Thrombus-targeted perfluorocarbon-containing liposomal bubbles for enhancement of ultrasonic thrombolysis: in vitro and in vivo study.

BACKGROUND: External low-frequency ultrasound (USD) in combination with microbubbles has been reported to recanalize thrombotically occluded arteries in animal models. OBJECTIVE: The purpose of this study was to examine the enhancing effect of thrombus-targeted bubble liposomes (BLs) developed for fresh thrombus imaging during ultrasonic thrombolysis. METHODS: In vitro: after the administration of thrombus-targeted BLs or non-targeted BLs, the clot was exposed to low-frequency (27 kHz) USD for 5 min. In vivo: Rabbit iliofemoral arteries were thrombotically occluded, and an intravenous injection of either targeted BLs (n = 22) or non-targeted BLs (n = 22) was delivered. External low-frequency USD (low intensity, 1.4 W cm(-2) , to 12 arteries, and high intensity, 4.0 W cm(-2) , to 10 arteries, for both the targeted BL group and the non-targeted BL group) was applied to the thrombotically occluded arteries for 60 min. In another 10 rabbits, recombinant tissue-type plasminogen activator (rt-PA) was intravenously administered. RESULTS: In vitro: the weight reduction rate of the clot with targeted BLs was significantly higher than that of the clot with non-targeted BLs. In vivo: TIMI grade 3 flow was present in a significantly higher number of rabbits with USD and targeted BLs than rabbits with USD and non-targeted BLs, or with rt-PA monotherapy. High-intensity USD exposure with targeted BLs achieved arterial recanalization in 90% of arteries, and the time to reperfusion was shorter than with rt-PA treatment (targeted BLs, 16.7 ± 5.0 min; rt-PA, 41.3 ± 14.4 min). CONCLUSIONS: Thrombus-targeted BLs developed for USD thrombus imaging enhance ultrasonic disruption of thrombus both in vitro and in vivo.

Fibrinogen γ-chain peptide-coated, ADP-encapsulated liposomes rescue thrombocytopenic rabbits from non-compressible liver hemorrhage.

BACKGROUND: We developed a fibrinogen γ-chain (dodecapeptide HHLGGAKQAGDV [H12])-coated, ADP-encapsulated liposome (H12-[ADP]-liposome) that accumulates at bleeding sites via interaction with activated platelets via glycoprotein IIb-IIIa and augments platelet aggregation by releasing ADP. OBJECTIVE: To evaluate the efficacy of H12-(ADP)-liposomes for treating liver hemorrhage in rabbits with acute thrombocytopenia. METHODS: Thrombocytopenia (platelets < 50 000 µL(-1)) was induced in rabbits by repeated blood withdrawal (100 mL kg(-1) in total) and isovolemic transfusion of autologous washed red blood cells. H12-(ADP)-liposomes with platelet-poor plasma (PPP), platelet-rich plasma (PRP), PPP, ADP liposomes with PPP or H12-(PBS)-liposomes/PPP, were administered to the thrombocytopenic rabbits, and liver hemorrhage was induced by penetrating liver injury. RESULTS: Administration of H12-(ADP)-liposomes and of PRP rescued all thrombocytopenic rabbits from liver hemorrhage as a result of potent hemostasis at the liver bleeding site, although rabbits receiving PPP or ADP liposomes showed 20% survival in the first 24 h. Administration of H12-(ADP)-liposomes and of PRP suppressed both bleeding volume and time from the site of liver injury. H12-(phosphate-buffered saline)-liposomes lacking ADP also improved rabbit survival after liver hemorrhage, although their hemostatic effect was weaker. In rabbits with severe thrombocytopenia (25 000 platelets µL(-1)), the hemostatic effects of H12-(ADP)-liposomes tended to be attenuated as compared with those of PRP treatment. Histologic examination revealed that H12-(ADP)-liposomes accumulated at the bleeding site in the liver. Notably, neither macrothombi nor microthrombi were detected in the lung, kidney or liver in rabbits treated with H12-(ADP)-liposomes. CONCLUSIONS: H12-(ADP)-liposomes appear to be a safe and effective therapeutic tool for acute thrombocytopenic trauma patients with massive bleeding.

Development of a continuous temperature mapping system using a deep body thermometer.

To determine continuous body temperature distribution, an inexpensive temperature mapping system was developed using a deep body thermometer adopting the finite-element method. A stripe with 16 thermocouples was wrapped around the waist of rats to measure body surface temperatures (the boundary conditions). The abdominal deep temperature of the rats was measured from the dorsum using the thermal compensation probe of a deep body thermometer. The abdominal temperature of the rats was mapped by solving a heat conduction equation using surface and deep temperatures obtained in real time. The temperature measured with a thermocouple inserted into the abdominal centre of the rats correlated well with the calculated temperature (r = 0.93, p < 0.01). The system is low cost and simple to use compared with the magnetic resonance temperature mapping system. Our temperature mapping system could potentially result in improved management of patients in critical care medicine.

Determining the temperature distribution of swine aorta with simulated atheromatous plaque under pulsed laser irradiation: an experimental attempt to detect the vulnerability of atherosclerosis.

We developed a method to determine the temperature distribution of swine aortas with simulated atheromatous plaques in order to measure the temperature of atherosclerotic lesions. The inflammation associated with temperature elevation is considered to be one of the aggravating mechanisms of atherosclerosis resulting in fissuring or rupture of atheromatous plaques. The temperature distribution of plaques covered by fibrous caps cannot be measured by conventional thermistors. Indocyanine green (ICG) solution was injected into the subintima of swine aorta to simulate the light absorption coefficient of human atheromatous plaques. The temperature distribution was calculated from measured temperature changes of the aortic intima under pulsed laser irradiation. The aorta was heated from the adventitial side with a halogen lamp to simulate the temperature elevation derived from inflammation. The temperature distribution of the aorta was obtained by solving the heat transfer equation using the surface layer thickness (corresponding to the fibrous cap thickness). The surface layer thickness can be calculated using the following working formula: D(microm)=1363-398DeltaTs+35DeltaTs(2), where AT, denotes intimal surface temperature change under pulsed laser irradiation. The calculated temperature of the ICG layer (corresponding to the atheromatous core) correlated well with the measured temperature (r=0. 97, p<0.0001).

A case of acute massive pulmonary thromboembolism treated by mechanical clot fragmentation using a percutaneous transluminal angioplasty balloon.

Large, bilateral central pulmonary thromboemboli (PTE) led to cor pulmonale and severe hypoxemia in a patient who had undergone Hardy's operation. After several unsuccessful efforts (thrombolysis using a percutaneous catheter and aspiration of the emboli), mechanical clot fragmentation using a percutaneous transluminal angioplasty (PTA) balloon was attempted. This procedure was successful, resulting in a decrease in pulmonary artery pressure from 58/22 (mean 34) mmHg to 20/10 (mean 13) mmHg together with an increase in aortic pressure from 64/36 (mean 45) mmHg to 112/60 (mean 77) mmHg. Thus, mechanical clot fragmentation using a PTA balloon is a promising method for reducing pulmonary artery pressure and increasing aortic pressure in patients with acute PTE.