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(1) the original aims:
The hypothesis is that application of ultrasound contrast agents can improve efficacy of HIFU hemostasis of injured solid organs, while maintaining treatment safety.
Specific Aim 1: Determination of efficacy and safety of HIFU hemostasis in the presence of ultrasound contrast agents (UCA).
Aim 1a: Mechanisms of HIFU hemostasis in the presence of commercially available UCA Optison.
Aim 1b: Efficacy and safety of HIFU hemostasis in the presence of Optison.
Specific Aim 2: Development and testing of autologous UCA for HIFU hemostasis.
Aim 2a: Development of autologous UCA.
Aim 2b: Determination of the efficacy of HIFU hemostasis in the presence of autologous UCA.
(2) the key findings:
Thermal measurements showed similar temperatures of the coagulum formed at the injury site treated with HIFU, with or without UCA administration.
Inertial cavitation activity, a signature of mechanical effects, was higher during HIFU application in the presence of UCA.
The presence of Optison in the blood stream during HIFU hemostasis of liver injuries resulted in 37% faster times (p<0.05) needed to achieve complete hemostasis as compared to control treatments (with no UCA present).
The presence of in-house UCA in the blood stream also resulted in faster hemostasis times for sealing of liver injuries (46% faster as compared to control treatments, p<0.05).
Coagulum formation at the injury site was faster as the concentration of administered UCA increased.
Hemostatic seal over the injury site achieved with HIFU or HIFU+UCA was more robust as compared to the seal achieved with electrocautery.
UCA (both Optison and in-house UCA) increased the rate of successful bleeding detection and localization of hidden solid organ injuries (in rabbit kidneys and liver) and vessel injuries (in rabbit and porcine arteries). With regular ultrasound imaging methods (B-mode and Color Doppler) injuries with slow bleeding could not be detected unless UCA were present in the blood stream.
The levels of systemic blood hemolysis during HIFU therapy increased if UCA were administered before the therapy.
Light microscopy observations showed no histological difference between the liver tissue treated with HIFU only or HIFU in the presence of UCA.
The presence of in-house UCA resulted in 35% reduction of the lesion depth (i.e., resulted in the production of shallow lesions localized at the injury site), and prevented the formation of HIFU lesions beyond the focus.
The presence of bubbles at the HIFU focus prevented the temperature increase at the tissue-air interface in the post-focal region.
(3) the impact of these findings :
Both in-house UCA and commercially available UCA Optison can be used to achieve faster hemostasis times of liver injuries and faster coagulum formation at the injury site. Our findings showed that faster coagulum formation and hemorrhage control was due to the mechanical effects of HIFU application in the presence of UCA. Bleeding detection experiments showed that UCA (both Optison and in-house UCA) can be used to improve the detection and localization of bleeding sites, which could be of significant importance during HIFU treatment of hidden bleedings and for eventual extracorporeal HIFU application.
1. Development of in-house ultrasound contrast agents (UCA) for High Intensity Focused Ultrasound (HIFU) therapy. The size of UCA had to be optimized to be less than 10 µm to allow passage through lungs. A variety of UCA manufacturing methods were explored. Our current in-house UCA solution consists of 5% albumin and 10% dextrose in saline. This solution is sonicated in the presence of perfuoropropane gas for 90 s using 20 kHz sonicator (at ~40 W/cm^2) to produce microbubbles of appropriate size. These in-house UCA have concentration of 3x10^8 bubbles/ml with the bubble size of 1-8 µm (mean size of 3 µm).
2. Bleeding detection in the presence of in-house UCA. Scalpel cuts (3 cm in length and 0.5 cm deep) were produced in the posterior surface of rabbit livers and kidneys; or puncture injuries were produced transcutaneously in the rabbit femoral arteries. The in-house UCA made of albumin, dextrose and perfluoropropane gas improved detection and localization of slow bleeding from solid organ injuries and punctured vessels. This bleeding is otherwise not detected using standard ultrasound methods.
3. Determination of the efficiency of HIFU treatment in the presence of in-house UCA. HIFU treatments (at the frequency of 5.5 MHz, in-situ intensity of 6,800 W/cm^2) of liver lacerations were performed in rabbit in-vivo, with or without the presence of in-house UCA (0.8 ml, 1:2 saline dilution) in the blood stream. The average hemostasis times normalized with the bleeding rate were 39 s/ml*min for HIFU only treatments and 21 s/ml*min for HIFU+UCA treatments. The presence of home-made UCA in the blood stream resulted in 44% percent reduction in the times to the first formation of the blood coagulum at the HIFU treatment site, and 46% reduction (p<0.05) in HIFU hemostasis times.
4. Determination of the size and shape of HIFU lesions in the rabbit liver in-vivo, which were produced immediately after the injection of in-house UCA or without the presence of UCA. The objective of this study was to see whether it would be possible to customize the shape of HIFU lesions such that the lesion is localized at the site of interest (i.e., organ surface injury), without causing damage in the healthy deep tissue regions. The presence of in-house UCA resulted in 35% reduction of the lesion depth (i.e., resulted in the production of more shallow lesions). The maximal diameter of the lesions increased by 30% in the presence of in-house UCA, as compared to control lesions. It appeared that the presence of in-house microbubbles in the liver tissue caused the shielding of the postfocal region from the HIFU exposure.
(1) the original aims The hypothesis is that the application of ultrasound contrast agents will improve efficacy of HIFU hemostasis of injured solid organs, while maintaining the treatment safety. Specific Aim 1: Determination of efficacy and safety of HIFU hemostasis in the presence of ultrasound contrast agents. Aim 1a: Mechanisms of HIFU hemostasis in the presence of commercially available UCA Optison. Thermal, mechanical and biological mechanisms of hemostasis in the presence of Optison will be investigated for the treatment optimization. Aim 1b: Efficacy and safety of HIFU hemostasis in the presence of Optison. Hemostasis efficacy will be determined, as well as healing of hemostatic liver incisions in rabbits for up to 60 days after the treatment. Specific Aim 2: Development and testing of autologous UCA for HIFU hemostasis. Aim 2a: Development of autologous UCA. UCA consisting of blood, saline and air will be produced, characterized, and optimized for hemostasis application. Aim 2b: Determination of the efficacy of HIFU hemostasis in the presence of autologous UCA. HIFU treatment of liver incisions will be performed in the presence of autologous UCA to determine the treatment efficacy in producing hemostasis. (2) the key findings - Thermal measurements showed similar temperatures of the coagulum formed at the injury site treated with HIFU, with or without UCA administration. - Inertial cavitation activity, a signature of mechanical effects, was higher during HIFU application in the presence of UCA. - The coagulum formation was faster as the concentration of administered Optison increased. - Hemostatic seal over injury site achieved with HIFU or HIFU+UCA was more robust as compared to the seal achieved with electrocautery. - Our results showed that UCA can increase the rate of successful bleeding detection. - The levels of systemic blood hemolysis during HIFU therapy increased if UCA were administered before the therapy. - Light microscopy observations showed no difference between the liver tissue treated with HIFU only or HIFU in the presence of UCA. - We developed a method for occlusion of large blood vessels of up to 1 cm in diameter. - Ultrasound-guided phased array was used for occlusion of blood vessels at different depths inside a liver. - We showed the feasibility of ultrasound-guided HIFU treatment of occult injuries located in the posterior surface of the liver. - The presence of bubbles at the HIFU focus prevented the temperature increase at the tissue-air interface in the post-focal region. - Color Doppler HIFU can be used for transcutaneous detection and sealing of puncture wounds in the femoral arteries in a porcine model. (3) the impact of these findings Our findings showed that faster coagulum formation and hemorrhage control of liver incisions was due to the mechanical effects of HIFU application in the presence of UCA. Initial safety experiments showed a potentially higher blood hemolysis after the administration of UCA. The safety of our method will be explored in more detail during long-term survival studies proposed for the next funding year of this project. Bleeding detection experiments showed that UCA can be used to improve the detection and localization of bleeding sites, which would be of significant importance during HIFU treatment of hidden bleedings and eventual extracorporeal HIFU application. (4) the proposed research plan for the coming year: Specific Aim 1b: Efficacy and safety of Optison-enhanced HIFU hemostasis (Months 13-18). A survival study will be performed to observe healing of liver lacerations for up to 60 days after the treatment. A total of 35 adult New Zealand White rabbits will be divided into 2 groups: Optison treatment (n = 21) and control treatment (HIFU only) (n = 14). Ultrasound images, blood and histological samples will be collected immediately (day 0) and on days 1, 3, 7, 14, 28, and 60 after the treatment. Specific Aim 2a: Investigations for development of in-house UCA for HIFU therapy (Months 13-18). The shelf life of Optison of 2 years may be too short for longer space flights, for example to Mars. Therefore, we will pursue the development of contrast agents that could be made in Space. These could potentially consist of blood or blood components, saline, and air or other biologically compatible gases. This work will provide valuable guidelines on eventual development of fully-autologous contrast agents that can be made on site during flight missions. The properties of the developed UCA such as bubble size, concentrations, life time, and echogenicity, will be studied specifically for therapy applications. Specific Aim 2b: Determination of the efficiency of HIFU treatment in the presence of in-house UCA (Months 19-24). HIFU treatment of liver lacerations in rabbit in-vivo will be performed in the presence of in-house UCA. The application of in-house UCA, optimized in Specific Aim 2a, is expected to provide similar values of the hemostasis time reduction as the application of Optison. Specific Aim 2c: Determination of the utility of in-house UCA for improving the bleeding detection using ultrasound imaging (Months 19-24). The in-house UCA will be administered at the distal site after induction of injury in the posterior surface of solid organs in rabbits. Conventional B-mode, Color Doppler, Pulsed Doppler, Harmonic Imaging, and Pulse Inversion Harmonic Imaging (PIHI) will be used to visualize and potentially locate the bleeding site. We expect that our in-house contrast agents will show similar enhancement of bleeding detection as Optison during the first phases of interrogation by ultrasound.
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(1) Original aims. The hypothesis is that the application of ultrasound contrast agents will improve efficacy of HIFU hemostasis of injured solid organs, while maintaining the treatment safety.
Specific Aim 1: Determination of efficacy and safety of HIFU hemostasis in the presence of ultrasound contrast agents. Aim 1a: Mechanisms of HIFU hemostasis in the presence of commercially available UCA Optison. Thermal, mechanical and biological mechanisms of hemostasis in the presence of Optison will be investigated for the treatment optimization. Aim 1b: Efficacy and safety of HIFU hemostasis in the presence of Optison. Hemostasis efficacy will be determined, as well as healing of hemostatic liver incisions in rabbits for up to 60 days after the treatment.
Specific Aim 2: Development and testing of autologous UCA for HIFU hemostasis. Aim 2a: Development of autologous UCA. UCA consisting of blood, saline and air will be produced, characterized, and optimized for hemostasis application. Aim 2b: Determination of the efficacy of HIFU hemostasis in the presence of autologous UCA. HIFU treatment of liver incisions will be performed in the presence of autologous UCA to determine the treatment efficacy in producing hemostasis.
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