Key Points
- Dr. Holland develops ultrasonic tools for the treatment of cardiovascular disease, including blood clots, stroke, deep vein thrombosis, and peripheral artery disease (PAD).
- Her proudest achievement is in the number of – and quality of – students she has trained.
In 2024, Christy Holland, PhD, became the interim director of the University of Cincinnati (UC) Center for Cardiovascular Research and has served as a professor of internal medicine in the Division of Cardiovascular Health and Disease, Biomedical Engineering, and Radiology at UC for the past 16 years. During her 31-year tenure at UC, she has mentored students from both the College of Medicine and the College of Engineering and Applied Sciences in the Image-Guided Ultrasound Therapeutics Laboratories and taught courses in biomedical engineering, medical imaging, and biomedical research design.
With nine issued patents and two patent applications in her intellectual property portfolio, Dr. Holland conducts basic and translational research on the bioeffects of diagnostic and therapeutic ultrasound, acoustic cavitation, sonothrombolysis, ultrasound-mediated drug and bioactive gas delivery, echogenic liposomes, and histotripsy. She has developed ultrasonic tools for the early detection of cardiovascular disease, and the catheter devices that she has helped engineer are used therapeutically for ultrasound-guided thrombus ablation. Dr. Holland also has a personal interest in developing treatments for deep vein thrombosis as well as PAD and other cardiovascular diseases.
Since starting her acoustics research career in 1989 on the American Institute of Ultrasound in Medicine (AIUM) Bioeffects Committee for diagnostic ultrasound imaging, Dr. Holland has been a pioneer in recognizing and developing the therapeutic potential of the technology. Beyond her academic prowess, however, her proudest achievement is in the number of – and quality of – students she has trained. In fact, if you have read many of our investigator profiles and research stories, you will see Christy Holland mentioned as a mentor for Constantin Coussios, PhD, Tyrone Porter, PhD, Kenneth Bader, PhD, Kevin J. Haworth, PhD, Himanshu Shekar, PhD, Karla Mercado-Shekhar, and Maxime Lafond,PhD, among others.
We interviewed Dr. Holland to learn more about her research and her “most important work:” mentorship.
How did you first begin working with ultrasound?
I became interested in ultrasound after I was recruited to work in Bob Apfel’s acoustics laboratory at Yale University. He studied ultrasound cavitation and cavitation physics. When I was in my postdoctoral training, Mark Schafer was serving on committees for NEMA (the National Electrical Manufacturers Association), IEEE (the Institute of Electrical and Electronics Engineers), and AIUM – organizations that work together to develop safety standards for ultrasound devices. Mark asked me to assist one of the committees help the FDA understand how to regulate the output of diagnostic ultrasound scanners, as there were concerns about thermal energy deposition and cavitation. Because there is a theoretical relationship between cavitation nucleation and the acoustic pressure output, I set the optimal size nucleus as a worst-case calculation and used that to create a mechanical index. Bob and I wrote that paper in about two days, over a weekend, and it has become my highest cited paper (See R. E. Apfel and C. K. Holland, “Gauging the likelihood of cavitation from short pulse, low duty cycle diagnostic ultrasound,” Ultrasound Med Biol, 1991.) Mark Schafer encouraged me to develop the theoretical underpinning of this index. After Bob shared a draft of the paper with the AIUM Bioeffects Committee as it was reviewed for publication, I was asked to respond to all the comments! My response to the reviewers’ comments was about 85 pages long, but that is what I had to do. After that, I was on everybody’s dance card as an invited speaker.
In a full-circle moment at AIUM 2024, Dr. Holland was awarded the prestigious William J. Fry Memorial Award. The title of her Fry Lecture was “Ultrasound Image-Guided Catheter-Directed Therapies to Treat Cardiovascular Disease.”
You then presented that project to the FDA?
The ultrasound companies invited me to present my work at many different seminars and wanted Bob and me in the room for FDA review of regulating diagnostic ultrasound output. But I wanted to present the mechanical index to FDA independently, without being paid by a company to do so. I had to talk Bob into spending National Institutes of Health (NIH) travel money to go to the FDA and present our work. So, we drove some clunky car down through New York to get to Silver Spring, MD, and the first question we were asked was, who paid for your trip here? We were not in anybody’s back pocket, so that decision to attend independently helped. I did not patent that work, but it was incorporated on the screen of every diagnostic ultrasound scanner in the world. I was proud of that.
How did you move from diagnostic into therapeutic ultrasound?
Because we were still concerned about the potential for negative or deleterious bioeffects from diagnostic ultrasound in the early 1990s, we conducted preclinical studies to try to cause damage in the lungs with diagnostic ultrasound exposure. The pathology revealed the presence of erythrocytes in the alveolar septa (small bruises), which meant that tight endothelial junctions were opening up, leading to the potential to develop ultrasound-mediated drug delivery. It was super cool. That was when my whole career took a 90-degree turn. I was so fascinated that I was no longer worried about the bioeffects of diagnostic ultrasound, even with the advent of echocontrast agents that could serve as cavitation nuclei. I wanted to use ultrasound for therapeutic benefit instead of worrying about the deleterious effects of diagnostic ultrasound. In fact, that worry has probably held the field of therapeutic ultrasound back.
What ultrasound applications do you study?
Sonothrombolysis. Many drugs do not work well, such as tissue plasminogen activator (tPA) – the only US Food and Drug Administration (FDA)–approved lytic. On its own, tPA cannot penetrate highly retracted or “organized” blood clots or diffuse into biofilm. I have always thought that there is a Goldilocks, or “just right” amplitude of ultrasound that could aid diffusion and help drugs work better, so I had the idea to use a low amount of bubble activity to increase drug absorption through microstreaming and radiation force. The applications are for stroke, DVT, and pulmonary embolism. The lytic tPA can also be used for treating biofilms, which are built on a mesh of fibrin. We have also looked at histotripsy as a method to accelerate sonothrombolysis.
Cerebral Protection After Stroke. I am also interested in using Xenon as a cerebral protectant during ischemia reperfusion events in the brain, which occurs when blood flow is restored for ischemic stroke. The brain’s neurons contain receptors for an excitatory neurotransmitter called N-methyl-D-aspartate (NMDA). If we can place Xenon onto to overexcited NMDA receptors, the overexcitement is blocked, and apoptosis or cell death is prevented until oxygen comes flowing back in. We can use ultrasound to prevent an ischemia reperfusion injury by putting the cells in sleep mode and waking them up slowly. I have patented some of this work and am keen to license this technology.
What ideas and designs have you patented?
I now have been a part of developing 11 patents, including a recent Boston Scientific device. It has been fun to have the folks at Boston Scientific who produce the EKOS catheters ask me to help them build better catheter-based products.
How do you file and maintain patents?
UC sometimes sends intellectual property to a local patent firm that completes the filing and maintenance on a pro bono basis. The firm writes the patent applications quite efficiently after talking with me for about 20 minutes. After one or two editing cycles, they submit the application. If you really care about changing the way people practice medicine, you have to care about licensing patents. Publications help, but until a company can own something, it is not going to invest in developing a device. It is expensive to take a device all the way through FDA approval and get it into a physician’s hands. So, you must be willing to file patents. I have not benefited from it financially, but I am passionate about it.
What are your funding sources?
Most of my work has been funded by the NIH National Heart, Lung, and Blood Institute (NHLBI) and National Institute of Neurological Disorders and Stroke (NINDS). Like many scientists in the United States, I’m waiting to hear whether my research applications will be funded. My application for an ultrasound-mediated drug delivery approach to treating PAD with David McPherson at University of Texas Health Sciences Center received a fundable score, so in normal times it would have already been funded. I also have two pending R01 applications in collaboration with other researchers. A couple of my projects are funded by Lantheus, and I have a few other industry-sponsored projects.
What is your personal interest in treating PAD?
My mother-in-law, a dynamic Italian American woman who played tennis every day, stopped playing tennis when she was 82 years old because she couldn’t feel the ground and was worried about falling. A vascular surgeon diagnosed her with severe PAD, despite not having diabetes. She underwent several procedures that failed, including balloon angioplasty and grafts, but ended up with an above-the-knee amputation. When she was 83 years old, she actually learned how to walk again with a prosthetic leg because she had strength from playing tennis all of her life. That inspired my interest in treating PAD, so I hope the project funding comes through.
How would you use therapeutic ultrasound to treat PAD?
The deployment of stents for PAD causes proliferation of the cells lining the arteries, or neointimal hyperplasia. We would use ultrasound to push pioglitazone beyond the endothelium at the time of stent deployment. Pioglitazone is an anti-inflammatory drug that slows the progression of atherosclerosis, rather than just move the plaque out of the way. However, the drug has been shown to increase the risk of bladder cancer and other common cancers when taken orally. Direct release through a catheter enables a lower effective dose to be employed. The hypothesis is that ultrasound-mediated drug delivery at the time of stent deployment might prevent – or at least prolong – the action of one stent and delay the need for grafts and amputation.
What devices do you use for your research?
We use the Boston Scientific EKOS™ endovascular system catheter right out of the box. But we can also tailor the ultrasound pulses to explore other strategies to increase penetration of drugs into atheromatous tissue, or blood clots. The multi-sideport catheter design uses an ultrasound core with either 6 or 12 pairs of transducers. This catheter allows us to infuse drugs or DEFINITY® microbubbles with pulsed ultrasound exposure. We are studying ways to optimize the pulsed ultrasound scheme to maximize bubble activity and the diffusion of the drug into target tissue.
Have your translational research studies been integrated into clinical trials?
Some of my thrombolysis work has been included in clinical trials. The clinical investigators often reached out to me during the trials. For sonothrombolysis in stroke trials, recanalization times are shorter, but the clinical outcomes have not improved. We can dissolve a clot faster, but that doesn’t yet mean that that patient will be able to feed themselves and swallow. I like doing translational studies, because it is such an important step for getting innovation to patients.
How many people are currently working in your lab?
I have one resident, one masters student, and one undergraduate senior capstone student right now. I have additional administrative roles serving as interim director of the Center for Cardiovascular Research and Vice Chair for Basic Research in the Department of Internal Medicine, so I am doing less of my own research.
Who are your internal collaborators?
Internally, I collaborate with Kevin Haworth, PhD, who stayed at UC after completing his postdoctoral work in my lab. I am helping him develop ultrasound-mediated, controlled hypoxemic reperfusion for inhibition of reperfusion injury. The goal of this project is to develop a catheter-based system to reduce myocardial injury during reperfusion.
I am also a co-investigator with Riccardo Barrile, PhD, on a proposed project to leverage focused ultrasound for targeted drug delivery in glioblastoma using an organ-on-chip approach. The goals of this project are to determine tissue repair mechanisms following ultrasound-mediated blood-brain barrier disruption, identify new therapeutic strategies to improve drug delivery, and provide a validated model for personalized glioblastoma treatments.
Who are your external collaborators?
I have had many external collaborations over the years, including the following:
- John Racadio, MD, pediatric interventional radiologist at Cincinnati Children’s Hospital Medical Center: Lead surgeon for the porcine stroke and DVT studies
- Todd Abruzzo, MD, head of pediatric neuroendovascular therapy at Phoenix Children’s Hospital: Ultrasound-assisted thrombolysis for stroke therapy
- David D. McPherson, MD, FACP, FACC, FAHA, director of cardiovascular medicine at the University of Texas Health Science Center at Houston: Delivery of targeted echogenic liposomes
- Curtis Gentsler, MD, senior fellow at Boston Scientific: Catheter-directed therapies for acute DVT
- Kenneth Bader, PhD, assistant professor of Radiology at the University of Chicago: Localized thrombus ablation with histotripsy and echogenic liposomes
- Adam Maxwell, PhD, research associate professor of biomedical engineering and mechanics at Virginia Tech: Localized thrombus ablation with histotripsy and echogenic liposomes
- Klazina Kooiman, PhD, associate professor and head of Therapeutic Ultrasound Contrast Agents at Erasmus MC, The Netherlands: Sonobactericide: Biofilm treatment
- Nico de Jong, PhD, professor of Molecular Ultrasonic Imaging and Therapy at the Erasmus MC and the Technical University of Delft, The Netherlands: High-speed imaging of echogenic liposomes
- J. Brian Fowlkes, PhD, professor of Radiology and Biomedical Engineering at the University of Michigan: Bioeffects and safety of diagnostic ultrasound
How many focused ultrasound investigators have trained in your lab?
It is a cohort, for sure. I have trained 18 postdoctoral fellows, 20 graduate students, 8 medical students, and 41 undergraduate students, many of whom are industrial, academic, or clinical scientists.
What is your greatest achievement?
What I talk about most (according to my mom) is the people I have trained. My mom recently said, “I have no idea what your patents are. I have no idea about your publications, but I know the names of all your postdocs and grad students.” Of the awards that I have received, the ones that are the most meaningful are for teaching, especially when the students nominated me.
Do you have any major disappointments?
I have learned from my mistakes. I am frustrated in not being able to spawn companies. I like Cincinnati, and there are great people here – so I would love to see them employed locally after finishing their degrees. I don’t mind being a conduit for the people that I’ve trained to go to big name schools afterwards, but it would be nice if they had companies here to return to.
What do you see as impediments to your success?
The US Federal Government is launching an attack on science. I would love to talk about the next idea instead of defending scientifically established facts. It bothers me when people aren’t truthful, because scientists want to uncover the truth, no matter what it is. It is very hurtful for scientists to be accused of not being truthful.
What is on your research wish list?
People! I’ve always thought of the world as the world, not as United States against the world. And I have been successful in attracting the best and brightest minds to my lab, but now I think it’s going to be difficult. The next generation of students coming through were hit by the COVID-19 pandemic academically, so I’m concerned about that. I am always focused on people.
Has the Foundation played a role in your work?
I served on some of the Foundation’s early working groups, including the Ischemic Stroke Working Group and Intracerebral Hemorrhage/Intraventricular Hemorrhage Working Group. I have been a champion of therapeutic ultrasound for a long time.
You also served as the editor for the UMB journal for many years. Tell us about that.
I was the editor-in-chief of Ultrasound in Medicine & Biology for 15 years. It was a night job that was a huge amount of work. For example, I adjudicated 1,200 papers in 2021. One positive outcome from that time was a program that the World Federation of Ultrasound in Medicine and Biology (WFUMB) created to establish new centers of diagnostic ultrasound education in several countries in Africa, Central America, and Asia. I was able to travel to many countries to help establish the centers, and the program is continuing. Now there are ultrasound scanners in places like Kenya, Guatemala, Tanzania, and Vietnam.