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Triangle terarylene derivatives based on the 4,5-diarylthiazole structure have been synthesized and their photochromic properties have been studied both in solution and in the crystalline state. The thiazolyl-substituted terarylenes displayed reversible photochromism in solution, with photocyclization quantum yields as high as 60 %, while a 4,5-dithienylthiazole derivative underwent photochromic reaction even in the single-crystal state, although a 4,5-dithiazolylthiazole (terthiazole) showed no photochromic reaction in the crystalline phase. The difference in photochromic reactivity between the 4,5-dithienylthiazole and the 4,5-dithiazolylthiazole was found by X-ray crystallographic analyses to originate from conformational differences in the crystalline state. The thermal cycloreversion activation energies in the solution phase were measured for thiazolyl-substituted terarylenes and for a corresponding terthiophene derivative. The activation energy for the transition from photogenerated closed-ring isomer to open-ring isomer increased with the number of substitutions of thiazole unit for thiophene. The lower aromatic stabilization energy of thiazole in relation to that of thiophene was considered to be responsible for the thermal stability of the closed-ring isomers of thiazolyl-substituted terarylenes.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Novel photochromic triangle terarylenes are synthesized, and their photochromic properties and thermal bleaching kinetics are investigated. Fairly high photochemical coloration reactivity is observed with photochemical quantum yield as high as 0.6 for 4,5-dithienyl thiazole derivative. Introduction of phenyl-ethynyl groups into the molecular structure allows systematic control of thermal cycloreversion time constant over 105 times, and the half-lifetime shorter than 2 s is achieved at 303 K. The kinetic analysis of thermal cycloreversion reaction clearly shows significant contribution of frequency factor A. A novel molecular designing concept for systematic control of thermal bleaching reaction rate is presented without taking bulky functional groups on reaction center.

A new methodology for the evaluation of complementary and alternative medicine (CAM) using individual response to replace randomized controlled trial (RCT) is introduced. Two research projects on “Scientific criteria for the evaluation of CAM” are discussed. The new methodology would be especially useful in the field of psychosomatic medicine.

The University of Tokyo has been involved in research and development of the artificial heart since 1959. This paper is a brief review of 40 years of total artificial heart research in the University of Tokyo. Many types of artificial heart and various kinds of materials, blood pumps, valves, drive units, control methods, and pathophysiology have been investigated in our original fashion. The longest survival was 532 days for a goat with a total artificial heart (TAH) placed on the chest wall. These results made us take a step toward the development of an implantable TAH. Two kinds of implantable TAH are now being developed: FTPTAH (flow-transformed pulsatile total artificial heart) and UPTAH (undulation pump total artificial heart). Recently, a goat survived for 31 days with an UPTAH.

To obtain a physiological response by a total artificial heart (TAH), while eliminating the hemodynamic abnormalities commonly observed with its use, we proposed the use of a conductance- and arterial pressure-based method (1/R control) to determine TAH cardiac output. In this study, we endeavored to make use of a variable more closely tied to central nervous system (CNS) efferents, systemic conductance, to provide the CNS with more direct control over the output of the TAH. The control equation that calculates the target cardiac output of the TAH was constructed on the basis of measurement of blood pressures and TAH flow. The 1/R control method was tested in TAH-recipient goats with an automatic method by using a microcomputer. In 1/R control animals, the typical TAH pathologies, such as mild arterial hypertension and substantial systemic venous hypertension, did not occur. Cardiac output varied according to daily activity level and exercise in a manner similar to that observed in natural heart goats. These results indicate that we have determined a control method for the TAH that avoids hemodynamic abnormalities exhibited by other TAH control systems and that exhibits physiological responses to exercise and daily activities under the conditions tested. The stability of the control and the complete lack of inappropriate excursions in cardiac output is suggestive of CNS involvement in stabilizing the system.

A total artificial heart (TAH) goat survived for 360 days on the new automatic control method (1/R control), in which the cardiac output of the TAH can be controlled through the cardiovascular center by making it function by reflecting the beta-adrenergic reaction in peripheral vascular resistance. This is thought to be the only long-term, real-time, measurable parameter by which information on the activity of the cardiovascular center can be received directly by the TAH system. In this goat, the hemodynamic parameters (RAP, AoP, and so forth) were kept within physiologic limits when control was stable, and the cardiac output was automatically increased in response to exercise, not unlike that in the natural heart. There were no abnormal blood chemical or hormone data except at end stage. Based on these results 1/R can be considered a physiologic control method for a TAH.

Chronic study of the peripheral circulation and metabolism is very important in evaluation of artificial organ performance. However, there has been no way to observe the microcirculation in situ, chronically and continuously, without restriction. In this study, the authors developed a new apparatus that could be implanted and connected to an artificial organ that would allow continuous observation of the microcirculation while the subject is awake. The apparatus uses a charge coupled device (CCD) under a new principle: thin living tissue, such as mesentery, is put directly on a highly integrated CCD and transilluminated with a light emitting diode (LED). The vascular nets in the tissue are projected onto the CCD like a contact photograph, which is sent to a television screen and can be analyzed for motion and function. A 0.5 inch CCD with 25K pixels was used in this study. The cover glass of the CCD was removed so the tissue would be able to directly contact the CCD surface. The CCD, as well as LED, were molded with hard polyurethane as electrical insulation. The apparatus is 35 mm in diameter and 10 mm high with a micro stand for lighting with the LED, which is easy to implant in a goat or calf. The resolution of this apparatus was tested by putting a micro scale on the CCD surface. Several tenths of micrometers could be seen. In an animal experiment with a rabbit, configurations of arterioles and venules and their motions could be observed continuously for a night until the electrical insulation was broken. This method might be a strong weapon in artificial organs research.

For percutaneous observation of lesions near the spinal cord and percutaneous spinal laser surgery under the visual field, we studied a method and approach to the spinal cord and intraspinal surgical procedures with laser using a newly developed, small-diameter laser endoscope. The subarachnoid and epidural spaces of a goat were punctured using a 17-gauge epidural needle, and the endoscope (diameter 0.7 mm) was inserted through the needle. The spinal cord and surrounding tissue were observed. Next, an endoscope (diameter 1.5 mm) was inserted into the subarachnoid space, and the quality of the picture and manageability of the endoscope were examined. The Xe:Cl excimer laser was irradiated to a nerve root through a 0.4 mm optical fiber for laser transmission through this endoscope. The spinal cord, nerve roots, and arachnoid were clearly observed through this endoscope. The pulsation of the artery accompanying a root was seen clearly, and the quality of the picture of the endoscope was thought to be sufficient for diagnosis. The nerve root was cut within 30 seconds by excimer laser, and the possibility of laser surgery was demonstrated. Although it was shown that this endoscope could be a useful diagnostic and therapeutic tool, improvement in the manageability of the tip of the endoscope was considered to be important for a clinically usable endoscope.

In 1986, APLMS was established to promote the various activities of Laser Medicine Surgery in the Asia-pacific regions. The purpose of APLMS is not only to deliver academic information but also technological, industrial and social ones. Until now, the 9 congresses had been taken place in the different countries in Asia-Pacific regions. As the results of the 18 years' efforts, the organizations of each country on laser medicine and surgery have been established, and the network of researchers and clinicians has been completed. The next challenges are proposed such as education, training, and standardization of methods. To establish guidelines and regulation for laser medicine and surgery, and to transfer technology are also important issues.

The undulation pump (formerly called the pre-cessional displacement pump) is a continuous flow displacement-type blood pump that is being developed as an implantable total artificial heart. A new undulation pump was developed for chronic use and was examined with animal experiment and flow visualization studies. In the animal experiment using a left ventricular bypass in goats, severe hemolysis occurred. After driving for 12 h, thrombus formation inside the pump was found. In the flow visualization studies, the flow pattern showed that the flow inside the pump was a very complicated turbulent flow. Improvement of hemolysis and thrombus formation is important to realize implantable total artificial hearts using undulation pumps.

Luminescent EuIII complex having photochromic ligand is synthesized, and its reversible control of the luminescent properties based on photochromic reaction was demonstrated.

The 1/R control was developed to provide control over the output of a total artificial heart (TAH) by the central nervous system by using the peripheral vascular conductance (1/R) the vasodilatation in for the control signal. The physiologic stability of the 1/R control algorithm was tested by using goats with TAH. To apply the 1/R control equation to TAH in goats, real-time and continuous measurements of cardiac output, aortic pressure, and right atrial pressure were performed throughout the survival period. Left atrial pressure was also measured, to prevent lung edema. Under the 1/R control, 532 days’ survival was obtained in a goat with a TAH. Findings over the course of the experiment showed no hemodynamic or metabolic abnormality. Autopsy findings showed macroscopically no congestion in the liver. The experiment demonstrated the physiologic stability of the 1/R control algorithm for an extended period. Improvement of methods for measurement, such as the development of feasible techniques for the noninvasive measurement of the required hemodynamic parameters, will make it possible to use 1/R control in practice, especially for a totally implantable TAH system.

The undulation pump is a small size continuous flow displacement type blood pump that has been developed for an artificial heart. Using undulation pumps, 2 types of implantable total artificial hearts (TAHs), the undulation pump TAH (UPTAH) type 1 (UPTAH 1) and UPTAH type 2 (UPTAH 2) were developed. Both UPTAHs were designed to be small enough to implant into the chest of a goat, the experimental animal. UPTAH 1 could be reduced in size to 75 mm in diameter and 78 mm in length. The weight was 520 g. UPTAH 2 could be reduced in size to 75 mm in diameter and 80 mm in length. The weight was 650 g. UPTAH 2 could be tested in an animal experiment using an adult female goat weighing 52.3 kg. The UPTAH 2 could be implanted successfully into the goat's chest with a good fit. The goat stood after the surgery and extubation and survived for 3 h and 40 min; thus, the potential of the UPTAH for a practical implantable TAH was demonstrated.

The spectral profile of fluctuations of hemodynamic parameters was investigated in the natural heart, the total artificial heart (TAH) with fixed drive condition, and in the TAH with automatic (1/R) control. The inverse frequency (1/f) fluctuations were found in the heart rate (HR) and peripheral conductance (1/TPR) in the natural heart, and in the pulse rate (PR) and 1/TPR in the TAH with 1/R control. The PR of the TAH with 1/R control is considered to have some compatibility with the HR of the natural heart, although the control loop is completely different.

A new prototype model of a flow-transformed pulsatile total artificial heart (FTPTAH), which consists of one undulation pump (UP; formerly known as a precessional displacement pump; PDP), four jellyfish valves, and a flexible membrane has been developed. Flow transformation between pulmonary and systemic circulation is brought about by the switching direction of motor rotation, so that no electrical flow switching valve is needed. The undulation pump is a continuous flow pump, and it can also be driven as a reversible pump. A prototype model perfused 3.01/min alternately in the pulmonary and systemic circulations with pulsatile flow in a mock circulatory system. A compensatory chamber has been designed, with the objective of preventing deoxygenated blood from being sent to the systemic circulation. The chamber is formed by a flexible membrane located between immediately in front of the mitral valve and immediately behind the tricuspid valve. Its volume is nearly equal to the priming volume of the undulation pump. Deoxygenated blood present in the undulation pump at the end of pulmonary circulation is stored in the compensatory chamber by shifting the flexible membrane to the direction of the left atrium, thus preventing the deoxygenated blood from being sent to the systemic circulation.

Of 77 University of Tokyo ventricular assist devices used in a total of 70 patients at 21 institutions, 13 pumps were found to have macroscopic thrombus formations. Because 19 devices that were used for less than 24 hours showed no thrombus deposition, they were considered not to have been sufficiently exposed to the thrombogenic environment for macroscopic thrombus deposition and were removed from the subsequent multivariate study. A total of eight potential risk factors were assessed in relation to thrombosis. Prevalences of thrombus formation were compared between two groups with or without each of the risk factors. In a univariate analysis, the following categoric variables were demonstrated to be significantly associated with complications, in descending order of significance: use of gabexate mesilate (protease inhibitor) as an anticoagulant (p = 0.005), normal platelet count (p = 0.010), duration of support (p = 0.038), leukocytosis (p = 0.042), and minimum pumping flow (p = 0.042). Use of heparin and the consequent increase in activated clotting time showed no relationship. Multivariate discriminant analysis, which was done to identify risk factors rejecting cross correlation between each variable, demonstrated platelet count (p = 0.006), use of gabexate mesilate (p = 0.007), and minimum flow (p = 0.008) to have significant and independent risks. These results indicate the importance of maintaining pumping flow above a certain minimum level, addition of antiplatelet drugs to the antithrombogenic regimen, and nonuse of gabexate mesitate.

Antithrombogenic regimens for pneumatic ventricular assist devices (VADs) were evaluated in 77 VADs used clinically in a total of 70 patients. Macroscopic thrombus formation in the devices was assessed in relation to potential risk factors, including hematological and hemodynamic derangements, during use of the VAD. Effects of varions antithrombogenic regimens were assessed on the basis of this risk analysis. A thrombus score was used to quatititate the grade of thrombosis. As a linear increase in the thrombus score was noted in accordance with increase in support duration, a time-adjusted thrombus score was calculated to compare scores in anticoagulant groups with different pumping duration. The scores appeared to be high in patients in those groups which received gabexate mesilate (GM, a protease inhibitor). Heparin was not demonstrated to be effective in this study. Univariate risk analysis showed that the use of GM, low-flow pumping, prolonged pumping, and semi-normal platelet count were significantly correlated with the incidence and grade of thrombosis. A multivariate regression analysis also indicated that the use of GM, low-flow, and prolonged pumping were detrimental to anti-thrombogenicity. As the use of GM was demonstrated to be predominantly detrimental, its withdrawal from use should lead to a substantial reduction in the incidence and grade of thrombosis.

The artificial heart (AH) is already being used clinically as a bridge to heart transplantation or a circulatory assist for post-cardiotomy. However, there are, as yet, no established control methods for the AH, except for some that are very primitive. Consequently, such problems as elevation of the central venous pressure (CVP) and poor response of cardiac output to exercise still remain to be overcome.