We have developed a new technology for producing three-dimensional (3D) biological structures composed of living cells and hydrogel in vitro, via the direct and accurate printing of cells with an inkjet printing system. Various hydrogel structures were constructed with our custom-made inkjet printer, which we termed 3D bioprinter. In the present study, we used an alginate hydrogel that was obtained through the reaction of a sodium alginate solution with a calcium chloride solution. For the construction of the gel structure, sodium alginate solution was ejected from the inkjet nozzle (SEA-Jet, Seiko Epson Corp., Suwa, Japan) and was mixed with a substrate composed of a calcium chloride solution. In our 3D bioprinter, the nozzle head can be moved in three dimensions. Owing to the development of the 3D bioprinter, an innovative fabrication method that enables the gentle and precise fixation of 3D gel structures was established using living cells as a material. To date, several 3D structures that include living cells have been fabricated, including lines, planes, laminated structures, and tubes, and now, experiments to construct various hydrogel structures are being carried out in our laboratory.

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This study has three purposes, as follows. The first is to develop a microscopic system to observe the microcirculation of animals implanted with an artificial heart. The second is to investigate the influence of flow pattern change from pulsatile to nonpulsatile on the microcirculation. The third is to study the effects of pulsatility in blood flow on endothelium-derived nitric oxide release in the microvasculature. When the flow pattern was changed from pulsatile to nonpulsatile, the velocity of erythrocytes in many capillaries dropped and remained at a low level, and the number of perfused capillaries decreased. After the flow pattern was returned to pulsatile, the velocity of erythrocytes recovered to the initial level. In many cases, the flow of nonperfused capillaries recovered to the initial level as well. Also, the pulsatile flow enhances the basal and flow-stimulated endothelium-derived nitric oxide release in microvessels.

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.

Antiplatelet therapy is the mainstay of pharmacologic treatment to prevent thrombotic or ischemic events in patients with coronary artery disease treated with percutaneous coronary intervention and those treated medically for an acute coronary syndrome. The use of antiplatelet therapy comes at the expense of an increased risk of bleeding complications. Defining the optimal intensity of platelet inhibition according to the clinical presentation of atherosclerotic cardiovascular disease and individual patient factors is a clinical challenge. Modulation of antiplatelet therapy is a medical action that is frequently performed to balance the risk of thrombotic or ischemic events and the risk of bleeding. This aim may be achieved by reducing (ie, de-escalation) or increasing (ie, escalation) the intensity of platelet inhibition by changing the type, dose, or number of antiplatelet drugs. Because de-escalation or escalation can be achieved in different ways, with a number of emerging approaches, confusion arises with terminologies that are often used interchangeably. To address this issue, this Academic Research Consortium collaboration provides an overview and definitions of different strategies of antiplatelet therapy modulation for patients with coronary artery disease, including but not limited to those undergoing percutaneous coronary intervention, and consensus statements on standardized definitions.

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We have developed an automatic diagnosis system of an artificial heart in order to ensure the safety of the patient implanted with the artificial heart. The automatic diagnosis system is composed of an electro-stethoscope system, adaptive noise canceller (ANC), and artificial neural network (ANN). The ANC effectively eliminates ambient noise from the sound signal of the artificial heart detected by the electro-stethoscope, and a filtered sound signal is separated into each frequency components by fast Fourier transformation. Each frequency component of an artificial heart's acoustic signal is fed into the ANN in order to make a diagnosis of pump condition. The automatic diagnosis system was evaluated in mock circulatory tests and a long-term animal experiment using a goat implanted with an undulation pump ventricular assist device (UPVAD). In mock circulatory tests, the ANN was able to detect pump failing conditions, which were occlusion of inflow and outflow cannula and deterioration of the ball bearing. In a long-term animal experiment, after training the ANN using UPVAD's sound signal in normal condition, the diagnosis system continuously monitored UPVAD's sound signal detected by the electro-stethoscope placed on the surface of the left thoracic cavity of the goat. The UPVAD was stopped by rupture of a diaphragm in the pump on the ninth day of operation. We were able to identify initial signs of malfunction of the pump on the eighth day, while the UPVAD was able to operate normally. In conclusion, the automatic diagnosis system for malfunction of the artificial heart has enough performance to detect early stages of malfunction of the artificial heart, and it contributes to ensure the patient's safety.

The development of mechanical circulatory support devices at the University of Tokyo has focused on developing a small total artificial heart (TAH) since achieving 532 days of survival of an animal with a paracorporial pneumatically driven TAH. The undulation pump was invented to meet this purpose. The undulation pump total artificial heart (UPTAH) is an implantable TAH that uses an undulation pump. To date, the UPTAH has been implanted in 71 goats weighting from 39 to 72 kg. The control methods are very important in animal experiments, and sucking control was developed to prevent atrial sucking. Rapid left-right balance control was performed by monitoring left atrial pressure to prevent acute lung edema caused by the rapid increase in both arterial pressure and venous return associated with the animal becoming agitated. Additionally, 1/R control was applied to stabilize the right atrial pressure. By applying these control methods, seven goats survived more than 1 month. The maximum survival period was 63 days. We are expecting to carry out longer term animal experiments with a recent model of TAH. In addition to the TAH, an undulation pump ventricular assist device (UPVAD), which is an implantable ventricular assist device (VAD), has been in development since 2002, based on the technology of the UPTAH. The UPVAD was implanted in six goats; three goats survived for more than 1 month. While further research and development is required to complete the the UPVAD system, the UPVAD has good potential to be realized as an implantable pulsatile-flow VAD.