Is it possible to accumulate anti-cancer drugs for target organs
without side effects of such drugs?
A new methodology of magnetic accumulation chemotherapy for cancer using magnetic liquid contained in O/W and W/O/W emulsions was studied for this purpose.
Magnetic liquids, such as dextran or oleic magnetite, are injectable intraveneously without any toxity and pathological change. We used these ferro-magnetic materials for the carrier of anti-cancer drugs.
The W/O/W emulsion was first reported by Matsumoto in 1976, but used paraffin which is toxic to animals. Our W/O/W emulsion was made by using vegetable oils, oleic and stearic acids, using a different method and surfactants from the original report.
The O/W emulsion was prepared_easily by high pressure homogenizer with HCO as a surf act ant.
Studying the rheological aspects of these emulsions under various conditions, successful results of accumulation were obtained, where the magnetic field was over 1200 Oe/cm and the flow velocity was below 12 cm/sec. Encouraged by these results, metyl -CCNU contained in O/W emulsion and adriacine contained in W/O/W emulsion were injected for the treatment of AH-81, hepatoma of rats, and the magnetic field was applied over the inoculated part of rats tumor for 30 minutes, Me-CCNU was not effective, but adriacine contained in W/O/W emulsion was effective, especially in magnetic therapy.
From these results, it may be concluded that this new methodology is very promising for the treatment of cancer if magnetic materials such as not storaging and not toxic are obtainable.

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New therapeutic modalities for advanced cancer are eagerly sought since clinical results of the ever-existing treatments are rather disappointing. Hyperthermia to which tumor cells are reportedly more susceptible than normal cells has been expected to be a candidate for a new approach. Whole body hyperthermia, as anticipated to be indicative even for remotely disseminating cancers, has been investigated in mongrels from standpoints of technical feasibility and pathophysiology. Whole body hyperthermia was induced by means of extracorporeal circulation technic which was familialized by hemodialysis. For this purpose, an extracorporeal circulation system including a heat exchanger was made to be disposable.
Functional portion of a heat exchanger resembling a hollow fiber dialyzer was composed of immpermeable polyvinyl alcohol capillaries, Temperature of thermosate (thermal perfusate) irrigating the capillaries was regulated by a specially designed thermotatic system. Thirtysix to 42°C of blood at an inlet was warmed or cooled to 42°C to 36°C at an outlet while passing through the heat exchanger at a wide flow range from 50 to 500ml/min. Temperatures at various portions of canine body converged to 41.5 to 42°C in 60 to 90min after a start of the thermal perfusion.

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We are working on a preservation of Cadaveric organs for transplantation. 10% Fluosol-DA (FDA) was used as a perfusate for 12 adult mongrel dogs.
Even if at 2-10°C, the cadaveric organs was needed 0.16ml/kg/min oxygen and FDA transported about 60% of the oxygen demand. The safty limit of the warm ischemic time was 120min for the kidney and 60min for the liver and the pancreas.

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We have already developed a new vessel access type glucose sensor, which can automatically measure blood glucose levels up to 700mg/dl without sampling and diluting blood. A proportional controll type closed-loop artificial β-cell system has been constructed of the sensor, a micro insulin infusion pump and the controll circuits which have an integrator, a comparator and a pulse generator to supply the power for the pump. The system has been examined in dogs.
In this system, the infusion interval of the pump is controlled by the sensor output current. When the B. G. L. is normal, the infusion pump is operated and infuses about 14μl every 5 minutes. If the sensor output becomes higher, i. e. higher B. G. L., the infusion rate becomes faster to fall the B. G. L.
The system was checked by an in vitro test using high Meg-ohm resisters instead of the sensor, and showed good results.
In vivo, this system has performed so well that the reciprocal of infusion interval showed a fairly analogous profile to one of the sensor out put, and the infusion volume of insulin per every 5 minutes also showed the same profile.
The assembled system, therefore, may be promising as a closed-loop artificial β-cell.

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The vessel access type glucose sensor for the implantable artificial pancreas has been developed in our labolatories. The sensor is connected to a vessel access through which the blood flows and enable to measure blood glucose levels without sampling and diluting blood.
Clinically, the sensor was applied on renal failure patients using hemodialysis circuit. The sensor responded well in parallel with the blood glucose levels measured by Autoanalyser from 110 to 350mg/dl in increasing phase, however, at initial measurement it takes about 30 minutes' delay to response in decreasing phase.

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Recectly a long term culture technique has been developed by us which brings larg monolayer formation with small fibroblast content from adult rat pancreas.In the presence of phosphodiesterase inhibitor (IBMX), the most islets became adherent to the dish and formed extensive monolayers. The strong relation was ovserved between morphological state and insulin secretory function, therefore monolayered islets showed significantly higher secretion, but remained spherical, the secretion gradually decreased.
The dynamics of insulin secretion in response to glucose stimulation with culture medium were studied in perifusion experiment, the typical biphasic pattern was shown rapidly to the high glucose medium.

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Artificial pancreas containing of 1) 2ml culture medium without islet, 2) approximately 1200 (1000-1300), 3) approximately 2400 (2000-2600), and 7500 (7000-8000) xenogeneic rat islets were implanted in totally pancreatectomixed dogs. Devices were inserted femoral arteriovenous shunts of diabetic dogs and allowed to remain in place as long as 24hrs prior to removal. In group 1, as anticipated, there was no improvement of diabetic state with, passage of time. The plasma glucose concentration in group 2 fell gradually, but normoglycemia. was not achieved. In all 5 diabetes studied in group 3, a gradual decrease in blood glucose was found and normoglycemia was achieved after 10 to 12hrs. IRI showed rise shortly after insertion of device. However, glucose tolerance test remained abnormal. When the number of islets seeded was increased to about 7500, plasma glucose concentration fell rapidly from 339 to 200mg/dl 2hrs after insertion of the devices, and followed by eventual stabilization at normoglycemic levels after 5 to 6hrs. The results of glucose tolerance tests in these group showed normal.
These data showed that about 7500 xenogeneic rat islets in the artificial pancreas was required to restablish normoglycemia in totally pancreatectomized dogs.

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The hybrid artificial pancreas consisting of hollow fibers surrounded by allogeneic canine pancreatic fragments or xenogeneic hamster isolated islets was attached to the vascular system of totally pancreatectomized diabetic dogs.
The hollow fibers (Ethylene Vinyl Alcohol) used in this device had an internal diameter of 210μm, wall thickness of 32μm and a molecular weight cut-off of 70000 daltons. One of four dogs using fragments of a canine pancreas, and four of six dogs using 10000 isolated hamster islets achieved normoglycemia between 3 and 8 hours after attachment of the device. And then normoglycemia and normal plasma insulin levels were maintained for about 20 hours until the device was detached. Furthermore intravenous glucose tolerance tests showed a near normal plasma glucose and insulin response. While, in two of six dogs using 10000 hamster islets, plasma glucose levels gradually decreased until 3 hours after attachment of the device and maintained levels of 200 to 250mg/dl.
These results indicated that (1) the hybrid artificial pancreas was able to reverse diabetes in totally pancreatectomized dogs, (2) the device using isolated islets was more effective than using pancreatic fragments, and (3) at least 10000 hamster islets were necessary to restore normoglycemia in diabetic dogs.

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Mathematical model of the circulatory glucose and insulin dynamics has been made by combining the compartments which express major vessels, capillaries in the major organs such as brain, liver, gut, kidney, and periphery, and extravascular spaces. The depancreatized dog loaded with iv glucose was controlled with peripheral or portal insulin infusion by open- or closed-loop devices. After the input of initial conditions and time-sequence of insulin delivery rate, the model well simulated the experimental results of both glycemia and insulinemia over the experimental period. Dynamics of glucose and insulin kinetics in liver and periphery were also depicked clearly.
These data indicated that the model is useful to analyse the dinamic properties of glucose and insulin kinetics in specific organs.

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The pharmacokinetic method for computercalculating the subcutaneous (SC) insulin infusion rate (IIR) for open-loop system was studied using the plasma insulin or freeinsulin profile obtained by the closed-loop intravenous (IV) insulin infusion system. Onecompartment open model was appropriate for estimating the absorption kinetics of SC infused insulin. The plasma insulin or freeinsulin profile was measured by RIA in 4 insulin-dependent diabetics during the control period with the closed-loop IV infusion system after taking test meals.
In order to reproduce similar plasma insulin profile with the open-loop SC system to those with the closed-loop IV infusion system, the SC IIR was calculated by substituting the pharmacokinetic parameters of each patients such as Ka, Ke and Vd in our formula, that is, IIR (t→t+τ)=A·ΔCp (t+T)+Cp (t+T)·Vd·Ke, where A is the weighting coefficient for the rate of change in plasma insulin concentration (Cp), T is the time regulatory constant. The computer-calculated IIR was preprogrammed to the open-loop SC infusion system, which we developed. The unit measured 121×70×26mm and its weight was 270g including the battery. The IIR could be programmed at 100 steps and ranged from 20μl to 2ml/h. The plasma insulin profile were reconstructed almost in the same degree except 40min after the meal by the open-loop SC infusion system as those by the closed-loop IV infusion system. The postprandial blood glucose levels during the closed-loop control period reached the peak values of 162±12mg/dl, while those during the open-loop control period reached the peak values of 128±15mg/dl (Mean±SEM).
It was possible to calculate the suitable IIR for the open-loop SC infusion system by applying the pharmacokinetic technique based on the information obtained by the closed-loop IV insulin infusion system.

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Standardization of strength-duration curve and presumption of pacing threshold were tried from pacing thresholds at various pulse durations measured clinically.
Standard curves were drawn from the mean value of thresholds at several pulse durations. Pacing threshold at the 0.5 msec pulse duration was mutually related to those at other pulse durations. These two charts are very useful to save the time of clinical measurement of threshold and to prolong the battery lifetime by means of setting shorter pulse duration.

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Since 1979, the multiprogrammable pulse generators with the telemetry function has been implanted in 37 patients.
As the resistance was loaded, the value of the lead impedance in the telemetry system was 33±15 ohms higher than the value which calculated data from the oscillograph. In cases of implantation of the multiprogrammable generator, the difference ranged between 29-49Ω. But this mechanism to show the number of lead impedance digitally is considered to be of clinical value.
In the case where the displaying function of the battery current was compared with the pulse energy that was measured at the same time, they had a correlation. It is the convenient index to measure how much electric current has been spent, and by adjusting this the longevity of the batteries will be prolongated.
Telemetry system becomes easier to follow up patients in pacemaker clinic.

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Since April 1976, we have follow up the pacemaker patients by analysing their pacergrams.
For a voltage constant pacemaker, predicted battery voltage calculated by pacergram was nearly equal to actual one measured at the time of the generator replacement as far as the time constant of a patient had been remained within 0.3.
The time constant calculated by the pacergram was closely corresponding with the lead impedance obtained by telemetry (Pacesetter 221) and measured impedance at the time of replacement.

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Intracardiac signals from 66 patients undergoing permanent pacemaker implantation have been analyzed. Intracardiac wave form was obtained at the time of insertion of the endocardial electrode and at 3rd and 7th day after implantation using temporary-permanent technique. At the implantation of the electrode, three types of right ventricular electrographic pattern were identified. Type I pattern (S-pattern) was most frequently seen in 47% of the patients. Change of ST-segment and T-wave configuration was observed until the 7th day after implantation. T-wave inversion was occurred about 80% of the patients. ST-segment elevation was observed about 72% of the peak-to-peak Rwave amplitude at implantation but found to be decreased to the 18% of the peak-to-peak value at the 3rd day after implantation. The peak-to-peak voltage was found to be changing in the early stage of implantation. Intracardiac signals from the right atrium was recorded and ST-segment and A-wave amplitude was analyzed during 7 days. Recording of the intracardiac signals were useful for the avoidance of the electrode complication i. e. threshold elevation, sensing abnormalities, catheter floating and myocardial perforation.

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Several abnormalities of silicone insulator in its microscopic structure and foundamental microscopic structure of silicone itself were found in Medtronic #5816 pacemaker lead which has been implanted more than 12 yrs, in a human body, although Nickel/alloy lead wire was seemed intact. Recent newer silicone pacemaker insulators are much improved in their microscopic structural qualities.
Further examinations on pacemaker lead insulators will be required for making great progress in this field.

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Forty-nine patients with sick sinus syndrome treated with a ventricular pacing in our hospital from 1970 to 1981 were evaluated. Thromboembolism was observed in sixteen (32.7%), and 68.8% of them occurred in the first year after implantation.
Prophylactic anticoagulant therapy was performed on the other sixteen patients. Thromboembolism was found in only one (7.7%) of the thirteen who had been well controlled by anticoagulants, and the incidence of thromboembolism was lower in this group than the non-anticoagulant group.
It is concluded that patients with sick sinus syndrome treated with ventricular pacing should be on prophylactic anticoagulant therapy immediately and for at least one year after implantation.

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During the past 11 years, 19 cases of pacemaker implantation in children were done at our clinic.
Indication for implantation were congenital A-V block 2, sick sinus syndrome 2, postoperative paroxysmal atrial tachycardia 1 and postoperative complete A-V block 14. Postoperative paroxysmal atrial tachycardia was terminated by right ventricular overdrive pacing (100/min). So bipolar endocardial lead was placed at right ventricular apex and high-frequency receiver was implanted at anterior upper chest. Complication were included as follows. Elevation of threshold in 5 cases, lead rupture in 3 cases, Twiddler's syndrome in one case, left ventricular rupture by screw type lead in one et al. During the surgery measurement of threshold of lead in the primary implantation and also at the time of generator change is very important to. prevent the exit block. Pacemaker was placed at retroperitoneal pocket. Six cases (31.6%) were died. Three cases were died from cardiac failure, two cases were from low cardiac output syndrome after cardiac operation and one case from sepsis. Other cases have been doing well under periodic check up at pacemaker clinic.

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Four extracorporeal perfusion conditions (continuous beating, continuous fibrillating, pulsatile beating, pulsatile fibrillating) were tested for 15 minutes each in dogs. Coronary flow, myocardial oxygen consumption and hemodynamics were measured. No significant hemodynamic differences in any of these variables were found between pulsatile and continuous flow states in either fibrillating or beating hearts. In both fibrillating conditions, significant elevations of myocardial oxygen consumption by continuous perfusion were found (P<0.01). These data suggest caution in the expection that pulsatile perfusion will reverse myocardial oxygen consumption changes seen with fibrillation.

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Biochemical analysis of epinephrine and nor-epinephrine, along with radioimmunoaasay of angiotensin II were carried out during extracorporeal circulation with pulsatile flow and non-pulsatile flow. Twenty-two patients with acquired valvular diseases were used as the materials. Increase in level of plasma catecholamines were observed both in pulsatile and non-pulsatile perfusion. The level of catecholamines, especially of epinephrine was significantly low in pulsatile flow perfusion than in non-pulsatile perfusion.

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The pulsatile cardiopulmonary bypass is useful from the point of minimizing the organ damage from extracorporeal circulation.
In this paper, we studied effect of pulsatile cardiopulmonary bypass on renal function.
Non-pulsatile flow delivered by a roller pump was used in 25 patients and pulsatile flow induced by PBP or PAD was utilized in the other 23 patients at the same mean flow rate.
Renal function study included urine volume, free water clearance, creatinine clearance and urea clearance. Blood and urine sumples were taken before, during and after bypass, and on the postoperative period.
Significant deference in urine volume was not found between two groups. Free water clearance was maintained excellently during and after bypass in pulsatile flow group. Creatinine clearance recovered immediately after surgery in pulsatile flow group.
It can be concluded that pulsatile cardiopulmonary bypass is more ben-efical on the renal performance during and after bypass.

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In studies on mongrel dogs, the microcirculation of the greater omentum during perfusion cooling by pulsatile flow was observed. With perfusion cooling for thirty minutes, the esophageal temperature lowered to about 20°C (the perfusion rate about 150ml/Kg. and the temperature of perfusate about 15°C). During cooling the arterial pressure was almost constant with satisfactory pulse pressure. In those periods, arterioles maintained good axial flow with axial accumulation similar to physiological circulation. Capillary flows were kept well without stasis or shutdown untill circulatory arrest. Those indicate good tissue perfusion and uniform cooling. We suggest that this method of cooling is quite excellent

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This experimental study compares the effects of pulsatile perfusion (N=6) with nonpulsatile perfusion (N=6) on hemodynamics and metabolism during about 2 hour's nonworking beating heart. Following results were obtained.
Myocardial blood flow, myocardial oxygen consumption, myocardial lactate extraction/myocardial oxygen consumption, systemic lactate extraction/systemic oxygen consumption and postperfusion's DPTI/TTI of pulsatile group were significantly higher than nonpulsatile group. Myocardial vascular resistance, Systemic vascular resistance, Systemic blood flow of pulsatile group were significantly lower than nonpulsatile group. The results demonstrate that the pulsatile perfusion in nonworking beating heart minimized the deleterious effects of nonpulsatile perfusion on hemodynamics and metabolism.

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Pulsatile cardiopulmonary bypass with AVCO pulsatile bypass pump (PBP) was employed in 13 infants undergoing elective open heart surgery. Arterial pressure was monitored both on radial artery and descending aorta to get ideal direction of the arterial cannula. Flow velocity was monitored by Millar cathter-tip electromagnetic flow probe placed in the descending aorta. The driving conditions of PBP were 350mmHg of driving pressure and 100bpm. The perfusion rate was 120ml/kg/min and central venous pressure was kept around 10mmHg. The size of arterial cannula was Bardic #10 at body weight less than 3kg, #12 at 3 to 6kg, #14 at 6 to 9kg, #16 at 9 to 12kg.
PBP produced excellent pulsatile flow with 63±6/31±4mmHg of arterial pressure, 635±81mmHg/sec of max dp/dt, and 86±13cm/sec of peak flow velocity which was similar to physiological hemodynamics. Arterial pressure and pulse pressure were gradually increased on going cardiopulmonary bypass, but peak flow velocity was constant.
These pulsatile cardiopulmonary bypass was compared with nonpulsatile cardiopulmonary bypass of the same perfusion rate and central venous pressure in the similar age group. Pulsatile perfusion was found to offer the following advantages: lower systemic vascular resistance, higher urine output, lower angiotensin II and higher elevation rate of plantal temperature at rewarming. These date indicate the superiority of pulsatile flow over nonpulsatile flow during cardiopulmonary bypass.

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The distribution of deep temperatures of the patients (pts) and their changes during cardiopulmonary byuass (C. P. B.) was studied in 45pts with congenital heart diseases.
The forehead deep temperature (F-DT) and the sole deep temperature (S-DT) were measured and recorded by deep body thermometer system (Terumo Corp.) during C. P. B. for 15pts (9yrs, 27kg, 1.0m²BSA) with atrial septal defect, 15pts (4yrs, 15kg, 0.6m²BSA) with ventricular septal detect and 15pts (5yrs, 14kg 0.6m²BSA) with tetralogy of Fallot. Moderate hypothermia was applied using C. P. B..
The time for monitoring was 244±44min and for C. P. B, 53±12min. The time for cooling (28±8min) and warming (25±6min)was almost eaual. The F-DT (36.0±0.6°C) dropped auickly by cooling (29.7±1.4°C) and increased steeply by warming (35, 57plusmn;0.8°C) When the C. P. B. was terminated, the F-DT (35.1±0.6°C) slightly dropped and increased gradually again (36.3±0.8°C). However the S-DT (35.1±1.2°C) dropped very slowly by cooling (31.5±1.4°C) and increased slowly with a delay w. r. t. F-DT by warming (33.1±1.2°C). S-DT increased promptly when C. P. B. was terminated (34.2±2.1°C). The delay (20±7min) between the transition voints of F-DT and S-DT seemed to be due to low perfusion of lower extremities during C. P. B..

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The Hollow fiber oxygenator (1.55m²) was studied to evaluate hemodynamics and elements of blood in 14 mongrel dogs of extra corporeal circulation during two hours complete bypass.
At perfusion flow of 1.5 to 2.0liter/min, an O² to blood flow ratio was adequate by 0.56 in the hollow fiber oxygenator. In this condition PaO² was mainteined 126 to 190mmHg and PaCO² was mainteined 30 to 39mmHg during 2 hours.
Hemoglobin volume and platelet counts were decreased 30 and 39% on ECC compared to Pre-ECC by hemodulution but were recoverd to end of ECC by transfusion of blood of the circuit. Platelet function was mainteined adequately during ECC.
But fibrinogen was reduced 60% on ECC compared to pre-ECC and was not recovered at the end of EGG by transfusion of blood of circuit.
Serum K⁺ was decreased during EGG and Serum Na⁺/K⁺ ratio was increased by EGG. Insulin to blood sugar ratio, Lactate and Glucagon were elevated during EGG. Serum free hemoglobin was recognised of 0.25mg/dl/min during EGG by hallow fiber oxygenator is hopefull for clinical usage.

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We developed a new membrane oxygenator. It consists of silicone hollow fibers with 23cm in length, 200μ in inner diameter and 400μ in outer diameter.
The surface area available for gas transfer was 5.4M². Six fasted dogs were used for experimental evaluation.
Total extracorporeal circulation was carried out for 6hrs. at 37°C.
Average PO₂ after silicone hollow fiber membrane oxygenator was 286±131mmHg, PCO₂ was 34.6±10.2mmHg, O₂ transfer rate was 30.8±8.9mL/min/m², CO₂ transfer rate was 68.5±20.2ml/min/m².
Serum hemoglobin after 6hrs perfusion was 86mg/dl. This results showed this oxygenator was acceptable for clinical use.
We applied this membrane oxygenator for three cases undergoing open heart surgery.
The results were satisfactory.

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Clinical evaluation of newly developed membrane oxygenator, Terumo Hollow Fiber (H. F. O.) has been done during and after open heart surgery. The H. F. O. is consisted with 20, 000-60, 000 hollow fibers, 200μm in indiameter and 250μm inooutdiameter, made of polypropylene with 700Å micropores. It is suitable to set up the heart-lung bypass circuit with only one roller pump, from the view points of hemolysis and pressure gradient across the oxygenator. Function in O² and CO² transfer with the H. F. O. is maintained in satisfactory conditions for long-term perfusion. Amount of bleeding after surgery through the chest drainage tubes is much less with H. F. O. compared with Travenol (T. M. O.) and Kolobow (K. O.).

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The polypropylene hollow fiber oxygenator (H. F. O.) was used for open heart surgery in 217 patients. The sizes of 1.6m², 1.8m², 3.3m², two 3.3m² in parallel and 5.4 m² were available, one of which was employed for an individual patient depending on the patient body weight.
PaO₂, PaCO₂ and other gas and hematological data obtained during bypass were within normal range, although the tendency of CO₂ retention was recognized in case of more than 2 hrs perfusion.
In the bloodless cardiopulmonary bypass, there were no significant difference in change of hemoglobin value and platelet count during bypass between the patients treated with H. F. O. and bubble oxygena for (B. O.).
In the longer bypass, free water clearance of the kindney was -0.64±0.31cc/fnin/BSA m² in H. F. O. group (N=7), while it was -0.30±0.24cc/min/BSA m² in B. O. group (N=13). The difference between two groups was statistically significant, indicating that the kidney function was well preserved in H. F. O, group. When the oxygenator was used in the single pump system, the maximum pressure in the pumping tube frequently exceeded the critical pressure causing hemolysis. However, it was 210±70 mmHg and below the critical pressure in the two pump system.
Therefore it was recommended to use the oxygenator in two pump system. It was observed that kidney function was well preserved by H. F. O. especially in long time perfusion.

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We developed new silicone hollow fiber membrane oxygenator (SHMO) in order to get stable gas exchange capacity and to diminish blood damage during long term extracorporeal membrane oxygenation.
SHMO was compared with another type, silicone coil membrane oxygenator (MMO-6) with regard to blood damage during 24hours veno-arterial bypass in dogs. Platelet counts and plasma hemoglobin were measured, and morphological changes of oxygenator membrane surface, red cells and platelets in circulating blood were studied by scanning and transmission electron microscopy. In SHMO group, platelet counts and platelet ultrastructure were much preserved during veno-arterial bypass.
Scanning electron microscopy of red cells revealed less morphological changes in SHMO group.
Surface of SHMO were not covered any blood components. These findings . revealed that SHMO has prominent charactristics of stable gas transfer performance and less blood damage, and therefore is the excellent membrane oxygenator.

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Mechanical ventricular assistance is a valuable adjunct in the treatment of post cardiotomy left ventricular power failure and cardiogenic shock following myocardial infarction.
Our institute has been engaged in the design, development and in-vivo evaluations of pneumatically-actuated Left Heart Assist Device (LHAD).
A continuous monitoring system of pump flow changes is absolutely necessary to have the adequate drive and control of LHAD.
Experiments were designed to evaluate flow measurements using ultrasonic pulsed Doppler (PD) and continuous wave form Doppler (CWD) methods during LHAD pumping in the mock circulation.
Pneumatic source controls were changed from 200mmHg to 50mmHg to measure several flow changes by the PD and CWD methods.
The correlation between actually measured flow and PD (r=0.96) and CWD (r=0.99) were evident.
This results showed that both PD and CWD were stable and reliable method to determine the LHAD flow as the continuous monitoring system.
In the comparison of PD and CWD, CWD system is a very simple, not expensive and easy to fabricate the flow probe around the inflow or outflow tube of LHAD.
These results indicate that the continuous wave form Doppler method is useful as a non-invasive method for monitoring the LHAD flow.

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Artificial heart is made from polyurethane mainly because of its blood compa.tibilities. Small holes are apt to appear on diaphragms after long term driving, which ultimately becomes a bottleneck of durability for artificial hearts. With the object of removing this bottleneck, we made diaphragms under various conditions and observed their surfaces and sections with the aid of scanning electron microscopies. As a result of these experiments, we find that micro holes in the diaphragms enlarge their size and increase their number and moves toward the surface of the diaphragm during driving. The mechanism, we believe, of losing durability of a polyurethane membrane is resulted from surface located holes. However these holes are mainly originated by the character of the polyurethane as well as the dipping condition such as humidity, pressure, etc.

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Survival times of experimental animals with pneumatically driven artificial hearts and assist devices increased significantly. But any of these pumps are not totally implantable due to the bulky energy source and energy conversion system. An electrically powered and mechanically driven pump is the only choice for the long term application.
we chose the polarized electromagnetic energy conversion system with a rear earth magnet as a driving mechanism of the artificial heart.
The blood pump is a pusher plate type. a pusher plate is connected with the armature by a link to magnify the stroke of the armature.
To obtain the high efficiency, the dynamic responce of the armature, springs, links and so on are analyzed.
Specification of this pump is as follows; stroke volume=20mL, heart rate=0 to 150bpm, mean aortic pressure=100mmHg.
In the estimation of the computer simulation, the efficiency of this pump driving system is more than 35%. The bench test model of the driving mechanism to confirm the concept design of this pump have been assembled.

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In this study, heparinized hydrophilic polymer (heparinized polyurethan, H-USD) which has been developed for blood contacting surface was used.
This material has the property of low platelet adhesion and low fibrin deposition at lower shear rate.
Pneumatically driven sac-type blood pump with significant advantages in hemodynamics and durability has been designed. This pump was used as a LVAD for periods of one to 81 days in 24 beagle dogs in continuous pumping mode at a flow rate of 0.5-1.5l/min.
In a dog which survived for 81days, no anticoagulants was attemped for the whole surviving period.
This study suggested that left ventricular assist system with a pump fabricated with H-USD would be useful for the treatment of left ventricular failure, especially after open heart surgery, because this system can be used without anticoagulation with minimal thrombus formation on the blood contacting surface.

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The existing artificial heart air driving system is utilizing a stationary air compressor and a vacuum pump, so the moving area of the patient is restricted within a rather small region. To get rid of this limitation, we made up a compact air driving system making use of a rotary compressor which is rotated forward and reverse direction alternately by a D. C. motor. Next we performed an in vitro test using a mock circuit. Then it is shown that this driving system is usable in place of the existing system without any problems.

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It is difficult to control flow patterns on a pulsatile flow pump. To overcome this difficulty, we discussed here about the way to form flow patterns using the piston-bellows type of artificial heart pump. Flow pattern is governed by two factors; (1) volumetric changing pattern of the ventricle and (2) inlet and outlet valve actions. In this study, each factor was referred to eccentric radius of the cylindrical cam and two types of valves (SJM valve and ball valve) respectively. Through mockcirculation test, flow pattern could be formed according to pulse rate and stroke of the piston satisfactorily by virtue of stainless steel bellows (controled ventricular volume in proportion to stroke of its piston) and ball valves (small amount of regurgitation).

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As previously reported, a heparinized hydrophilic polymer containing polyethyleneglycolmethacrylate (SM) and quarternized dimethylaminoethylmethacrylate (DAEM) and ionically bound heparin has excellent antithrombogenicity due to the continuous release of heparin from its surface into blood stream for a longer period. In this study, an application of this polymer to vascular prostheses has been investigated by making this polymer porous. All of 40 prostheses implanted in the descending aorta of dogs were patent. The average implantation period was 145 days. In 28 prostheses implanted in the external iliac artery, 21 prostheses were patent and the residual 7 prostheses were occluded. The patency rate and the average implantation period were 75% and 33 days respectively. In 19 prostheses implanted in the inferior vena cava, 14 prostheses were patent and 5 prostheses were occluded. The patency rate and the average implantation period were 73% and 56 days respectively. Scanning and transmission electron microscopic studies revealed that neither neointima nor endoepithelial cell was observed but only protein deposition of 100 to 1000 Å in thickness was observed on the surface of the prostheses irrespective of the implantation period and site. Furthermore, it was found that albumin predominantly adsorbed onto the prostheses and that no adsorption of fibrinogen and γ-globulin did take place by immuno electron microscope.

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We have demonstrated that Polyvinyl alcohol-Silica composite had good tissue affinity and anticoagul ability. Using PVA-SiO₂ and PVA-SiO₂+Heparin coating artificial vessels the possibility of the artificial small artery or vein was experienced in vitro and in vivo.
The results are followed;
1. PVA-SiO₂ can prolong the coagulation time and on PVA-SiO₂+Heparin surface the blood coagulation was not noticed during two days by Lee-white methode and plasma recalcification time methode.
2. After preserving pieces of these artificial vessels in human platelet rich plasma the adherence of blood components to their surfaces changed each other. Blood components adhered to the non coating and PVA-SiO₂ surfaces, but the degree of the former was more than the latter. On PVA-SiO₂+Heparin surface the adherence was a little.
3. In vivo three types of artificial vessels were inserted in canin abdominal aorta. The inner surfaces of them were obserbed optically, microscopically and scaned electromicroscopically.
As a result the degree of blood component adherence was non-coating>PVA-SiO₂>PVA-SiO₂+Heparin.

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Based on the previous data on the implantation of bias-cut grafts into the thoracic aorta of dogs, experimental study using 4mm I. D. of this type of grafts into the bilateral external iliac arteries was performed to verify the original assumption of maintaining biological porosity close to the original porosity which resists scar contraction.
80% of patency was found both on the bias-cut grafts and on the control side of Microknit grafts by autopsy in a period of 2 years. Histologically, the inner capsule of bias-cut grafts showed a thinner, and more stable layer than those of control grafts did.
Wall structure of bias-cut grafts was found similar to the host artery; inner capsule (intima), graft layer (media), and outer capsule (adventitia).
Good biological porosity with a thin and stable inner capsule found in the bias-cut grafts is unique and advantageous to the development of a small caliber arterial prosthesis.

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Glutaraldehyde tanned human saphenous veins treated with or without ficin were implanted in the canine abdominal aorta. In the control group was implanted polytetrafluoroethylene (Gore-Tex). All animals were sacrificed more than one year following implantation, and recovered grafts were histalogically investigated. Graft natency was 85% in the f icin treated saphenous vein graft (FGHSV), 83% in the non-treated saphenous vein graft (GHSV) and 80% in the Gore-Tex, respectively.
Among 8 FGHSV grafts, aneurysm formation was found in one graft and graft dilatation was in another. Calcification of the graft was found in the 4 out of 6 Gore-Tex specimens In contrast, there were no dilatation, no degeneration or calcification among the 6 GHSV grafts, however the pannus growth was slightly hypertrophic. Therefore, it is concluded that GHSV graft is superior to FGHSV graft or Gore-Tex.

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Glutaraldehyde (GA)-tanned equine umbilical cord vessels (EUCV) is useful for venous reconstruction, however, it is somewhat hard for surgical application.
This is the study on GA-tanned ECUV with 1% ficin digestion in vitro and long term evaluation of GA-tanned EUCV in vivo.
1. Elasticity, antithrombogenicity and amino acid component of GA-tanned EUCV with ficin digestion were compared with that of the graft GA-tanned alone. There was no significant different between these two types of the grafts. However, ficin digestion makes EUCV more flexible and easy to suture without harmful effect.
2. Three patch grafts and 33 replacements of vena cava was performed using GA-tanned EU CV in mongrel dogs. The patch grafting dogs were sacrified on 365, 365 and 477th post operative day respectively. All of them showed good pseudoneointimal (PNI) healing at the time of exploration.
Patency of the replacement group was examined by venogram. On 7th day after operation 12 out of 14 was patent, on 14th day 9 dogs were performed venography, 100% patency was found. After one month, patency rate was decreased to 60% (6/10). Six and 12 months after surgery, the rate showed 100% (4/4 and 3/3) respectively. PNI healing was examined in one dog at 6 months after operation, in 3 dogs at 12 months after surgery. One dog showed completion of PNI healing at 6 months, other three showed imcomplete healing even at one year after operation.
GA-tanned EUCV was thought as a hopeful substitute for a venous reconstruction. Additionally, ficin digestion makes the graft suitable for surgical manipulation.

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Cryopreserved vessels were experimentally examined. Canine caratid arteries and jugular veins were cryopreserved in dimethyl sulfoxide (DMSO) or in physiologic salt solution (PSS), quality of which were evaluated macroscopiaclly, microscopically, by scanning electron microscope and by measurement of compliance. Then cryopreserved canine carotid arteries and jugular veins in DMSO were grafted to bilateral canine carotid arteries and were removed at any proper days in 270 days from 3 days after the operation in order to examine macroscopically, microscopically and by scanning electron microscope. In conclusion, by use of cell cryoprotective agent DMSO, satisfactory grafts were obtained. The results of these experiments revealed that cryopreserved vessels in DMSO were excellent as small arterial prosthesis.

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