Building a Better (Micro) Bubble

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Mark Borden

Mechanical Engineering

Champagne bubbles, bubble baths, Bubble Wrap, bubblegum . . . From food and drink to soap and packaging materials, bubbles offer us a variety of benefits from enjoyment to mind-bending functionality.

One kind of bubble you may not have heard of—unless you’ve been into the doctor’s office for an echocardiogram recently—is a microbubble, a gas bubble with an ultrathin shell made of fat molecules, no bigger than 10 micrometers in diameter, or about the size of a red blood cell.

Microbubbles are excellent contrast agents for ultrasound imaging, according to Mark Borden, a CU-Boulder assistant professor in mechanical engineering. Microbubbles can circulate easily within the vascular system, deforming as necessary to pass through the finest capillaries, and they create a unique echo that sounds significantly different to an ultrasound scanner than the adjacent body tissue.

“It’s like ringing a big bell that makes a lower note than the surrounding tissue,” says Borden. “Fortuitously, the resonance frequency of a microbubble is matched to the ultrasound scanner so the echo is very strong, so much so that you can image a single bubble traversing the microvessels.”

Ultrasound images resulting from the use of microbubbles clearly depict the internal structure of a given tissue as well as the abundance and direction of the blood flow, which is a great improvement over regular ultrasound. Microbubbles can remain in circulation up to about 10 minutes, which is enough time to perform the scan, and the gas— nitrogen or a perfluorocarbon—ultimately is filtered through the lungs and exhaled, while the fat lipid is absorbed into the body.

While a relatively small volume of microbubbles are injected into a patient’s blood stream for the procedure, it still amounts to billions of microbubbles, so bubble size, uniformity, and encapsulation are extremely important, Borden says. More than 2 million patients have received microbubble injections in the United States since the FDA approved bubble echocardiograms about a decade ago.

The role of Borden’s research is to optimize the mechanical process and surface chemistry, ensuring both safety and efficacy—and ultimately, to build a better bubble for use in various biomedical applications. With a dual background in colloidal science (the study of substances microscopically dispersed throughout another substance) and biomedical engineering, he is perfectly positioned to advance both disciplines simultaneously.

One factor that will be important to the expanded use of microbubbles in clinical procedures is the creation of a coating or shell that allows the microbubbles to bind to a specific part of the body, such as an organ or tumor where therapy needs to be delivered.

Borden is working to put targeting molecules on the bubble surface so that they bind to diseased blood vessels, such as in a tumor or atherosclerotic plaque. The accumulated microbubbles can then be imaged to identify the extent of disease, not just for diagnosis, but also for following the response to therapy.

Microbubbles are already being used routinely in ultrasonic imaging of cancer, heart disease, and stroke in Canada, Europe, and Asia, and their use in more advanced medical treatments in the United States is only a matter of time.

Borden says that the United States has relied heavily on more expensive scanning methods, such as MRI, but as the nation seeks to reduce healthcare costs and provide more personalized medicine, hospitals will increasingly look to ultrasound as the imaging modality of choice. Already, medical school students are learning to carry laptopsized ultrasound scanners instead of the traditional stethoscopes.

Microbubbles are being designed for targeted drug and gene delivery, where they act as micro-syringes that can inject their cargo into tissue through the application of focused ultrasound.

There is strong interest in the medical community to develop microbubbles as a “theranostic” agent, an agent that is capable of providing both diagnostic information and therapy. The ultimate goal is to close the feedback loop for image-guided drug and gene therapy, where the microbubbles are imaged as they enter the treatment zone in the tissue and are simultaneously disrupted to release their pharmaceutical cargo. This allows the physician to observe and control delivery of the therapy.

The main challenge is to build a microbubble that can both efficiently deliver the pharmaceutical and simultaneously provide a strong signal for imaging. This requires a cross-disciplinary approach employing physics, chemistry, and biology.

Ultimately, Borden hopes to enable noninvasive microscopic surgery through the use of microbubbles that oscillate and fragment under the pressure of ultrasound waves, allowing a drug to be dispersed at the proper time and place. Toward this end, he was awarded several grants from the National Institutes of Health and National Science Foundation, the James D. Watson Investigator Award, and the NSF CAREER Award to investigate lipid-coated microbubbles as theranostic agents.

He works with several collaborators at CU and across the world to develop microbubbles and theranostic methods for the treatment of cancer, heart disease, and neurological disorders, and this work has been highlighted in Wired magazine, The Economist, CNN, and the Discovery Channel.

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