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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.

An electrochemical sensor system to allow real-time measurement and feedback of catecholamine concentrations was developed for use in the control of artificial hearts. Electrochemical analyses were carried out using a carbon fiber working electrode, an Ag-AgCI reference electrode, and a potentiostat. The operating parameters of the pneumatically-driven artificial heart system were altered in accordance with the algorithm for changes in the catecholamine concentration. The minimum detectable concentrations of both adrenaline and noradrenaline in a mock circulatory system using a phosphate-buffered solution were approximately 1-2 ng/ml (10-8 mol/L). An artificial heart control system utilizing this set-up performed satisfactorily without delay, although sensor sensitivity decreased when placed in goat plasma instead of a phosphate-buffered solution, due to the adsorption of various substances such as plasma proteins onto the electrodes. This study demonstrated the future feasibility of a feedback control system for artificial hearts using catecholamine concentrations.

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.

In recent years refractory infection caused by methicillin-resistant Staphilococcus aureus (MRSA), which has been effective against multi-agents resistant S. aureus, has been remarked. We experienced a case of poststernotomy mediastinitis caused by MRSA in a 5-year-old girl operated on for tetralogy of Fallot. Several methods in treating the complication were performed. The first was drainage of the involved area combined with local irrigation with antiseptic agents soaked in povidone-iodine. The second was a thorough debridement of the mediastinum, including the edges of the sternum followed by continuous povidone-iodine irrigation. Complete healing could be achieved by drainage of the involved area, accompanied by the adequate selection of antibiotics. Vancomycin (VCM) is the first-choice for oxacillin-resistant MRSA, and no resistant straints have been found up to now. This patient for whom other antibiotics were ineffective, intravenous dosing of VCM could save her life. In addition, it was important for anti-infection strategies to specify the infected nosocomial places and to take epidermilogical measures coping with the spread of infection via medical professionals.

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.

The flow-transformed pulsatile total artificial heart (FTPTAH) is a new pulsatile total artificial heart that consists of a single continuous flow rotary blood pump and blood flow switching valves. It can perfuse the pulmonary and the systemic circulation alternately with pulsatile flow. A new version of the FTPTAH, which consists of one undulation pump (UP), 4 jellyfish valves, and a compensatory chamber, has been proposed. The UP is a reversible continuous flow blood pump, and flow transformation is caused by switching the direction of the motor rotation so that no electrical flow switching valve is needed. A prototype model could perfuse alternately pulmonary and systemic circulation with 3.0 L/min in a mock circulation. Unoxygenated blood in the UP at the end of pulmonary circulation will be stored in the compensatory chamber by shifting a flexible membrane to the direction of the left atrium (LA); therefore, the blood is not sent to the systemic circulation.

A goat survived for 532 days with a pneumatically driven total artificial heart (TAH) that was controlled by the 1/R (reciprocal of peripheral resistance) method. Pathological observations were compared with those of long-surviving goats which had been fitted with TAHs that were operated with fixed driving parameters. The most striking pathological differences were observed in the liver. In the goat under study, congestion of the liver was not as severe as in the past cases in which the central venous pressure (CVP) was high, although fibrosis was prominent around the hepatic veins in many areas of the liver. In both kidneys, severe infarctions were prominent (as in the past cases), but a characteristic of this case was the existence of marked hemosiderosis at proximal tubules; however, this was not prominent in the spleen and liver. This suggested that the hemosiderosis was due to hemolysis in the blood pump rather than due to an increased destruction of erythrocytes in the spleen and liver. The pathological improvements in the liver are believed to have been due to a comparatively low CVP (approximately 5–10 mmHg) which was achieved by the use of the 1/R control method, even though the existence of pathological abnormalities in the kidneys and liver suggested that such long-term driving of the TAH may still cause hemolysis and some damage to the liver. This point requires further investigation.

We have been developing a percutaneous-type left ventricular assist device named the Modified Assist Device (MAD). The system is composed of an air-driven sac-type blood pump and cannula in which an inflow and an outflow valve have been installed. With the MAD type 5, a maximum pump flow of 2.51/min was obtained in a mock circulation study. For clinical application of this ventricular assist device, a new model, MAD type 6, was developed and was evaluated in in vitro and in vivo experiments. To obtain satisfactory anatomical fit and durability, a spiral was installed in the cannula of MAD type 6. In in vitro evaluation, the pressure gradients across the inflow and outflow valves were 110 mmHg and 75 mmHg at a flow rate of 21/ min. With the MAD type 6, the index of hemolysis was almost the same as that of a centrifugal pump. The durability test was maintained for more than 30 days without deterioration of the new system. In an animal experiment, using dogs, more effective systolic unloading and diastolic augmentation were observed by the activation of the MAD type 6 than with an intra-aortic balloon pump (IABP) assist. As for the peripheral circulation, the MAD type 6 device produced greater carotid artery flow than did the the IABP assist. In conclusion, the MAD type 6, a pulsatile-flow device, appears to have a design and function suitable for clinical application.

Calcification and thrombus formation are still important problems in artificial heart research. The calcification and thrombus formation generated in artificial heart blood pumps, driven without anticoagulant for 312 days as the left side and 414 days as the right side, were analyzed in this study. A thrombus was observed at the circumference of the sac in the 312-day pump, but it was not associated with calcification. Several phenomena were observed on the polymer membrane valves (jellyfish valves) incorporated into the blood pump: plastic deformation of the valve membrane by creep fatigue; no calcification of stationary parts such as spokes and the center of the membrane; calcification of the particular portion which received repeated stretching stress; and no association of calcification with thrombus. The calcification of the valve area which received repeated stretching force might be explained as follows. Repeated stretching forces extend the polymer membrane, causing some loosening between polymer molecules and generating microgaps. Blood proteins and phospholipids invade these microgaps, which then attract Ca2+ ions followed by phosphate ions(PO4 2-) leading to the formation of calcium phosphate complexes.

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.

We developed a new miniature probe which does not require the use of a microscope for observing the microcirculation; the probe can be implanted chronically into the body with minimal invasion. The principle of the probe is quite new. A thin layer of living tissue is placed directly on a highly integrated charge coupled device (CCD) and illuminated with a very weak light source, i.e., a light-emitting diode. The vascular nets in the tissue are projected on the CCD like a contact photograph, and this is sent to a television monitor; the motion and function of the microvasculature can then be analyzed. A 1/2 inch CCD with 250 K pixels was used in this study. The CCD was molded with epoxy resin for electrical insulation. The probe was implanted into a rabbit for 18 h. The configuration of arterioles and venules 20–30μm in diameter and their motion in subcutaneous tissue could be observed. This method should be of great help in artificial heart studies, especially for the evaluation of control methods and for the evaluation of differences between pulsatile and non-pulsatile pumping.

To provide a circulatory assist system with percutaneous access, a new system was developed. In our laboratory, three types of assist system have already been developed; modified assist devices (MAD) type-1 to type-3. The newly developed system described here is the MAD type-4. The system consists of a sac-type blood pump and a cannula. Inflow and outflow jellyfish valves are mounted in the apex and at the side wall 10cm from the apex of the cannula, respectively. During systole, the blood is sucked from the left ventricle through the inflow valve of the cannula connected to the blood pump, and during diastole, the blood is ejected to the root of the aorta through the outflow valve. In vitro and in vivo evaluation of the pump performance was carried out. A maximum flow rate of 2.31/min was obtained in a mock circulatory system. In the animal experiment, effective systolic unloading and diastolic augmentation were observed with an on-off trial. This MAD, which was designed to be percutaneously accessible, increased systemic and coronary flow.

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.

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.

The development of a polymer membrane valve for artificial heart blood pumps is very much required, since the mechanical valves, such as the Bjork-Shiley (BS) and Hall valves, used in the present artificial heart (AH) blood pumps have the following problems: 1. A ring thrombus is often formed at the interface between the valve ring and pump housing, because these cannot be fixed seamlessly. 2. Valve failure sometimes occurs at the disc and stent due to a water-hammer effect. 3. Regurgitant and leakage flow generated in the mechanical valve induces hemolysis and the AH patient becomes mildly anemic. 4. The valves are too expensive to popularize the AH as a therapeutic method.

To reduce the pump size of the total artificial heart for future implantation, a new mechanized pulsatile total artificial heart, the flow-transformed pulsatile total artificial heart (FTPTAH), was developed. This device consists of a single continuous flow pump and two three-way valves; it can perfuse the pulmonary and systemic circulation alternately by pulsatile flow. The prototype and secondary model revealed that the system worked well in terms of the mechanism [1,2]. However, low performance, heat generation at the solenoid to drive the spool valve, and blood mixture or inversion of arterial and venous blood were noted in the secondary model. In this study, the third model was developed to overcome these problems.

For the purpose of future total implantation, a new pulsatile total artificial heart, a flow transformed pulsatile total artificial heart (FTPTAH), in which the continuous flow from a single centrifugal pump (CFP) was converted to pulsatile flow by switching two three-way valves that could alternately perfuse the systemic and pulmonary circulation, was proposed, and the data from the prototype model were reported. As the next step, the second model, in which a CFP and a spool valve (SV) driven with a solenoid were fabricated in one piece, was made and tested in a mock circulatory system. The system could send 4.7 L/min of pulsatile output alternately to the pulmonary artery and aorta, with 30 and 100 mmHg afterload, respectively, at 3000 rpm CFP. However, three problems were encountered: the output was not enough, mixture or inversion of venous and arterial blood in the CFP would occur, and heat generation at the solenoid was very severe. To solve these problems, a third model was designed in the current study. To increase pump output, hydrodynamic analysis was performed. The SV was divided into inlet and outlet to control the blood mixture or inversion. To suppress heat generation, each SV was driven back and forth by two solenoids, one on each side of the SV. The model revealed satisfactory results in a mock circulatory system.

For a valve to be fabricated seamlessly into an artificial heart (AH) blood pump, a jellyfish valve has been developed, in which a thin membrane is fixed at the center of a valve seat having several spokes to protect against prolapse of the membrane. The valve is superior in performances to a Bjork-Shiley valve, and reveals good blood compatibility. The valve would be very useful not only for AH animal study, but for future clinical use in infants to adults. Several institutions are already trying the valve. In this paper, the fabrication of the jellyfish valve is introduced, and in vitro and in vivo results summarized. A computer aided design (CAD) system was developed to cut a male wax mold of the valve seat. The input parameters to the CAD are diameter, height, thickness of rim, number of spokes, width and thickness of spokes, etc. Jellyfish valves with diameters of 4 to 27 mm have already been fabricated for many types of AHs and assist pumps.

To realize a totally implantable total artificial heart (TAH), a new pulsatile TAH, the flow-transformed pulsatile TAH (FTPTAH), was developed. The system was composed of a single centrifugal pump (CFP) and two three-way valves. One port of each three-way valve was connected to the inlet and outlet of a CFP. The other two ports of each valve were connected to the right and left atrium, and the pulmonary artery and aorta. The CFP can perfuse the pulmonary and systemic circulation alternately with pulsatile flow by switching the two three-way valves. A prototype and the secondary model in which the solenoid valves and a spool valve were included, respectively, were connected to a mock circulatory unit with the results that a pulsatile TAH with physiological flow wave form could be obtained from a single CFP, about 5 Llmin of pulsatile output could be obtained alternately on the right and left side by switching the solenoid valves or a spool valve, and flow balance between the right and left could be easily controlled by the switching duration. The system is feasible for a totally implantable TAH because it does not need a compliance chamber and can be miniaturized.

The compliance chamber which is required for a totally implantable artificial heart, to compensate the volume change generated in a blood pump, makes it harder to implant the whole system inside a human body, for several reasons. To eliminate the compliance chamber from the totally implantable artificial heart, a new blood pump, in which no compliance chamber was required, has been designed by our group and was reported elsewhere. In this study, an actuator to drive this blood pump was developed. The mechanism of the actuator converts the rotation of the d.c. motor to linear motion of the pump diaphragm by permanent magnets without any connection. A prototype system was made and tested in a mock circulatory system. The results clarified the controversial points of the present system. However, the future feasibility of this mechanism was also exhibited.