Published: Aug 15, 2022 By Hayley Shasteen

3D-printed acoustic hologram/courtesy of Columbia University

To most people, the term “3D-printed acoustic hologram” might sound like something straight out of a sci-fi movie. However, the plastic device could be very important to the delivery of certain therapeutics for Alzheimer’s Disease (AD) and other neurological disorders.

Researchers from the Universitat Politècnica de València (UPV), the Spanish National Research Council and Columbia University recently collaborated to create a 3D-printed acoustic hologram. The device is used in conjunction with focused ultrasound to allow for a more controlled and precise opening of the blood-brain barrier, a protective covering over all of the brain capillaries. BioSpace spoke with lead author Sergio Jiménez-Gambín, Ph.D., a postdoctoral research scientist in the department of biomedical engineering at Columbia, about the team’s work.

Safely Opening the Blood-Brain Barrier with FUS

Focused ultrasound (FUS) is a non-invasive procedure that uses radiofrequency or focused beams of sound waves to treat certain conditions. Currently, the FDA has approved FUS to treat essential tremor and Parkinson’s disease, although it may also be used off-label to treat some types of tumors and uterine fibroids.

FUS works by concentrating and focusing over 1,000 beams on a specific target in the body. The beams are able to raise the temperature of the targeted tissue, causing a lesion which can help to improve outcomes in certain diseases.

For example, in those with essential tremor or tremor-dominant Parkinson’s disease, the focused ultrasound can be delivered to an area of the thalamus, a part of the brain responsible for sensory relay and motor activity. In patients with tremor, some of the circuitry within the thalamus is abnormal. By creating a lesion, the therapy can interrupt and alleviate the abnormality, leading to improvement in tremors.

However, there are also other uses for the technology.

Two well-known applications where focused ultrasound, with or without acoustic holograms, is used are neuromodulation and blood-brain barrier opening, Jiménez-Gambín said. With neuromodulation, “There are applications aiming to control pain perception by FUS within certain nerves in the arms or legs. Also, neuromodulation can be applied within the brain for behavioral studies or memory impairment,” he noted.

In terms of the blood-brain barrier, “There is a limitation when trying to deliver therapeutic drugs within the brain to treat neurological diseases or brain tumors because the blood-brain barrier…does not allow the drug to cross it and therefore the disease cannot be treated,” Jiménez-Gambín continued. “FUS in combination with microbubbles circulating through the brain capillaries [is] a way to open the barrier in a safe and transient manner. When FUS is on, microbubbles start vibrating and this vibration expands the barrier joints, facilitating the drug to cross it.”

FUS has a set of unique problems when being used for brain applications, whether using a single-element or multi-element transducer.

“On the one hand, the single-element transducer, which has just one emitting element, is a spherically focused surface that allows the ultrasound to be focused at the center of that. The main advantage is that this approach is low-cost and really simple to use,” Jiménez-Gambín said. However, “When focusing ultrasound through the skull, the waves suffer a distortion and it’s difficult to control the targeted region within the brain.” 

This is where multi-element transducers come in. These transducers allow the user to “control the properties of the wave emitted by each element, and thanks to that, skull distortions suffered by the FUS can be corrected,” Jiménez-Gambín explained. This technology is high-cost, however, and not affordable for most research laboratories and/or clinical centers and hospitals, he added.

Jiménez-Gambín and his team set out to solve this problem. He said the group has always been interested in single-element transducers that would allow FUS to be a low-cost treatment option worldwide. In order to combine the low-cost benefits of single-element transducers with the precision of multi-element transducers, the group created the 3D-printed acoustic hologram.

The device is a plastic piece that can be attached to the front of a single-element transducer. It has more than 100,000 columns or elements that behave as individual emitting elements, effectively converting it into a multi-element device. The plastic piece can correct for skull distortion, allowing FUS energy to be accurately and locally delivered to multiple locations of the brain simultaneously.

The team tested the acoustic holograms in mice to determine whether the device added to a single-element transducer could bilaterally open the blood-brain barrier. The results of the study, published in IEEE Transactions on Biomedical Engineering, demonstrated proof of concept, selectively opening the blood-brain barrier in both hemispheres of the brain. It was the first time such a feat had been accomplished, UPV stated in a press release. The team also achieved a resolution that was superior to current FUS standards, which will ultimately allow for more precise targeting of specific brain areas.

Jiménez-Gambín said the next step will be clinical procedures. “First, studies will be carried out in monkeys, whose skulls are more similar to [that of a human],” he noted. “Finally, the goal is to define a protocol in humans.” 

Inserting FUS and microbubbles into the bloodstream could open up the brain for the introduction of various therapeutics. This could enable the delivery of drugs to the central nervous system to treat diseases like AD. The blood-brain barrier limits drug delivery to the CNS because it generally only allows molecules that are lipophilic and those that have low molecular weight. Approximately 98% of small molecules, and nearly all large therapeutic molecules - including monoclonal antibodies - are unable to pass through the blood-brain barrier, limiting their ability to treat neurological conditions, researchers note in ACS Publications.

Currently, FUS is being studied in a variety of clinical trials for AD including a Phase II study headed by the Sunnybrook Research Institute in Toronto. The first-of-its-kind trial aims to investigate the safety and feasibility of FUS in people with AD. In preclinical studies, the group found that combining low-intensity focused ultrasound with microbubbles allowed them to directly deliver therapies into the brain.

“Currently, there is no available therapeutic technology to efficiently treat brain diseases that is affordable, which considerably limits the advances and improvement in developing therapeutic drugs for these neurological conditions,” Jiménez-Gambín said. “My research...has been demonstrated to have great potential to solve this limitation and defines a new path for the future in the biomedical field.”

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