Mechanisms of Focused Ultrasound

Tissue Destruction

These methods rely on the direct disruption of tissue architecture and cell viability.

Thermal Ablation

Thermal ablation involves using high-intensity ultrasound energy to raise tissue temperatures to above 55°C, causing localized cell death while sparing nearby healthy tissue. Imaging modalities like magnetic resonance imaging (MRI) or ultrasound guide the procedure, and MRI thermometry can provide real-time treatment monitoring and thermal dose control.

This approach has been widely used to treat tumors in the uterus, prostate, breast, and liver, as well as neurological disorders such as essential tremor and Parkinson’s disease.

Histotripsy

Histotripsy is a nonthermal method that uses focused cavitation bubbles to mechanically ablate tissue with a high degree of precision. Short, high-intensity pulses generate cavitation bubbles in the targeted tissue, and as these bubbles collapse, they produce shockwaves that mechanically disrupt cell membranes, effectively liquefying the tissue. This method minimizes damage to surrounding structures and can be monitored in real time with ultrasound imaging.

Clinically, histotripsy is under investigation for treating cardiovascular diseases and various cancers, including those in the liver, kidney, and soft tissues. In 2023, the US Food and Drug Administration (FDA) cleared HistoSonics’ Edison™ platform to treat liver tumors, marking the first regulatory clearance for histotripsy worldwide.

Sonodynamic Therapy

Sonodynamic therapy uses focused ultrasound to activate sound-sensitive chemical agents (sonosensitizers) that accumulate in tumors. When exposed to ultrasound energy, these agents generate toxic free radicals that induce apoptosis, mirroring the effect of photodynamic therapy but without invasive light delivery.

This method allows for deep tissue targeting, conformal dosing, and reduced damage to healthy tissue. It is currently under clinical investigation for brain tumors, offering a promising noninvasive cancer treatment alternative.

Microvascular Occlusion

Microvascular occlusion involves using ultrasound-induced thermal or mechanical cavitation effects to selectively damage small blood vessels, halting blood flow and triggering ischemic tissue death.  

Enhanced Therapeutic Delivery

These approaches alter tissue permeability and the tumor microenvironment, and produce localized release to facilitate drug delivery or biological response.

Blood-Brain Barrier Opening

The blood-brain barrier (BBB) restricts drug delivery to the brain. Focused ultrasound, combined with intravenously injected microbubbles (MB-FUS), can temporarily and safely modulate the BBB. This enables larger molecules, immune cells, and gene carriers, to reach the brain for several hours post-treatment. MB-FUS may also enhance the effectiveness of therapeutics through other cellular mechanisms still being investigated.

This technique is under clinical evaluation for conditions like Alzheimer’s disease, ALS, and brain tumors, offering targeted therapeutic access previously blocked by the BBB.

Blood-Nerve Barrier Opening

Like the BBB, a blood-nerve barrier exists among peripheral nerve vasculature. MB-FUS transiently disrupts the tight junctions of the peripheral nerve blood vessels, enabling localized delivery of therapeutics to nerves.

Local Release of Carrier-Mediated Payload

Focused ultrasound can release therapeutics from encapsulated carriers like liposomes, microbubbles, and nanobubbles at targeted sites. These carriers circulate systemically and only release their contents when triggered by localized ultrasound, ensuring precise drug delivery with minimal systemic toxicity.

This approach is being explored for cancer and neurological diseases. Real-time imaging tracks delivery, and ultrasound’s mechanical and thermal effects can further boost drug absorption in target tissues.

Hyperthermia

Mild hyperthermia (40-45°C) induced by focused ultrasound can improve drug delivery and absorption without damaging tissue. This localized temperature rise enhances blood flow, vessel permeability, oxygenation, and metabolic activity in the targeted region, increasing the efficacy of many therapeutics.

Hyperthermia is being explored in cancer treatment, making tumors more responsive to chemotherapy and radiation.

Mechanical Streaming

Mechanical streaming involves using ultrasound-driven radiation forces to generate fluid movement that enhances interstitial drug transport within tissues.

This approach is currently being studied clinically for the treatment of pancreatic cancer.

Sonoporation

Sonoporation is when microbubble-enhanced cavitation induces temporary pores in cell membranes, improving intracellular delivery of drugs and genes.

Stromal Disruption

Mechanical forces from focused ultrasound can loosen and break down the dense extracellular matrix and tumor stroma, reducing physical barriers to drug penetration and thus enhancing therapeutic delivery in solid tumors.

This effect is being studied for the treatment of pancreatic cancer.

Immune Modulation

Focused ultrasound can modulate the immune response either by releasing antigens or altering immune cell behavior. While not always sufficient alone, the technology is under active investigation as a combination therapy to amplify anti-tumor immunity, particularly in difficult-to-treat cancers with dense stroma or immune-suppressive environments.

Antigen Release

Focused ultrasound-induced tumor destruction releases antigens and triggers danger signals that stimulate both innate and adaptive immune responses.

Cytokine Signaling

Ultrasound can shift cytokine profiles which leads to signaling of the immune system to respond to the target.

Increased Immune Cell Infiltration

Ultrasound can enhance the infiltration of immune cells to the target through MB-FUS BBB opening and vasodilation.

Enhanced Immunotherapeutic Delivery and Activation

Ultrasound can lead to improved delivery of immunotherapeutic medications to tumors, using MB-FUS and hyperthermic vasodilation.

CAR-T Cell Activation

Focused ultrasound is being explored as a method to remotely and noninvasively activate CAR-T cells through thermal or mechanical gene switches, enabling spatial and temporal control of immunotherapy with reduced systemic toxicity.

Neuromodulation

Focused Ultrasound can noninvasively modulate neural activity without damaging tissue.

Excitatory/Inhibitory Modulation of Neuronal Activity and Nerve Fibers

Neuromodulation with focused ultrasound allows noninvasive stimulation or suppression of neural activity. Low-intensity ultrasound can reversibly alter brain or nerve function without causing tissue damage.

This technique shows promise for treating neurological and psychiatric conditions like depression, epilepsy, obsessive-compulsive disorder (OCD), addiction, and chronic pain. It is also used to map brain networks and verify targets before permanent ablative therapies, making it both a diagnostic and therapeutic tool.

Cancer Biomarker Enhancement

Focused ultrasound can improve the detection and monitoring of cancers through biological amplification.

Release of Cancer Biomarkers

Mechanical disruption promotes the release of tumor-derived biomarkers such at circulating tumor DNA (ctDNA) and exosomes, improving the yield of liquid biopsies.

Blood-Brain Barrier Opening

MB-FUS increases the concentration of brain tumor-derived biomarkers in the bloodstream and cerebrospinal fluid.

Sonoporation

MB-FUS causes transient pore formation in cell membranes or endothelial barriers. This promotes the release and systemic availability of tumor-derived molecules, increasing their detectability in blood samples.

Radiation Sensitization

Focused ultrasound enhances the effect of radiotherapy by modifying the tumor’s physical and biological environment.

Hyperthermic Tumor Preconditioning

Focused ultrasound-induced mild hyperthermia impairs DNA repair in cancer cells and improves oxygenation, making the cells more radiosensitive. This allows for reduced doses of radiation, maintaining efficacy and minimizing damage to healthy tissues.

Increased Tumor Oxygenation

Focused ultrasound enhances tumor oxygenation by increasing blood flow, reducing interstitial pressure, and remodeling vasculature – sensitizing hypoxic tumors to radiation therapy.

Other

Stem Cell Homing

Focused ultrasound improves stem cell therapy by enhancing cell homing to damaged tissues. It stimulates the release of chemoattractant signals and increases expression of adhesion molecules, making it easier for stem cells to exit the bloodstream and reach target areas.

This technique is under study for a variety of conditions, including heart attack recovery, neurodegenerative diseases, and peripheral artery disease. By improving targeting and retention, it increases the potential effectiveness of regenerative therapies.

Stem cell differentiation

Focused ultrasound can influence stem cell fate, including differentiation into specific cell types such as neurons, osteoblasts, or muscle cells. This occurs through mechanical and/or thermal cues that activate intracellular signaling pathways, guiding lineage-specific gene expression.

This has been studied in preclinical models to signal stem cells to differentiate into neurons, bone cells, and muscle cells.

Vascular Occlusion

Focused ultrasound can achieve vascular occlusion by thermally sealing vessels or mechanically triggering clot formation. It offers a noninvasive approach for stopping internal bleeding or cutting off blood supply to tumors.

This technique is being investigated for treating liver trauma, arteriovenous malformations, and complications like twin-twin transfusion syndrome. It avoids catheters and minimizes the risk of unintended clot migration, making it an attractive option for delicate vascular interventions.

Clot Lysis

Focused ultrasound, with or without thrombolytic agents or microbubbles, can dissolve blood clots by disrupting the fibrin matrix or enhancing the effectiveness of clot-busting drugs. Ultrasound energy causes mechanical vibrations that break apart clots or render them more susceptible to treatment.

This noninvasive approach is under investigation for treating ischemic and hemorrhagic stroke, as well as deep vein thrombosis, offering a safer alternative to surgical or catheter-based interventions for clot removal.

Glymphatic Stimulation

Focused ultrasound may enhance the glymphatic system’s ability to clear waste and toxins from the brain, which is vital in preventing and managing neurodegenerative diseases such as Alzheimer’s. By modulating cerebral blood flow and transiently opening the BBB, focused ultrasound facilitates fluid exchange between cerebrospinal and interstitial fluids.

It may also stimulate neural activity and neurotransmitter release, promoting the clearance of amyloid-beta and other toxic proteins. This emerging application is being explored for its potential to support brain health and neuroprotection.