Ultrasound-based pacemaker noninvasively steadies the heart

MIT engineers have developed a noninvasive pacemaker that stimulates the heart using ultrasound. The design could one day provide a surgery-free alternative to traditional cardiac implants.The new device is designed as a small sticker that can be worn on the chest. Tiny transducers on the sticker send ultrasound pulses through the chest to stimulate the heart. The ultrasound waves trigger the opening of certain ion channels in heart cells, an effect the researchers amplified through genetic engineering. When the channels open, they let in calcium, which signals a heart cell to squeeze and beat. In experiments in the lab, the researchers applied ultrasound waves to engineered human cardiac cells and found that the pulses effectively maintained the cells’ healthy contractions. They also tested the ultrasound sticker on rats and found the device quickly, safely, and noninvasively corrected arrhythmias and restored normal, regular heart contractions. The team has fabricated a prototype that includes the ultrasound sticker (about the size of a postage stamp) and a small, pocket-sized device containing associated batteries and electronics. The same group previously demonstrated a sticker design that uses ultrasound to image deep organs and tissues. They now plan to combine the two approaches into one ultrasound sticker to simultaneously monitor and regulate the heart’s activity. “We believe you could one day have stickers on the body that could do long-term imaging deep in the body and also do stimulation for therapeutic effects, in a noninvasive closed-loop way,” says Xuanhe Zhao, professor of mechanical engineering and of civil and environmental engineering at MIT.Zhao and his colleagues, together with collaborators from Professor Qifa Zhou’s group at the University of Southern California (USC), have published their results in a study appearing today in the journal Nature Biomedical Engineering. The study’s MIT co-authors include first author Chen Gong, together with Runze Li, Won Jun Song, and former postdocs Gengxi Lu, Shucong Li, and Hsiao-Chuan Liu. Other collaborators include researchers from Harvard University, the University of California at Los Angeles, and other groups at USC.Sound genesToday, around 3 million adults in the United States live with pacemakers. The small battery-powered devices are surgically implanted in a person’s chest, and act to deliver electrical impulses to regulate heart rate. Implantable pacemakers are a well-established and generally safe medical treatment that nonetheless comes with risks.“Pacemakers are one of the most important and widely used human implants, and they have saved millions of lives,” the paper’s co-corresponding author, Gengxi Lu, says. “But they are invasive, and they make direct contact with the beating heart. The dream for many years has been noninvasive heart stimulation with ultrasound.” Ultrasound encompasses a range of acoustic waves that safely penetrates the body. Ultrasound waves reflect and resonate off structures in characteristic ways that allow technicians to resolve and image organs and tissues inside the body. Ultrasound can also be directed and focused to stimulate certain therapeutic effects, for instance in the brain, where scientists are exploring the use of ultrasound to treat Parkinson’s disease, Alzheimer’s, and other brain disorders. Scientists have also found that ultrasound can benefit the heart. Previous studies in animals have shown that focused ultrasound can safely activate heart cells, though the effect has been inconsistent and weak. Zhao and his colleagues looked to amplify ultrasound’s effects on the heart. In their new study, they applied sonogenetics, which is a relatively new approach that takes after optogenetics — a technique that involves genetically manipulating specific parts of a cell to respond to light. Similarly, sonogenetics aims to genetically engineer cells to respond to sound, including ultrasound. In their work to develop an ultrasound pacemaker, the team first looked to increase heart cells’ sensitivity to ultrasound, through sonogenetics. In the lab, they used standard practices to derive heart cells from embryonic stem cells, and then delivered a genetic alteration to the cells that increased their sensitivity to ultrasound. Specifically, the manipulation produced ion channels that opened more readily in response to ultrasound. “These channels can now ‘hear’ ultrasound better, and can open to let calcium in, which is what directly activates the cell and causes it to beat,” explains by the paper’s first author, Chen Gong. Sticker healthIn experiments with sonogenetically engineered heart cells, the researchers found that when they exposed the cells to ultrasound, the cells beat in sync with the waves, unlike cells that were not genetically manipulated. In any clinical application of an ultrasound pacemaker, the team envisions that a patient could first receive a one-time injection, similar to a vaccine, that would act to genetically boost the sensitivity of cardiac cells to the pacemaker’s ultrasound waves. The injection would be a form of gene therapy — a treatment that is currently approved by the FDA to treat certain inherited conditions such as sickle cell disease and spinal muscular dystrophy.“We think this step would be clinically translatable as a form of gene therapy that could enable noninvasive pacemakers,” Gong says.The team then designed the core of the ultrasound pacemaker, in the form of a postage-stamp-sized sticker embedded with tiny ultrasound transducers. The sticky part of the device is made from a hydrogel material that Zhao’s group has refined over the years to adhere strongly to skin and many types of materials, while also allowing ultrasound waves to pass through without weakening. The transducers within the sticker can be tuned to generate ultrasound waves at specific frequencies. In experiments with rats, the researchers first administered a sonogenetic, ultrasound-boosting solution through their tails. They then adhered a miniature version of the pacemaker to the rats’ chests. When they turned the stickers on, they observed that the ultrasound quickly regulated the animals’ hearts. Some individuals with slow heart rates were brought up to a normal rate, while others with irregular heartbeats were steadied, keeping in sync with ultrasound’s “ticks.”“We can now use low-intensity ultrasound to open ion channels in cells to have very effective heart pacing,” Gong says. “We are now making these stickers into smaller form factors, and more integrated, so they are easier to wear, more stable, and more accurate over a longer term.”“In this paper, we demonstrated noninvasive pacemaking. However, we think this concept could be useful beyond just the heart,” Zhao says. “We believe you could one day have stickers over different parts of the body that could do long-term imaging, monitoring, and closed-loop therapeutic stimulation.”This work was supported, in part, by the National Institutes of Health, the National Science Foundation, the Department of Opthamology from Research to Prevent Blindness, and the U.S. Department of War.