Professor Constantin Coussios, PhD, is the Director of the Institute of Biomedical Engineering and the Statutory Chair of Biomedical Engineering at the University of Oxford. He received the Silver Medal of the Royal Academy of Engineering in 2017 for his contributions to the clinical translation of novel technologies and was subsequently elected a Fellow of the Royal Academy of Engineering (FREng) in 2019. He was appointed an Officer of the Most Excellent Order of the British Empire (OBE) for his services to biomedical engineering as part of the Honours List during Queen Elizabeth’s Jubilee Birthday. Prof. Coussios holds BA, Meng, and PhD degrees in engineering from the University of Cambridge. Following postdoctoral appointments in Cincinnati and Boston, he moved to Oxford in 2004 to take up the very first faculty position in biomedical engineering in the university.
Research and Training Laboratory
At Oxford, Prof. Coussios founded and still leads the Biomedical Ultrasonics, Biotherapy, and Biopharmaceuticals Laboratory (BUBBL), a multidisciplinary research and training environment for combinational engineering of biology, chemistry, and medical devices to improve noninvasive therapies and drug delivery under a single roof.
The BUBBL team recently moved into a dedicated 2,000-square-meter building with state-of-the art facilities for therapeutic ultrasound research that is adjacent to Oxford’s clinical focused ultrasound unit. Today, BUBBL has grown to include seven principal investigators and more than 50 postdoctoral, doctoral, and clinical researchers working on a wide array of therapeutic ultrasound applications, ranging from noninvasive surgery and drug delivery to sonodynamic therapy, immune-modulation, transdermal vaccination, and stimulus-responsive tissue engineering.
To date, Professor Coussios and colleagues, Profs. Eleanor Stride, Robert Carlisle, Robin Cleveland, Malavika Nair, and Drs. Michael Gray and Dario Carugo have filed more than 30 patents in the field of therapeutic ultrasound. These discoveries have been licensed and thus far led to the creation of four spin-out companies:
- OxSonics Therapeutics is focused on cavitation-enhanced oncological drug delivery.
- OrthoSon Ltd. is using ultrasound-mediated fractionation for the minimally invasive replacement of intervertebral discs.
- Avrox Technologies specializes in the development of ingestible and injectable oxygen nanobubbles for therapy.
- SonoTarg is developing sonodynamic therapy for the treatment of pancreatic cancer.
This team has also overseen the clinical translation of several technologies into first-in-human clinical trials, ranging from kidney and liver ablation to targeted drug release and enhanced drug delivery to treat solid tumours.
In the following Q&A, Prof. Coussios further describes his background, basic and clinical research projects, and vision for the future of therapeutic ultrasound.
Focused Ultrasound Work
When and how did you get interested in focused ultrasound?
My interest in ultrasound started following my undergraduate studies in engineering at the University of Cambridge, where I was given the opportunity to complete my PhD under the supervision of Prof. Shon Ffowcs Williams, a world-leading expert in acoustics who was also one of the designers of the Concorde. Under his supervision, I began investigating the interactions between ultrasound and red blood cells – both experimentally and theoretically – and I came to realize that exciting interactions occurred between cells and sound waves at higher amplitudes than those conventionally used in diagnostic ultrasound.
My discoveries led me to seek a first postdoctoral fellowship in therapeutic ultrasound under Prof. Christy Holland at the University of Cincinnati, who introduced me to drug delivery, sonothrombolysis, and theranostic agents (e.g., liposomes and microbubbles). Under the Hunt Fellowship of the Acoustical Society of America, I then moved to Boston University to work with Profs. Ron Roy, Glynn Holt, and Robin Cleveland, where I had the opportunity to train in theoretical and experimental aspects of ultrasound-induced cavitation, active and passive cavitation detection, nonlinear acoustics, and ultrasonically induced heating.
What are your areas of interest in focused ultrasound?
I am interested in all applications of acoustics and bubbles in noninvasive therapy and drug delivery. My three current focus areas are oncological drug delivery using both cavitational and thermal ultrasound mechanisms; the use of ultrasound and novel stimulus-responsive particles for immuno-modulation – both in the context of cancer and for transdermal vaccination; and the further development of clinically relevant methods for real-time treatment monitoring, including passive acoustic mapping for cavitation imaging.
What mechanisms and clinical indications do you study?
My primary expertise is in the seeding, generation, mapping, and control of acoustic cavitation for therapeutic applications. Our research group is currently investigating clinical indications for oncological drug delivery and immune-modulation across the liver, kidney, and pancreas; thermal ablation and cavitation-enhanced thermal ablation of the liver, kidney, and pancreas; and emerging applications of cavitation-mediated delivery, including intracellular and transdermal drug delivery.
What is the goal of your work?
Everything we do is ultimately patient centric. As a research group, we seek to develop new platform technologies for delivering, optimizing, and monitoring focused ultrasound treatments that can be readily translated to the clinic by virtue of maximizing safety, efficacy, and cost effectiveness. We are particularly interested in indications that demand the precision and noninvasiveness of focused ultrasound. Beyond oncology, we also like to stray into novel applications, including orthopaedic applications, transdermal vaccination, and tissue engineering.
What are your funding sources?
Our mechanistic and technology development studies are primarily supported by the UK’s Engineering and Physical Sciences Research Council, including under a national program grant supporting the Oxford Centre for Drug Delivery Devices (OxCD3). Our clinical translation work is primarily supported by the UK’s National Institute for Health and Care Research (NIHR), as well as several charities, including Cancer Research UK and the generous support of several private donors.
Who are your team members?
BUBBL research is led by seven principal investigators (Constantin Coussios, Eleanor Stride, Robin Cleveland, Robert Carlisle, Mike Gray, Malavika Nour, and Dario Carugo) and conducted by approximately 50 postdoctoral and doctoral researchers. Our expanded clinical team includes focused ultrasound specialists Prof. Feng Wu and Mr. David Cranston, leading interventional radiologists Prof. Fergus Gleeson and Mr. Paul Lyon, leading oncologists Prof. Mark Middleton and Dr. Rachel Kerr, clinical academic anaesthetist Mr. Shaun Scott, and a number of clinical research fellows, including Ms. Laura Spiers and Mr. Jeffrey Rubasingham.
Who are your internal and external collaborators?
Internally, we collaborate extensively with the Oxford Departments of Oncology, Clinical Neurosciences, Orthopaedics and Musculoskeletal Sciences, Surgical Sciences, the Jenner Institute for Vaccine Development, and the Weatherall Institute of Molecular Medicine.
Externally within the UK, we form part of the ThunDARR Network, involving close collaborations with the Institute of Cancer Research (Prof. Gail ter Haar) and all other UK institutions involved in therapeutic ultrasound research.
Internationally, we collaborate with the United States National Institutes of Health (Dr. Brad Wood), Sunnybrook and the University of Toronto (Dr. Meaghan O’Reilly), the University of Cincinnati (Prof. Christy Holland and Prof. Kevin Haworth), the University of Washington (Prof. Larry Crum, Prof. Tom Matula, and Prof. Mike Bailey), the University of Illinois Urbana-Champagne (Prof. Ken Suslick), the University of Twente (Prof. Michel Versluis and Dr. Guillaume Lajoinie), and the University of Ulster (Prof. Tony McHale and Prof. John Callan).
What are your greatest achievements? Any major disappointments?
Our greatest achievement was the recent initiation and successful treatment of nine patients with metastatic colorectal cancer in the world’s first clinical trial of cavitation-enhanced drug delivery (CEeDD) from sonosensitive particles. This built on the successful completion of the first-in-human trial of extracorporeally triggered oncological drug delivery (Lancet Oncology 2018) and the establishment of the OxCD3 by working with several pharmaceutical and medical device companies to bring ultrasound-enhanced drug delivery to the clinic across several indications. No major disappointments to date!
What do you see as impediments to your success?
There are no major impediments to future success, only challenges that need to be overcome. A key challenge for our community is the continuous funding of brilliant international students from all walks of life and areas of expertise to seed and be trained within a vibrant, cross-disciplinary ecosystem; the purchasing and upkeep of an internationally cutting-edge infrastructure for preclinical and clinical focused ultrasound research; and the national and international funding and implementation of larger-scale, randomized clinical trials that can help make both the efficaciousness and health economic case for therapeutic ultrasound interventions over the current standard-of-care.
What is your research wish list?
To never have a finite research wish list…
Has the Focused Ultrasound Foundation played any role in your work?
The Foundation both directly funds pilot research within our laboratories and plays a significant role in connecting us to the international community of peers, the regulatory and reimbursement authorities, and a wide range of potential stakeholders involved in making focused ultrasound therapies a success.
How many patients have you treated?
We have treated more than 400 patients with focused ultrasound, both in the context of four consecutive clinical trials for liver ablation, kidney ablation, and drug delivery from thermosensitive liposomes (TarDox) and cavitation-inducing sonosensitive particles (via CEeDD), and as private patients for ablation in the liver, kidney, pancreas, and uterine fibroids.
Do you have any clinical research highlight stories?
Under the work of Feng Wu, Gail ter Haar, David Cranston, James Kennedy, Rowland Illing, and Tom Leslie, the first clinical highlight was the CE-marking of the first extracorporeal focused ultrasound device in Oxford in 2005.
The second major clinical highlight was the 2014 creation of the Oxford University spin-out company OxSonics, aimed at translating CEeDD to the clinic, which resulted in a first-in-human clinical trial of CEeDD for metastatic colorectal cancer in 2022.
The third major clinical highlight was the completion and publication of the first published study of focused ultrasound–triggered drug delivery in 2018 (Lancet Oncology), as described in the recent press release.
Any follow-up funding opportunities? What comes next?
Building on the momentum of the TarDox trial, we are keen to expand on translation and further clinical trials of ultrasound-mediated drug delivery, both in oncological and non-cancer indications, using current and emerging therapeutics.
The next frontier is the clinical exploitation of therapeutic ultrasound for targeted and systemic immune-modulation, both in the context of cancer and for other applications such as transdermal vaccination.