molecules to diffuse farther into tissue after they are released.“Getting a drug into the brain is only part of the challenge. It also needs to spread through the surrounding tissue. We brought a delivery channel and a tiny ultrasound array together in one implant to help molecules reach a larger area, even during slow infusion,” says Hou.The implant’s reservoir carries about 100 microliters of fluid, and infusion is supplied by a passive osmotic pump, while ultrasound can be controlled wirelessly through Bluetooth. The device also contains a small battery that can be recharged wirelessly. In tests in a “tissue phantom” — a gel-like material engineered to mimic human tissue — the researchers showed that ultrasound-aided delivery spread drug molecules much farther than when the drugs were delivered without ultrasound. “By enhancing that distribution locally and programmably with ultrasound, you can reduce systemic toxicity in nontarget organs, while the therapy that you’re using has a better chance of reaching whatever tumor cells are within the affected area,” Ornellas says.Wider distributionThe researchers also tested their system in mice, using it to deliver an MRI contrast agent. When the ultrasound array was activated, the contrast agent spread further through the brain than when ultrasound was not used.If developed for use in patients, the drug cannula and ultrasound array would be placed inside the skull, while the part of the device containing the battery and other electronics could sit outside the skull, the researchers say.In addition to delivering small-molecule drugs, this technology could also be used to deliver immunotherapies or nucleic acids, including gene therapies. It could also be potentially used in organs other than the brain.“We started with the brain as a follow-up to our ImPULS technology, but eventually this can be used for other soft tissue treatments for different types of drugs, different types of interventions in deep body tissue,” Dagdeviren says. “We are showing that we can make any kind of payload be distributed in a better way.”Other authors of the paper include Michal Nowicki, a research associate at Massachusetts General Hospital; Jerry Li, a recent graduate of Harvard University; Heloise Leblanc, a graduate student at Boston University; Betul Serra Tulu, an MIT undergraduate; David Sadat, a research specialist at MIT; Marco Mineo, an instructor in neurosurgery at Harvard Medical School; Steve Ramirez, an associate professor of psychological and brain sciences; and E. Antonio Chiocca, a professor of neurosurgery at Harvard Medical School and Massachusetts General Hospital. The research was funded by the MIT Media Lab Consortium and the National Institutes of Health.