Focused Ultrasound: Engineering Sound into a Therapeutic Tool

Written by: Akash Gupta

Edited by: Nour Abou-Izzeddine, Gerard Murillo, Azeemah Odusanya, and Alanna Xue

Illustrated by: Jegg Yoon

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Introduction

Sound was previously perceived solely through hearing. Subsequently, the field of medicine revealed methods to visualize sound, converting reflected echoes into diagnostic imagery via ultrasound. In contemporary times, biomedical engineering is once again transforming the concept of sound, this time as a therapeutic approach. Focused ultrasound (FUS) utilizes high-frequency acoustic energy to destroy tumors, temporarily disrupt the blood–brain barrier (BBB), and adjust neural circuits without any surgical incisions. What originated as a practical application of physics has swiftly progressed into one of the most adaptable platforms in noninvasive medical practices. Unlike conventional ultrasound imaging, which distributes low-intensity sound waves broadly, FUS concentrates acoustic energy at millimeter precision deep within tissue. This allows clinicians to deposit energy at a target site while sparing surrounding structures. Over the past decade, advances in transducer design, real-time imaging guidance, and bioengineered adjuncts such as microbubbles have accelerated the translation of FUS from benchtop systems to FDA-approved therapies and human clinical trials [1,2]. Recent advances in focused ultrasound reveal the bioengineering principles that enable precise control of acoustic energy, the diverse mechanisms through which sound interacts with tissue, and a growing range of therapeutic applications in oncology, neurology, and regenerative medicine. Together, these developments illustrate how engineers are transforming sound from a diagnostic signal into a precision therapeutic tool.

Bioengineering Principles of Focused Ultrasound

Physics of Acoustic Focusing

At its core, focused ultrasound relies on the controlled propagation of acoustic pressure waves through biological tissue. By synchronizing the phase and amplitude of ultrasound waves emitted from multiple transducer elements, engineers can constructively interfere with sound energy at a focal point while minimizing exposure elsewhere. Modern FUS systems use phased-array transducers containing hundreds to thousands of individually addressable elements, enabling dynamic control over focal depth and geometry [2]. Acoustic lenses and adaptive beamforming further refine this process. Beamforming algorithms adjust the phase delays of individual transducer elements in real time to compensate for tissue-specific heterogeneity, such as variations in acoustic impedance across muscle, fat, or bone. This is particularly critical in transcranial applications, where the skull introduces significant attenuation and wavefront distortion [3].

Modes of Action: Thermal and Mechanical Effects

FUS operates across a spectrum of intensities, producing distinct biological effects depending on acoustic parameters. At high intensities, focused ultrasound induces rapid tissue heating through acoustic absorption, raising temperatures above 55°C and causing coagulative necrosis. This thermal ablation mechanism underlies FDA-approved treatments for uterine fibroids and prostate cancer [2]. At lower intensities, nonthermal mechanical effects dominate. Oscillating pressure waves can induce cavitation-controlled oscillation or collapse of gas bodies within tissue. When combined with intravenously injected microbubbles, these effects temporarily disrupt cell membranes and vascular tight junctions, a phenomenon known as sonoporation. Sonoporation enables localized drug delivery and transient BBB opening without permanent tissue damage [1,4]. Acoustic radiation forces provide an additional mechanism, exerting micron-scale mechanical stresses that can influence cellular signaling pathways and neural excitability. These forces form the basis of low-intensity pulsed focused ultrasound (LIFU) used in neuromodulation [6].

Control Systems and Real-Time Feedback

Precision control is essential to ensure both efficacy and safety. Modern FUS systems integrate real-time imaging—most commonly magnetic resonance imaging (MRI)—to guide targeting and monitor treatment. MRI thermometry allows clinicians to visualize temperature changes during sonication, enabling closed-loop feedback that dynamically adjusts acoustic power to prevent overheating [2]. Ultrasound-based feedback methods are also emerging, offering lower cost and higher temporal resolution. These control architectures reflect a broader trend in biomedical engineering toward intelligent, adaptive therapeutic systems that respond to tissue-level feedback in real time [3].

Engineering Challenges

Despite its promise, FUS faces significant engineering hurdles. Acoustic attenuation and scattering limit penetration depth, particularly in heterogeneous tissues. Skull-induced aberrations remain a major challenge for transcranial delivery, requiring patient-specific imaging and computational correction [3]. Additionally, ensuring reproducible acoustic dosing across devices and manufacturers remains an unresolved standardization issue, complicating regulatory approval and multicenter clinical trials [8].

Therapeutic Applications of Focused Ultrasound

Oncology

In oncology, high-intensity focused ultrasound (HIFU) has emerged as a noninvasive alternative to surgery and radiation for select solid tumors. Clinical applications include ablation of prostate, liver, breast, and uterine fibroid tumors, where FUS offers reduced recovery time and minimal collateral damage compared to conventional interventions [2]. Beyond ablation, FUS is increasingly explored as an adjuvant therapy. Microbubble-enhanced sonoporation improves local drug uptake by transiently increasing vascular permeability, enabling higher intratumoral concentrations of chemotherapeutics while reducing systemic toxicity [4]. Recent studies also suggest that FUS can remodel the tumor microenvironment, enhancing immune cell infiltration and potentiating immunotherapies through localized inflammation and antigen release [4].

Neurology

Neurological applications represent one of the most transformative frontiers for focused ultrasound. The BBB, while essential for neural protection, poses a major obstacle to drug delivery in neurodegenerative diseases. FUS-mediated BBB opening, achieved through low-intensity ultrasound combined with circulating microbubbles, allows large-molecule therapeutics such as antibodies to enter targeted brain regions safely and reversibly [5]. Clinical trials in Alzheimer’s and Parkinson’s disease have demonstrated the feasibility of this approach, with early evidence of enhanced amyloid clearance and improved drug penetration [5]. Importantly, these procedures are performed without craniotomy, marking a paradigm shift in neurotherapeutic delivery. FUS also enables noninvasive neuromodulation. LIFU can alter neuronal firing rates by applying mechanical forces to neural membranes, offering spatially precise modulation without implanted electrodes. This technique is being investigated for movement disorders, psychiatric conditions, and epilepsy, positioning FUS as a potential competitor to deep brain stimulation [6].

Regenerative and Pain Therapies

At even lower intensities, low-intensity pulsed ultrasound (LIPUS) promotes tissue regeneration rather than destruction. LIPUS has been shown to stimulate angiogenesis, osteogenesis, and soft tissue repair by activating mechanotransduction pathways and growth factor signaling [3]. Focused ultrasound is also gaining traction in pain management. Peripheral nerve ablation using FUS offers a noninvasive approach to treating chronic neuropathic pain, with recent U.S. clinical trial data demonstrating sustained pain reduction without surgical nerve damage [7]. These applications highlight FUS’s adaptability across a broad therapeutic spectrum.

Limitations, Safety, and Regulatory Considerations

Despite rapid progress, focused ultrasound is not without limitations. Physical constraints such as limited penetration depth and energy distortion restrict its applicability in deeply situated or acoustically shielded tissues. Biological safety remains paramount; uncontrolled cavitation can lead to hemorrhage or off-target tissue damage, necessitating conservative dosing and real-time monitoring [3]. From a regulatory standpoint, variability in acoustic parameters across devices complicates standardization. While several FUS applications have received FDA approval, most notably for uterine fibroids and essential tremor, broader adoption will require consensus on acoustic dose metrics, reporting standards, and long-term safety data [8]. These challenges underscore the need for interdisciplinary collaboration. Successful clinical translation of FUS depends on close integration between engineers, imaging scientists, clinicians, and regulatory bodies.

Conclusion

Focused ultrasound represents a rare convergence of physics, biology, and engineering into a single precision platform. Its ability to transition seamlessly between tissue ablation, drug delivery, neuromodulation, and regeneration makes it a compelling model for future theranostic technologies. As innovations in microbubbles, smart materials, and imaging feedback systems continue to mature, FUS is poised to redefine what noninvasive medicine can achieve. By engineering sound itself into a therapeutic tool, focused ultrasound exemplifies how fundamental physical principles can be translated into transformative clinical impact—quietly, precisely, and without a single incision.

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References

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