Ten-year NEDO BVAD development program: moving forward to the clinical arena.

Since 1995, the Baylor Group has been developing a totally implantable NEDO BVAD system. This 10-year program was completed in March 2005, and preparation for clinical trials is underway. This article summarizes the entire 10-year NEDO program and describes the strategy for clinical trials. The project aimed to achieve: (1) dual centrifugal pumps with the ability of full biventricular support, (2) a compact system implantable into small adults, (3) a totally implantable system with transcutaneous energy transmission system (TETS), (4) a durable system with a lifetime of over 5 years, and (5) a system free of thrombus and with minimal hemolysis. The final goals are to complete preclinical system evaluations and commence the clinical trials in the near future. In vitro studies have demonstrated a pump capacity of over 8.5 l/min and an Index of Hemolysis of <0.004 g/100 l. The pump-bearing life expectancy was over 5 years. To date, eight pumps endured in vivo studies of over 3 months without complications, including thromboembolic events. The in vitro endurance studies of eight pumps are longer than 1 year. There were no mechanical malfunctions or pump failure. A stepwise clinical trial is being planned: Step1, a wearable BVAD/VAD will be clinically studied; Step 2, the BVAD/VAD will be implanted intracorporeally without TETS; and, Step 3, a totally implantable system will be clinically evaluated. The NEDO BVAD system has completed preclinical testing. Clinical trial preparation is underway.

Indirect flow rate estimation of the NEDO PI Gyro pump for chronic BVAD experiments.

In totally implantable ventricular assist device systems, measuring flow rate of the pump is necessary to ensure proper operation of the pump in response to the recipient's condition or pump malfunction. To avoid problems associated with the use of flow probes, several methods for estimating flow rate of a rotary blood pump used as a ventricular assist device have been studied. In the present study, we have performed a chronic animal experiment with two NEDO PI gyro pumps as the biventricular assist device for 63 days to evaluate our estimation method by comparing the estimated flow rate with the measured one every 2 days. Up to 15 days after identification of the parameters, our estimations were accurate. Errors increased during postoperation days 20 to 30. Meanwhile, their correlation coefficient r was higher than 0.9 in all the acquired data, and estimated flow rate could simulate the profile of the measured one.

Development of a clipped single-bag with bicarbonate replacement fluid to ensure proper mixing.

A clipped single-bag for bicarbonate replacement fluid was developed to ensure proper mixing before administering to the patient. Nonmixture can cause imbalances of electrolytes and pH, which is a key problem for the current double-bag type bicarbonate replacement fluid sets. To resolve this problem, this single bag properly mixes the solutions before use. The new bag consists of a clip that is placed in the middle to keep the two solutions separated and sealed. When the caregiver is ready to administer treatment, the bag is simply unfolded and the clip automatically detaches, releasing the fluids. Thereby, the bicarbonate fluids are effectively mixed. An optimal clip size with an outer diameter of 16 mm and thickness of 2 mm was determined using compression tests and drop tests. This bag may be a safer and more effective way to provide proper replacement fluid supply for both hemofiltration and hemodiafiltration.

Evaluation of flow rate estimation method for rotary blood pump with chronic animal experiment.

Rotary blood pumps are expected to be used as an implantable ventricular assist device (VAD). In the VAD system, flow rate is important for monitoring of the state of a recipient and for automatic control to maintain appropriate blood perfusion. To obtain flow rate of the pump without any sensors, we proposed a method of estimating flow rate with supplied power and rotational speed using a time series model. To evaluate the accuracy of the proposed estimation method from the aspect of long-term use, we implanted NEDO PI Gyro pumps in a calf and performed a chronic animal experiment. Flow rate, supplied power and rotational speed were measured until post operation day (POD) 63, and the estimated flow rate was compared with the measured one. We confirmed that waveforms of the measured flow rate was sufficiently similar to the measured one, and correlation between them was higher than 0.9 in all the datasets. On the other hand, the root mean square error increased after 15 days. This error was probably due to the change in physiological condition, the operating point of the pump, or mild intima formation.

Therapeutic left ventricular assist device and apheresis on dilated cardiomyopathy.

Pathogenesis and therapies of dilated cardiomyopathy (DCM) have been discussed for a long time, but both of the ultimate answers are still unknown. In the last decade, the pathogenic role of immunological factors, such as cardiac autoimmune antibodies and cytokines, have been discussed attentively. This has led to one possible new therapy, immunoadsorption, which removes antibodies, and it has made a remarkable effect. However, there are other factors to remove. For the removal of cytokines and neurohormones, the most effective method is hemofiltration (HF). Also, double-filtration plasmapheresis (DFPP) removes immunoglobulin as well as low-density lipoprotein (LDL) and coagulation factors that may improve blood circulation, including the coronary arteries. Therefore, to eliminate all deteriorative factors, both apheresis therapies, HF and DFPP, should be performed. Due to the shortage of donor hearts, left ventricular assist systems (LVAD) have been used as a bridge to transplantation. It has now been reported that the total unloading of the left ventricle does not only maintain, but also recovers, the cardiac function, even from end-stage heart failure. However, the patients who have obtained a long-lasting recovery of cardiac function from an LVAD are still in a minority. To make this the majority, therapeutic LVAD should be combined with the apheresis therapies, DFPP and HF. We believe that this concept, a combination of HF and DFPP with therapeutic LVAD, will be the next generation of treatment that has a potential to postpone, or even avoid, heart transplantation.

Artificial organs versus regenerative medicine: is it true?

Individuals engaged in the fields of artificial kidney and artificial heart have often mistakenly stated that "the era of artificial organs is over; regenerative medicine is the future." Contrarily, we do not believe artificial organs and regenerative medicine are different medical technologies. As a matter of fact, artificial organs developed during the last 50 years have been used as a bridge to regeneration. The only difference between regenerative medicine and artificial organs is that artificial organs for the bridge to regeneration promote tissue regeneration in situ, instead of outside the body (for example, vascular prostheses, neuroprostheses, bladder substitutes, skin prostheses, bone prostheses, cartilage prostheses, ligament prostheses, etc.). All of these artificial organs are successful because tissue regeneration over a man-made prosthesis is established inside the patient's body (artificial organs to support regeneration). Another usage of the group of artificial organs for the bridge to regeneration is to sustain the functions of the patient's diseased organs during the regeneration process of the body's healthy tissues and/or organs. This particular group includes artificial kidney, hepatic assist, respiratory assist, and circulatory assist. Proof of regeneration of these healthy tissues and/or organs is demonstrated in the short-term recovery of end-stage organ failure patients (artificial organs for bridge to regeneration). A third group of artificial organs for the bridge to regeneration accelerates the regenerating process of the patient's healthy tissues and organs. This group includes neurostimulators, artificial blood (red cells) blood oxygenators, and plasmapheresis devices, including hemodiafiltrators. So-called "therapeutic artificial organs" fall into this category (artificial organs to accelerate regeneration). Thus, almost all of today's artificial organs are useful in the bridge to regeneration of healthy natural tissues and organs. It does not matter whether these tissues are cultivated inside or outside the patient's body. Thus, we strongly believe in the need for joint development programs between artificial organ technologies and regenerative medicine technologies. In particular, the importance of using both man-made substitute organ technologies and natural tissue-derived substitute organ technologies is stressed for improved medical care in the future.

A novel method for faster formation of rat liver cell spheroids.

Hepatocyte spheroids are expected to be the main component of the artificial liver bioreactor for their higher function. The preparation of hepatocyte spheroids, however, can require as many as 24 to 96 h. To reduce this time, we investigated a method employing a new technique of rat hepatocyte preparation and a dynamic culture. The modified Seglen's method for standard hepatocyte isolation was altered by elimination of ethyleneglycol bis(aminoethylether) tetraacetate from the first perfusate and calcium from the second perfusate. Isolated hepatocytes were cultured in a spinner flask by spinning at 120 rpm. The modified Seglen's method was used as a control. Cells obtained by the new method were more cohesive and formed a higher proportion of cell aggregates than control cells. In the spinning culture, hepatocytes had a tendency to aggregate and 80% of cells formed spheroids within 6 h of culturing. The mean size of spheroids was 68.5 +/- 18.5 microm. Confocal laser scanning microscopy revealed that individual spheroids contained approximately 30% of nonparenchymal cells over their surface. Using the new hepatocyte preparation method followed by a spinning culture, we were able to produce hepatocyte spheroids in as few as 6 h.