We have developed a safe, noninvasive imaging-guided localized antivascular method, namely photo-mediated ultrasound therapy (PUT), by applying synchronized laser and ultrasound pulses. Through our experimental and theoretical studies, we demonstrate that cavitation plays a key role in PUT. PUT promotes cavitation activity in blood vessels by concurrently applying ultrasound bursts and nanosecond laser pulses. The collapse of cavitation can induce damage to blood vessel endothelial cells, resulting in occlusion of microvessels. This study presents the effect of laser pulse energy, laser pulse length, ultrasound intensity, and synchronization time between laser and ultrasound. We found that, in order to produce controllable blood vessel occlusion, linear oscillation of cavitation (or non-inertial cavitation) might be the key, while strong collapse of cavitation (inertial cavitation) might induce bleeding. Under the guidance an optical coherence tomography (OCT) system, we utilized PUT to remove microvessels in the rabbit choroid. We were able to monitor cavitation activity in real-time in vivo during PUT treatment, and predict treatment outcome. Histology findings confirmed that fibrin clots were developed in the microvessels in the treated region, while no damage was found in the surrounding tissue.
Wet age-related macular degeneration (AMD) is a leading cause of vision loss in the United States. Choroidal neovascularization (CNV), the creation of new blood vessels in the choroid layer of the eye, plays a central role in the pathophysiology of wAMD. Despite advanced anti-VEGF therapy, 20% of patients become legally blind and other 30% suffer significant vision loss after 5 years. Given the significant burden imposed by wAMD on a growing aging population, there is an urgent need for developing new therapeutic techniques to remove microvessels induced by CNV. We developed a safe, noninvasive imaging-guided photo-mediated ultrasound therapy (PUT) technique as a localized antivascular method, and applied it to remove microvessels in the rabbit choroid. This technique promotes cavitation activity in blood vessels by concurrently applying ultrasound bursts and nanosecond laser pulses. The collapse of cavitation can induce damage to blood vessel endothelial cells, resulting in occlusion of microvessels. PUT takes advantages of the high native optical contrast among biological tissues, and has the unique capability to self-target microvessels without causing surrounding damages. Under the guidance of a fundus camera and an optical coherence tomography (OCT) system, our PUT system now has the capability to precisely target the treating area before the treatment procedure (through the fundus camera), and real-time intra-treatment cavitation monitor to evaluate the therapeutic effect (through the OCT system). Additionally, the safety of PUT technique is confirmed by histopathological studies.
Retinal and choroidal neovascularization play a pivotal role in the leading causes of blindness including macular degeneration and diabetic retinopathy (DR). Current therapy by focal laser photocoagulation can damage the normal surrounding cells, such as the photoreceptor inner and outer segments which are adjacent to the retinal pigment epithelium (RPE), due to the use of high laser energy and millisecond pulse duration. Therapies with pharmaceutical agents involve systemic administration of drugs, which can cause adverse effects and patients may become drug-resistant.
We have developed a noninvasive photo-mediated ultrasound therapy (PUT) technique as a localized antivascular method, and applied it to remove micro blood vessels in the retina. PUT takes advantage of the high native optical contrast among biological tissues, and has the unique capability to self-target microvessels without causing unwanted damages to the surrounding tissues. This technique promotes cavitation activity in blood vessels by synergistically applying nanosecond laser pulses and ultrasound bursts. Through the interaction between cavitation and blood vessel wall, blood clots in microvessels and vasoconstriction can be induced. As a result, microvessels can be occluded. In comparison with other techniques that involves cavitation, both laser and ultrasound energy needed in PUT is significantly lower, and hence improves the safety in therapy.
We developed a novel localized antivascular method, namely photo-mediated ultrasound therapy (PUT), by applying synchronized laser and ultrasound pulses. PUT relies on high optical contrast among biological tissues. Taking advantage of the high optical absorption of hemoglobin, PUT can selectively target microvessels without causing unwanted damages to the surrounding tissue. Moreover, PUT working at different optical wavelengths can selectively treat veins or arteries by utilizing the contrast in the optical spectra between deoxy- and oxy-hemoglobin. Through our experiments, we demonstrated that cavitation might have played a key role in PUT. The addition of a laser pulse to an existing ultrasound field can significantly improve the likelihood of inertial cavitation, which can induce microvessel damage through its mechanical effect. In comparison with conventional laser therapies, such as photothermolysis and photocoagulation, the laser energy level needed in PUT is significantly lower. When a nanosecond laser was used, our in vivo experiments showed that the needed laser fluence was in the range of 4 to 40 mJ/cm2.
Laser-induced thermotherapy (LITT), i.e. tissue destruction induced by a local increase of temperature by means of laser light energy transmission, has been frequently used for minimally invasive treatments of various diseases such as benign thyroid nodules and liver cancer. The emerging photoacoustic (PA) imaging, when integrated with ultrasound (US), could contribute to LITT procedure. PA can enable a good visualization of percutaneous apparatus deep inside tissue and, therefore, can offer accurate guidance of the optical fibers to the target tissue. Our initial experiment demonstrated that, by picking the strong photoacoustic signals generated at the tips of optical fibers as a needle, the trajectory and position of the fibers could be visualized clearly using a commercial available US unit. When working the conventional US Bscan mode, the fibers disappeared when the angle between the fibers and the probe surface was larger than 60 degree; while working on the new PA mode, the fibers could be visualized without any problem even when the angle between the fibers and the probe surface was larger than 75 degree. Moreover, with PA imaging function integrated, the optical fibers positioned into the target tissue, besides delivering optical energy for thermotherapy, can also be used to generate PA signals for on-line evaluation of LITT. Powered by our recently developed PA physio-chemical analysis, PA measurements from the tissue can provide a direct and accurate feedback of the tissue responses to laser ablation, including the changes in not only chemical compositions but also histological microstructures. The initial experiment on the rat liver model has demonstrated the excellent sensitivity of PA imaging to the changes in tissue temperature rise and tissue status (from native to coagulated) when the tissue is treated in vivo with LITT.