A Centrifugal Pump (CP) for prolonged use has been developed in our institute. Antithrombogenicity of the initial CP (N1) is provided by aggressive wash-out around the impeller (IM) with a balancing hole (BH) in the center of the IM. But the N1 stopped driving in the 1st, 11th, 22nd and 80th day. The current iteration (N2) was ameliorated to get better antithrombogenicity, where the BH diameter was widened to increase wash-out flow and an edge of a thrust bearing (TB) was rounded off to minimize flow stagnation. Wash-out flow velocity in the BH in the N2 was evaluated to be three second of that in the N1 by the Doppler velocimetry. Less flow stagnation around the TB in the N2 was visualized by light cutting method. In vitro hemolysis tests were performed at a 100mmHg head and a 5L/min flow rate. Allen's hemolytic indexes of the N1, the N2 and the BP-80 were 0.023, 0.008 and 0.008mg/dl, respectively. In vivo antithrombogenicity and hemolytic property in the N2 was investigated by using 3 goats. The N2 was installed paracorporeally between the LA and the Ao. Peroral anticoagulant therapy was conducted with warfarin. The N2 could run for 50, 91+ and 200 days. Plasma free hemoglobin was kept around 8mg/dl.

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An effect of tandem operation of turbo pumps on hemolysis was investigated in this study. The Bio-pump (BP-80) was chosen as a representative pump and a tandem operation of two BP-80s (TOBP) were compared with single operation of a BP-80 (SOBP) in in vitro hemolysis tests in three driving conditions at pressure loads of 200mmHg, 350mmHg and 500mmHg under a pump flow rate of 5L/min. The hemolysis was evaluated with Allen's hemolytic index (HI). Each closed mock loop was filled with heparinized goat blood at the temperature of 38-40°C. The HI of the TOBP at pressure heads of 200mmHg, 350mmHg and 500mmHg were 0.012±0.002mg/dl, 0.019±0.003mg/dl and 0.102±0.032mg/dl, respectively. The HI of the SOBP at pressure loads of 200mmHg, 350mmHg and 500mmHg were 0.013±0.003mg/dl, 0.046±0.014mg/dl and 0.15±0.014mg/dl respectively. These results indicate that the TOBP is one of good methods to reduce high HI and an effect of exposure to higher shear stress on hemolysis may be more serious than that of longer duration of exposure to shear stress in turbo pumps.

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Vibrating flow pump (VFP) was designed as a disposable type blood pump. Basic study of VFP was performed in the mock circulation concerning the effect of the changes of a diameter and length of vibrating tube on pump performance. The pump efficiency was also studied from the point of driving frequency of vibrating tube. To develop VFP as a blood pump for extracorporeal circulation with membrane oxygenator (ECMO), oxygen transport rate during ECMO was evaluated by acute animal experiments using adult goats. From the results of the mock circulation study, pump efficiency showed significant good value in the 15mm diameter of vibrating tube, but no significant change was shown in the length of vibrating tube. Oxygen transport rate of ECMO using VFP was also improved compared with that of the centrifugal pump and air-driven sac type artificial heart. These results indicates that VFP has the advantages in the oxygen transport rate which is important role to develop the ECMO system.

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In order to analyze the effect of left ventricular assist (LV-assist) on the stunned myocardium, acute animal experiments using 4 adult goats were carried out using the model of transient ischemia occluding the left anterior descending coronary artery for 3 minites. In this study, the end-systolic point (ESP) and the end-diasolic point (EDP) were, calculated using pressure-volume curve (P-V curve) during transient ischemia and the recovery period, with and without LV-assist. In all parameters of ESP and EDP, LV-assist decreased the recovery time from transient myocardial ischemia. These results suggest that the decrease in pre-load and after-load with LV-assist contributes to the early recovery from stunned myocardium.

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We study charge and discharge characteristics of a lithium ion rechargeable backup-battery under a condition of same temperature as inside of body for a totally implantable artificial heart. The seven cells of lithium ion battery in series connection were charged on condition of constant voltage of 29.4V (maximum charging current of 1000mA), and they required 84 minutes to be fully charged. We connected the 7-cell lithium ion battery with a mock load of 25Ω, which electrically simulates a typical TAH actuator, and measured dischargeable time of the battery for the mock load. It was dischargeable for 60 minutes, and the terminal voltage varied from 28.9V to 18.9V in this process. The dischargeable time was compared with 20-cell NiCd rechargeable battery with same voltage and same volume as the 7-cell lithium ion battery. It was found that the lithium ion was dischargeable twice as long as the NiCd. Using the terminal voltage of the lithium ion varying in discharging process, we investigated to monitor residual energy of the lithium ion battery. As a result, the residual energy of the battery could be monitored in either of continuously and intermittently discharging using the terminal voltage. And the surface temperature rise of the lithium ion battery was 2°C in case of charge and 8°C in case of discharging. It was found that the lithium ion battery had higher energy density and smaller temperature rise compared with NiCd battery.

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A mechanical circulatory system (MCS) has been developed in order to evaluate artificial organs including artificial blood pumps and artificial prosthetic heart valves. The MCS contains a fluid circuit, drive and measuring devices. It is necessary that the fluid circuit consists of an artificial atrium, a ventricle and an aorta which are physically and functionally identical to those of the natural system. The purpose of this study was to examine characteristics of the aortic pressure wave. The aorta was made of silicone and was encased in acrylic. Catheter-tip pressure manometers were used to measure aortic pressure at two different locations separated by a distance of 100mm. Pulse wave velocity (PWV) was calculated by measuring the time taken by the pressure wave to travel the distance between these two locations. As a result, the range of measured PWV was 7 to 16m/s which increased in accordance with aortic pressure at the diastolic phase. This pattern was close to that observed in the natural aorta.

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A new IABP balloon is a standard single chamber type and its volume is 35cc. The length of it is 71cm. The outer annular lumen of the balloon catheter is 12F in size, and is used for inflation and deflation of the balloon. The inner lumen of it is 7F in diameter and permits the insertion of a guiding catheter for CAG or PTCA. The bottom has a Y-shaped connector and is attached with a one-way valve and a side lumen just as a regular sheath introducer. The material of the balloon is polyurethane. We experienced seven patients who were applied PTCA and twenty patients CAG with the intraaortic balloon pump, and no complications related to CAG, PTCA and IABP were observed.

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We developed two types of intraventricular axial flow pumps (AFPs) for biventricular assistance (L-AFP and R-AFP) such as coronary revascularization surgery without cardiopulmonary bypass. Each pump has a miniature impeller, 8mm in diameter. The mock test showed the flow rate of 2L/min against the pressure head of 80mmHg at 25, 000rpm in L-AFP, and the flow rate of 2L/min against the pressure head of 40mmHg at 20, 000rpm in R-AFP. For basic evaluation of the pumps, an acute experiment was carried out using five adult mongrel dogs weighing 17.0-21.0kg. Under general anesthesia, L- and R-AFP were installed after left thoracotomy. L AFP is inserted into the left ventricle and the ascending aorta via the apex using introducing equipment. R-AFP was inserted into the right ventricle via a graft sutured to the main pulmonary artery. As a consequence of this experiment, biventricular assistance with L- and R-AFP improved animal hemodynamics more than only L-AFP. Under induced bradycardia, We achieved same data. We concluded that right heart assistance was considered necessary for coronary revascularization surgery without cardiopulmonary bypass.

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In order to provide an inexpensive ventricular assist device (VAD), we developed a 20mL-VAD which was followed by Prof. Kolffs design, but two problems were found; 1) Big amount of regurgitation through inlet bileaflet valve, 2) High resistance of outlet trileaflet valve. Following trials were carried out to settle them; 1) In the manufacturing process of the bileaflet valve, elastic material was used instead of hard plastic plate. Then, regurgitation could be reduced to 1/6. Moreover, total manufacturing process could be dramatically simplified. 2) In the manufacturing process of the trileaflet valve, leaflet thickness was well controlled around 0.2mm with the aid of a special ring which was located around the valve mold. Then, lower resistance could be achieved by a thin (0.19mm) leaflet valve. Moreover, all valves could be passed the durability testing for 14 days. These data is helpful towards a pre-production stage of the VAD development.

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In order to facilitate the handling of cardiopulmonary bypass and simplify the circuit, we have developed a new membrane oxygenator with a hemofiltration function. The hollow fiber unit for gas exchange and that for hemofiltration were combined on concentric circles in cylindrical component (outer diameter 95mm, length 140mm). We used a silicon-coated (0.2 micron) hollow fiber membrane for gas exchange. Both units possess a blood-outside perfusion system. All blood flows in a radial direction from around the central core to the surrounding follow fiber units, first to hemofiltration and then gas exchange. With this flow method, the blood can flow to all hollow fibers evenly and the efficiency was improved significantly. Filtrated fluid was easily collected through a stopcock mechanism. The oxygen transfer rate was 312mL/min at a blood flow rate of 6L/min and 35% hematocrit, and the ultrafiltration rate was 3.5L/hour at a blood flow rate of 4L/min and 25% hematocrit and 200mmHg transmembrane pressure in an in vitro study. The pressure drop was 62mmHg at a blood flow rate of 4L/min. We found no adverse effects in an in vivo study using mongrel dog. In conclusion, this combined system could achieve excellent and simplified hemoconcentration by all the blood in the units flow to hemof it tration part.

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We assessed usefulness of simultaneous monitoring of bloot flow velocity of middle cerebral aretry(MCA-V) measured by TCD and short latency SEP during cardiopulmonary bypass (CPB). MCA-V promptly responded to a temporal decrease in systemic perfusion rate or cerebral blood flow during CPB. MCA-V during CPB did not differ from that of pre-CPB period, it significantly increased after CPB, possibly reflecting hyperdynamic state due to hemodilution and administered inotropic agents immediately after CPB. Latency of each wave component of SSEP prolonged during hypothermic CPB, but P2 and CCT completely recovered to the pre-CPB value. On the other hand, P1, N1 and N2 remained prolonged after CPB, although no neurologic disorder was observed in all patient. Positive correlation was observed between postoperative P1 latency and MCA-V and negative correlation between CCT and MCA-V, suggesting that there may be some relationship between cerebral blood flow and electroencephalic response. It is difficult to conclude from this study because there was no patients with neurologic complication, however, simultaneous monitoring of TCD and SSEP is expected to be a reliable combination of the modality warning of reversible cerebral ischemia during CPB.

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We have employed left heart bypass (LHB) using a centrifugal pump for twenty-six patients with thoracic descending aortic operation. Types of aneurysms were descending thoracic aneurysm in 13 patients, dissecting aneurysm (DeBakey type III) in 11 patients and both in 2 patients. Operative method was graft replacement in 25 patients and closure of entry in 1 patients. During LHB, mean pulmonary aortic pressure was controlled to maintain from 15 to 20mmHg. Three patients perioperatively occurred temporally ventricular tachycardia or fibrillation, two patients occurred the temporally elevation of ST segment in a ECG monitor. The rectal temperature of these patients was the tendency of low. Maintenance of body temperature needs to provide cardiac complications. In addition, the insertion of cannula from pulmonary vein was effective to avoid bleeding.

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The kinetics of serum enzyme were studied by comparing the serial changes during and after extracorporeal circulation (ECC) in 33 cases of open heart surgery. Serum amylase, isoenzyme of amylase, lipase, CPK, and isoenzyme of CPK were measured at eight points (pre-ECC, 30min after ECC, just after ECC, skin closure, arrival on ICU, 1st post operative day(1POD), 2POD, 3POD). Then the relationships between those and intraoperatve factors-age, operative procedures, aortic crossclamp time, ECC time, mean aortic pressure during ECC, ECC flow, the lowest rectal temperature, and cardiac index after operation-were estimated. The timing of peak of CPK level was different from that of CPK-MB/CPK. Also the timing of peak of amylase was different from those of Pamylase and lipase. There was no relationship between CPK levels and CPK-MB/CPK. Neither there was no relationship between serum amylase levels and P-amylase, lipase levels. There was no corelationship between CPK, serum amylase levels on 1POD, which showed abnormally high concentration, and the intra-operative factors, except the relationship between CPK and lowest temperature during ECC. Although serum CPK and amylase showed abnormally high concentration, specially after ECC, the relationship between those and ECC related factors could not be identified.

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The completely closed circuit system is the future direction of cardiopulmonary bypass because of its compactness and superior biocompatibility. The most serious obstacle to its clinical application is sucking of air into the drainage circuit. To overcome this problem, we have developed a new air filter for the low pressure drainage circuit. This filter consists of silicon-coated hollow fibers. Serum leakage cannot occur in these hollow fibers. Blood flows outside of the hollow fibers, and air bubbles entering the drainage circuit are sucked out through the hollow fibers by a strong negative pressure, 650mmHg, applied inside the hollow fibers. Three prototypes were made, and in vitro evaluation was performed in a mock circulation. Effectiveness of air removal was evaluated macroscopically and by using an ultrasound bubble detector. Prototype 3 (membrane surface area; 0.95m², priming volume; 90ml, pressure drop; 64mmHg at a blood flow rate of 6L/min) completely removed the air in the water irrespective of the size of air bubbles and amount of air and water flow rate. Although air in the blood was also completely removed macroscopically, a slight amount of mi crobubbles was detected. In conclusion, the concept of using a hollow fiber and negative pressure for a reliable and effective air filter in the drainage circuit seems to be promising, and further improvement of the design and specifications will be continued.

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This paper describes development of a membrane oxygenator using a silicone hollow fiber which has a small diameter and a thin wall thickness. The hollow fiber is 300μm in outer diameter and 50μm in wall thickness.
The prototype of membrane oxygenators using the hollow fiber were developed. The membrane surface area of the oxygenators are 1.6m² (type I) and 2.0m² (type II). The in-vitro tests were conducted. The O² transfer rate was 195mL/min, and the CO₂ transfer rate was 161mL/min at a blood flow rate of 3L/min(typeII). The oxygenator is considered applicable to long term lung support.

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To determine the optimal perfusion flow rate of the lower body area during partial cardiopulmonary bypass (CPB) under desending aortic cross-clamping, we studied the relationship of perfusion flow rate to regional oxygen consumption (VO2) at various perfusion temperature. Experimental circuit was provided with two arterial cannulation sites and two drainage canula with pump oxygenator. Measurements were made at various perfusion flow rates in a setting of various perfusion temperature. In a bidirectional arterial perfusion during total CPB with descending aortic cross-calmping, we studied the relationship between the total perfusion flow and blood flow distribution to the IVC area. In result, the blood flow distribution to the IVC area decreased as perfusion cooling increased.Secondly, we investigated the relationship between pump flow rate and VO2, venous oxygen saturation in IVC area. In result, there were a significant positive correlation between perfusion flow rate and VO2, and between flow rate and perfusion temperature. Moreover, we divided three groups by the grade of hypothermia, and estimated the range of the optimal perfusion flow rate from relationship between perfusion flow rate and VO2. Finally, we studied the influence of the temperature in the upper part of the body as perfusion cooling. In result, the changes in temperature of the upper body area increased as both perfusion flow rate and duration of perfuion increased.

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To induce a pulsatile flow in a centrifugal pump, we developed a new device (Pulsatile Assist Device for Centrifugal Pump: PAD·CP) using a new concept. Hemodynmic performance of this device was satisfactory in a mock system and in animal experimentation, as previously reported. To expand into clinical application, the hemolysis of this device was evaluated using a test circuit in vitro and in animal experimentation. In in vitro testing using a hemolysis test circuit and calf blood, plasma hemoglobin levels were less than 40mg/dl after 3 hours driving under a pump flow of 2l/min. Hemolysis increased severely after 4 hours of 4l/min pump flow. In vivo evaluation using 5 adult sheep (average body weight, 47kg), resulted in hemolysis of less than 30mg/dl of plasma hemoglobin after 4 hours of open chest extracorporeal circulation with 3.0-3.6l/min of flow rate and using the PAD·CP. We concluded that this PAD·CP has proven to have possible clinical applications.

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Two patients with congenital and acquired Antithrombin III (ATIII) deficiency experienced surgery under cardiopulmonary bypass (CPB) with heparinization. We examined ATIII activity, TAT, D-Dimer, PIC and platelet counts before and after CPB in these patients and compared with those of other 17 cardiac surgical patients without ATIII deficiency. There were no difference in total perfusion time, administration of heparin or protamine. During CPB, ATIII activity had been reduced by half in both groups. On the 1st postoperative day, patients without ATIII deficiency recovered 75% of and patients with ATIII deficiency equal to the preoperative level of ATIII. In all cases, TAT, D-Dimer and PIC had increased and platelet counts had decreased during CPB. It took for a week to recover these factors to the preoperative level. During heparinized CPB, all the patients illustrated the activation of coagulation system; the usual dosage of heparin for CPB did not show the consumption of ATIII even in the patients with ATIII deficiency.

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A closed circuit system coated with MPC (2-methacryloyloxyethyl phosphorylcholine) copolymer was filled with 150ml human whole blood. Platelet count, platelet adhesion, platelet agguregability and serum complement activity were measured during the circulation for 2 hours by a 30ml/min flow rate. A system without coating was used as a control. After circulation, total amount of protein adhered on the Iuminal surface of the system was measured. Luminal surface of the system after circulation was observed by means of a scanning electron microscope. Total protein adhered was less, platelet adhesion was kept and complement activity was reduced, compared with those of the control. These results indicated that a blood circuit system coated with MPC copolymer maintained platelet adhesion and reduced complement activation.

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The clinical study was performed to evaluate the biocompatibility of heparin-coated bypass circuits. Ten patients undergoing elective cardiac surgery of valve replacement were randomly divided into two groups with (group H, n=5) or without(group C, n=5) use of heparin-coated circuits. Interleukin 1 & (IL-1 &), Interleukin 6(IL-6), Granulocyte elastase (GEL), C-reactive protein and Fibronectin (FN) were mesured before cardio-pulmonary bypass (CPB), 60 minutes after commencement of CPB, 60, 240, 480 minutes after termination of CPB, on the first, the third and the seventh postoperative days respectively. Respiratory Index (RI) was mesured before and immediately after CPB, on the first postoperative day. IL-1 & was not detected except one case in group C. IL-6 increased after CPB in both groups, but the response was significantly low in group H (P<0.05). CRP and GEL were increased after CPB in both groups, but showed no significant difference between the groups. FN recovered quickly after CPB in group H with a significant difference (p<0.05). RI increased after CPB in both groups, but tended to be lower in group H than in group C (p=0.05). This study demonstrated that the use of heparin-coated bypass circuits improved the biocompatibility by reducing the level of inflammatory cytokine and the pulmonary injury.

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Ultrasound was used to enhance the rate of peritoneal mass transfer for the success of partially intermittent peritoneal dialysis, i. e., NPD and DAPD. Rates of peritoneal mass transfer for urea-nitrogen and creatinine were enhanced in significant level with applying ultrasound; however, no significant difference was found in degree of enhancement between urea and creatinine. The enhancement was evaluated by the peritoneal dialysance and rates of enhancement were 159, 113, and 83% for urea-nitrogen and 149, 112, and 94% for creatinine by application of ultrasound of 28, 45, and 100kHz, respectively. From these results, the rate of peritoneal mass transfer enhancement seemed to be dependent on frequency of the ultrasound. In vitro permeation experiments were also performed with the parietal peritoneum taken from a rabbit. The rates of enhancement were 162 and 149% for creatinine by application of ultrasound of 28 and 45kHz, respectively. Then rates of peritoneal mass transfer enhancement in vitro were also dependent on frequency of the ultrasound, which corresponded well with experimental results obtained in vivo.

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Endotoxin concentration in dialysate fluid should be frequently monitored. But conventional limulus test needs complicated operation to prevent the contamination by atmospheric endotoxin. We have developed the flow type measurement system using single tube in which sample solution reacted to limulus reagent without contact with atmosphere. The objective of the present study is to gain a sensitivity of the system to measure the endotoxin concentration ranging under 100EU/1 accurately. Batch reaction experiments and flow type measurements were performed to determine the optimal wavelength and the reaction time for optimal operation of the continuous system. The highest sensitivity is obtained at a wavelength of 381nm for measuring the endotoxin concentration by limulus reagent. Proper reaction time differed depending on concentration range of samples. The sensitivity of measuring the endotoxin concentration ranging under 100EU/1 increased with reaction time. But longer reaction time in the flow type measurement system produces dispersion of the limulus reagent and lower sensitivity. Optimal reaction time of the flow type measurement system is then 45min. Handy and exact measurements of the endotoxin concentration ranging above 50EU/1 were able by the condition of a wavelength of 381nm and a reaction time of 45 min.

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Sieving characteristics in HF with high ultrafiltration were examined during an experimental study using an aqueous solution involving myoglobin. Significant conclusions were obtained as follows: A value of apparent sieving coefficient (SC) decreased with increasing blood flow rate (QB) under a constant filtration flow rate(QF) because a higher shear rate of blood flow reduced a thickness of concentration polarization layer. A SC value also decreased with QF increase in low filtration fraction (FF) due to developing concentration polarization with increasing QF value. On the other hand, a SC value increased with QF in higher FF filtration because of stronger solute condensation along the blood side stream.

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Treatment by on-line HDF or push/pull HDF requires special and expensive devices. We have developed and evaluated a new dialyzer, named a plug dialyzer (P), that can exchange much dialysate as substitution fluid without using special and expensive devices. P has a “plug” at the center of the dialysate path, with which it backfiltrates much dialysate by increasing dialysate pressure drop. In dialysis experiments using β₂-microglobulin (BMG)-added bovine blood at a filtration rate(Q_F) of 10ml/min/m², the values of BMG clearance (C_L) measured for P were 1.5 to 3 times those for a normal dialyzer (N). The backfiltration rates (BF) theoretically calculated for P were 74 to 84ml/min. In P, a decrease in dialysate flow rate resulted in a decrease in BF. However, in dialysis experiments using human serum at Q_F of 10ml/min/m², the values of C_L for low molecular proteins measured with P were much larger than those with N. CT photographs showed dialysate flow conditions were better in P than in N. Extracorporeal circulation testing on dogs did not present any significant difference in the change in leukocyte or platelet count nor in the loss of albumin between P and N. These results demonstrated that P is an efficient dialyzer that can substitute much fluid.

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We investigated the binding kinetics of charged drugs by dialysis membranes via an ionic bond in bovine serum. Four positively charged drugs, that is, nafamostat mesilate, cimetidine, procainamide, diltiazem, and four negatively charged drugs, that is, heparin, furosemide, cefotaxime, and carbazochrom were studied. Two dialysis membranes, that is, polyacrylonitrile (AN69) as a negatively charged membrane and hemophan (HE) as positively charged membrane were cut into small fibers and incubated in bovine serum prior to the adsorption test. Each drug also incubated in the bovine serum, and then dialysis membranes and drugs were combined. The adsorption of cimetidine and diltiazem to AN69 membrane were weak in the serum in comparison to the binding capacity in the water. On the other hand, the adsorption dose of nafamostat mesilate and procainamide were not different between the adsorption test in the water and serum. The adsorption of carbazochrom to HE membrane was weak in the serum. Heparin, furosemide, and cefotaxime were adsorped equally by HE membrane in the water and serum. These results suggest that each charged drug is adsorped by the dialysis membrane in the different manner for the protein binding of drugs and dialysis membranes.

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It is guessed that the behavior of the reactive oxygen species (ROS) in the blood may be affected by the characteristics of the membrane during the hemodialysis in practice. then. an attempt to measure the ROS concentration in the blood at the appointed times during hemodialysis has been done by the spin trapping technique.
In result, the ROS concentration creased remarkably on the cellulose membrane. on the other hand, the con centration slightly changed on the EVAL at the use of the anticoagulant agent and at the no use of the agent

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Vitamin E is reported to act as acavenger for reactive oxygen species. In This study, we evaluated the effectiveness of vitamin E coating on modified regenerated cellulose membrane on biocompatibility in vitro, ex vivo and in clinical use. In vitro study, met-hemoglobin retio in erythrocyte and the amount of generated superoxide dismutase protein (SOD) during exposure of blood with VECM were used as a parameter of erythrocyte injury. Two other memberane, i. e. conventional non-coating and fluorine coated regenerated cellulose membranes (NCM and FCM) were used as controls. In clinical study, serial blood sampling during hemodialysis using VECM of NCM dialyzer were performed to measure complete blood count, C3a, thrombin anti-thrombin III complex (TAT) and SOD. 1) In vitro, met-hemoglobin ratio in erythrocyte and the amount of generated superoxide dismutase protein were significantly lower in VECM than in NCM and FCM. 2) In clinical study, the attenuation of decrement of leukocyte count at 15 minutes after starting HD using VECM dialyzer was observed. SOD was lower in HD using VECM dialyzer than in HD using NCM dialyzer. Vitamin E coating on regenerated cellulose membrane was suggested to be effective to get a better biocompatibility.

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We examined bio-compatibility, solute removal efficiency, U. F. R. and SEM observation of a surface-modified regenerated cellulose membrane dialyzer, which is modified by attaching Vitamin E to increase its bin-compatibility (CL-E-15N; hereafter called E-membrane; made by Termo Co.), comparing with conventional dialyzer (CL-S-15N; hereafter called S-membrane).Bio-compatibility: the changes of leucocytes, C3a and oxidized LDL in E-membrane were significantly lower- than those in S-membrane, and the changes of platelets, TAT, t-PA, G-E and MDA were not different between E-membrane and S-membrane. Solute removal efficiency: removal rate, removal quantity and clearance were not different between E-membrane and S-membrane. U. F. R., in E-membrane was higher than that in S-membrane, and was not decreased during hemodialysis. SEM observation: a platelet agglutination on E-membrane was lesser than that on S-membrane and most of the platelets retained a spherical shape on E-membrane, clot and pseudopod were observedon S-membrane From the these results, it was concluded that CL-E-15N had similar solute removal efficiency and better bio-compatibility than conventional regenerated cellulose membrane.

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For long-term clinical application of the wearable artificial endocrine pancreas, closed-loop subcutaneous insulin infusion algorithm has been developed by analyzing the kinetics of subcutaneous absorption of Lys (B28)-Pro (B29) Human Insulin Analogue which was absorbed 2 to 3 times faster after subcutaneous injection than usual short-acting insulin. A 3-compartmental model was applied to mathematically express the relation between the insulin injected subcutaneously as an input and the plasma insulin response as an output. With this algorithm, glycemic levels were controlled without hyperglycemia nor hypoglycemia after oral glucose loads to pancreatectomized dogs. These data indicated feasibility of long-term glycemic control in diabetic patients with closed-loop subcutaneous insulin infusion by the wearable artificial endocrine pancreas.

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To prepare the long-life and stable subcutaneous tissue glucose monitoring system, newly designed biocompatible membrane, 2-methacryloyloxyethyl phosphorylcholine -co-n-butyl methacrylate (MPC-co-BMA) membrane, has been developed and applied to the surface of a microdialysis hollow-fiber probe. 1) Transmission electron-microscopic examination of microdialysis cuprophan hollow-fiber probe covered with MPC membrane revealed no protein fixation at all for up to 7 days. 2) In healthy volunteers, the subcutaneous tissue glucose concentrations measured by this system were consistent with changes in blood glucose excursions for 7 days without any in vivo calibrations, and for 14 days by introducing in vivo calibrations. We therefore conclude that this miniaturized extracorporeal glucose monitoring system which combines a needle-type glucose sensor with a microdialysis hollow-fiber probe covered with MPC membrane is stable and reliable, as compared to a microdialysis hollow-fiber probe covered without MPC membrane. Therefore, this monitoring sytem can be applied for the self blood monitoring system and for the sensing system of wearable artificial endocrine pancreas in ambulatory diabetic patients for longer-periods.

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To prepare the long-life and stable glucose sensor, we developed the ferrocene-mediated needle-type glucose sensor covered with newly designed biocompatible membrane, 2-methacryloyloxyethyl phosphorylcholine -co-n-butyl methacrylate (MPC-co-BMA) membrane. In this membrane, the hydrophilic phosphorylcholine chains were grafted on the hydrophobic polymer surface. 1. The subcutaneous tissue glucose concentrations could be monitored precisely for 7 days without any in vivo calibrations, and for 14 days by introducing in vivo calibrations in healthy volunteers. 2. This sensor applied to ambulatory diabetic patients for glycemic control with wearable artificial endocrine pancreas. When operating wearable artificial endocrine pancreas, physiological glycemic control was obtained by exchanging the sensor for 4 days.
We therefore conclude that this sensor is stable and reliable, as compared to any other glucose sensors we developed.

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We report the efficacy of artificial pancreas for the evaluation of glucose metabolism and blood glucose control of the severely ill patients. 11 patients was studied. The items studied as indicators of glucose intolerance were, (1) daily mean blood glucose level (BSm), (2) I/E (administered insulin/glucose) ratio, and (3) M-value (glucose disposal rate) obtained from euglycemic hyperinsulinemic glucose clamp method. [RESULTS] 1) Blood glucose control by artificial pancreas was good, because mean value of BSm was 169.4±28.6mg/dl. 2) There were 4 types of the improvement of glucose intolerance. Both (1) [M-value] and (2) [insulin secretion (CPR)] increased in cases without complication, (1) increased mainly in cases with DM, (2) increased mainly in cases with liver cirrhosis, and (3) [hepatic glucose production] supposedly decreased in cases with liver dysfunction. [SUMMARY] Application of artificial pancreas to severely ill patients with glucose intolerance was effective for the evaluation and treatment of impaired glucose metabolism.

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Secondary vascular impairments arefrequently observed among diabetic patients. It is considered that thereason of the impairments is theexistence of glycosylated compounds, especially glycosylated LDL. (glc-LDL) Newly designedadsorbents were synthesized and prepared aimingfor aselectiveremoval of glc LDLfrom human plasma The adsorbentshad two moieties for glc LDL, one is boronicacid for glycosylatedsites of glc-LDL, the otheris acrylicacid (AA) for positivecharge of apoprotein. The adsorbents weree valuated interms of glc-LDL adsorption efficiency in human plasma, and showed different characteristics depending on the polymer compositions. The AA compositions from 50 to 90% showed highselectivities for glc-LDL. The selectiveadsor ptions of glc-LDL were not inhibited in human plasma The sere sults suggested that the adsor bents would be promising materials for glc-LDL apheresis.

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Twelve long-term hemodialysis patients who complained of shouder joint pain were selected for the present study. In these patients, cuprophane dialyzer which had been employed to date was changed to PAN-22DX hemodiafilter^R (polyacrylonitrile). After hemodialysis treatment with the PAN-22DX hemodiafilter for 4 weeks, hemodialysis were switched to the push/pull HDF using the same hemodiafilter and performed for another 4 weeks. Then, the treatment was switched back to hemodialysis using the PAN-22DX hemodiafilter. The patients showed a significant increase in upper arm movement ranges following the switch to push/pull HDF treatment. The increased upper arm movement ranges were retained for nearly 2 weeks even after the switch back to the original hemodialysis. The pretreatment β₂-microglobulin concentration decreased following the switch from hemodialysis to push/pull HDF.

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T cell mediated immunity is the principal mechanism of inflammatory demyelinating diseases such as multiple sclerosis (MS). This has led to therapeutic attempt to modify the immune system in selective way in patients with T cell mediated disease. We attempted to remove CD4+T cells, including autoreactive T cells, selectively from the circulation by means of adsorption using anti-CD4 monoclonal antibody (MoAb). A column immobilized anti-CD4 MoAb on the surface of activated substance is designed to remove helper T cells. With direct perfusion of whole blood through the column, it was possible to remove selectively more than 90% of CD4+T cells from blood, resulting in abolishing the T cell response to antigen. This new strategy in immunotherapy should be useful treatment for MS.

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We have found that surfaces of the ternary copolymer (TAB) composed of 3-acrylamidophenylboronic acid, N-(3-dimethylaminopropyl) acrylamide and N-isopropylacrylamide induced bovine aortic endothelial cells into capillary networks after 26 days in culture. The interactions between phenylboronic acid groups in the IAB copolymer and glycoconjugates on the endothelial cell membranes were proposed to regulate the induction of tissue formation, since phenylboronic acid groups specifically formed reversible complexes with diol compounds such as glucose. In this study, a mixture membrane consisted with the IAB copolymer and collagen (typeI) was prepared from mixed aqueous solutions of these materials, and used as a cell-culture substrate. The endothelial cells cultured on the IAB/collagen mixture membrane exhibited network formation after 11 days. Since the cells on type-I collagen showed no capillary-like structure, it was considered that the TAB copolymer stimulated and induced the endothelial cells into capillary structures and that type-I collagen played a fundamental role to enhance the tissue formation in the process of the reorganization.

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Biodegradable hydrogels consisting of oligopeptide-terminated poly (ethylene glycol) (oligopeptide-PEG) and dextran (Dex) with interpenetrating polymer network (IPN) structure were designed as novel biomaterials exhibiting a double stimuli-responsive function. IPN-structured hydrogels were synthesized by sequential crosslinking reactions of N-methacryloyl-glycilglycilglycil-terminated PEG and Dex. Specific degradation in the presence of papain and dextranase was observed in the IPN-structured hydrogel with a particular composition of oligopeptide-PEG and Dex whereas this hydrogel was not degraded by one of the two enzymes. Therefore, it is concluded that double stimuli-responsive degradation was achieved by the design of IPN-structured hydrogels composed of two chemically different biodegradable hydrophilic polymers. Such characteristic of double stimuli-responsive degradation in IPN-structured hydrogels can be useful as a fail-safe mechanism for medical functions in guaranteed drug delivery and/or medical micromachines.

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A potent fibrinolytic serine protease (Subtilisin CIR) of B. subtilis CIR 110 isolated from fermented food was covalently immobilized onto porous cellulose beads and polyurethane (PU) surfaces, in an attempt to develop a new and useful antithrombogenic materials. The immobilization methods were based on N-hydroxysuccinimide activation for cellulose beads and the surface treatment with maleic anhydridemethyl vinyl ether copolymer (MAMEC) as an enzyme carrier for PU surfaces, respectively. The immobilized Subtilisin CIR retained its caseinolytic and fibrinolytic activity to a significant extent, digesting fibrinogen and fibrin irrespective of the presence of plasminogen. It was stable up to 60°C, and demonstrated better storage stability at 37°C, and highly increased resistance to plasma protease inhibitors, such as a2-macroglobulin, compared to soluble Subtilisin CIR. In the preliminary studies of in vitro test with human whole blood and ex vivo rabbit A-V shunt experiment for Subtilisin CIR immobilized PU surfaces, it was demonstrated that the coagulation times were much prolonged and fewer blood cells adhered on the Subtilisin CIR immobilized PU surfaces, as compared with the control MAMEC treated PU surface. This indicates that Subtilisin CIR immobilized surfaces possess good blood compatibility as well as high thrombolytic activity. Thus, the immobilization of Subtilisin OR provides promise for potential applications in antithrombogenic biomaterials used in blood-contacting medical devices and artificial organs.

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The authors have evaluated blood compatibility of in situ heparin immobilized and sulfonated polyurethane (PU) using our epifluorescent video microscopy (EVM) combined with parallel plate flow chamber. EVM system measured the amount of adhered platelet on the surface under the flow of human whole blood containing mepacrine labelled platelets perfused at a wall shear rate of 100/sec every one minute intervals for 20min. Platelet activation (β-TG) and complement activation (C3a) were also measured. Both heparin immobilized and sulfonatedPUs showed significantly lower levels of platelet adhesion than the control PU.The β-TG levels of these modified PUs also correspond to the results of the platelet adhesion. As for the complement activation, while sulfonated PU and the control PIP showed a higher levels of complement activation. In situ surface modification techniques, which utilize either ozone oxidation or photo reaction are useful in a variety of medical devices even of a complex design, such as a membrane oxygenator or artificial heart.

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We demonstrated that microporous polyurethane small diameter vascular prostheses with hydraulic permeability (internal diameter: 1.5mm, length: 1.5-2cm, hydraulic permeability: 39ml/min/cm²) attained acceptable patency and a high degree of endothelialization at 3 months post-implantation. In the current study, microporous polyurethane small diameter vascular grafts (internal diameter: 1.5mm, length: 10cm, hydraulic permeability: 146ml/min/cm²) were fabricated. Patency, durability and endothelialization of the grafts were scheduled to be evaluated for more than 1 year after implantation. Those grafts were implanted end-to-end in a loop shape in the rat infrarenal aorta. At present, one rat has been alive for 207 days after implantation and two rats for 205 days. At 76 days and 133 days post-implantation, one rat out of the three was generally anesthetized, underwent lap aroto my in a clean condition, and graft pat ency was confirmed by direct palpation of the graft and the aorta in the neighborhood of the anastomo ses. The lap aroto my was closed and the rat has been raised for future periodical evaluation.

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We devised disc-type, polyester mesh-enforced sheet-type and tubular hybrid tissues, in which myoblasts (Mbs) of skeletal muscle cells (SKCs) were embedded in type I collagen gels and then differentiated into muscle fibers upon culture. Primary culture of satellite cells of SKCs, harvested from thigh muscle of newborn and fetal rat, failed due to contaminated fibroblasts which dominated at a prolonged culture period. On the other hand, hybrid muscular tissues were prepared using Mbs (C2C12 mouse cell line) and collagen. A cold mixed solution of the cells and type I collagen was poured into three different types of molds and were kept at 37°C in an incubator to form SKCs-embedded gels. Polyester mesh was incorporated into a sheet-type gel. Tubular tissue was prepared by pouring a mixed solution into a tubular mold of an outer sheath and a mandrel and subsequently by culturing after deassembling the outer sheath. Mbs were cultured in 20% FCS-DMEM for first 4 days and then in 2% horse serum-DMEM for later 10 days. Transparent fragile gels as prepared were time-dependently shrunk to form opaque gels, irrespective of the model. At 14 days-incubation, proliferated Mbs fused and differentiated to form multinucleated muscle fibers. Hybrid tissue became time-dependently dense and both collagen and cells were circumferentially oriented. We discuss the possibility of use as a transplantation vehicle for reconstruction of damaged and diseased skeletal and cardiac muscle tissues.

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Since the commercially available small c alliber vascular prosthesis are not totally satisfactory in regard to long-term patency, an autogenous vein remains to be the best vascular conduit in distal bypass procedures at present. And hence an effort to explore thepossibilities of a new biol ogical prosthesiswas undertaken. Canine venous endothelial cells (ECs) and smooth muscle cells (SMCs) were harvested and cultured. A human umbilical vein graft (HUV) was stored for one month in the normal saline and thenimpregnated with SMCs and the ECs were seeded to it. In two weeks, the ECs formed a monolayer liningbut the spreading of SMCs was circumferential covering only some portions of the graft. The future study, we hope, will improve the results, with the technique of cells'implantation and culture in the graft modified.

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Surface-modified ePTFE grafts (2mm internal diameter and 30μm fibril length) produced by immobilization of fibronectin (FN) and by intermediary methacrylic acid (MA) grafting were implanted into the carotid arteries of New Zealand White rabbits to study early thrombogenicity, patency, and graft healing. In MA- or MA/FN-immobilized grafts, there were observed a smooth and thin fibrin thrombus layer on the luminal surface at 1 day, equivalent patency rates up to 12 weeks, and 3-6 times increase in endothelial coverage at 4 weeks, as compared with those observed in untreated grafts. In MA/FN-immobilized grafts, the improved endothelialization was seen at 12 weeks but not MA-immobilized grafts and thick pseudointima was formed compared with untreated and MA-immobilized grafts. These results suggest that the improved endothelialization of FN-immobilized ePTFE grafts is dependent on the appropriate pseudointima formation in addition to the formation of smooth thrombus layer on the luminal surface.

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New gelatin impregnated woven Dacron grafts (Gelweave) were used for 32 patients with aortic diseases. Gelweave was easy to penetrate by the needle and nice in the handling. Only one patient (3%) died due to acute myocardial infarction after the surgery. Other 31 patients (97%) discharged and returned to their daily life. Abnormal fever and inflammatory response was not detected in this series. No bleeding from the graft itself was observed in all patients. However, some patients showed the needle hole bleeding after the anastomosis using cardiopulmonary bypass. 4-0 or 5-0 suture material is preferred to prevent the needle hole bleeding. No other complication was observed in the perioperative period and in the intermediate follow up. Gelweave is the useful graft for replacement of the aorta.

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We developed a new method of implanting a graft in the distal anastomotic portion that does not require direct touch, suture, or lateral thoracotomy. In this method, the tight circumferential attachment between the graft and the aortic inner wall, produced by the hoop-strength of a self expanding (Gianturco) stent that is anchored into the woven Dacron graft, takes the place of the conventional anastomotic suture at the distal end of the graft. This new surgical method requires only a median sternotomy and relatively short circulatory arrest time for repairing a thoracic aneurysm or dissection involving the aortic arch. This new surgical stented graft method should be considered one of the less invasive surgical treatments for thoracic aneurysm and dissection involving the aortic arch.

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Plasmin treated fibrin impregnated vascular grafts (PF-V: 6mm ID, 8-10cm in length) were implanted bilaterally in carotid arteries of dogs, and evaluated for their anti-tlironibo genicity, handling characteristics, and healing properties. Knitted Dacron graft of identical size impregnated with a gelatin (GELSOFT) was used as a control. The grafts were electively retrieved and analyzed at different time intervals of 6hrs, 1, 3, and 6 months after implantation. Both PF-V and GELSOFT showed good handling characteristics, especially PF-V was able to be suturwithout stripping outer reinforce. No bleeding was observed during surgery in both rafts. At 6 firs after imlantation, GELSOFT produced significant amount of tlirombi and neutrophil aggregates on the graft lumen, whereas PFP V showed only minimal fibrin deposits on the surfaces. Through 6 months alter implantation PF-V demonstrated excellent healing properties with neointinia formation and cellular ingrowtli into graft fibers, which were apparently superior to GELSOFT. In the present study, PF-V demonstrated improved anti-thrombogenicity during the early periods of implantation as well as excellent healing chracteristics in viva long-term implantation. Thus, PF-V has a potential value for a small vessel substitute.

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Puncturing a vascular graft is common during implantation, cardiac catheterization and dialysis without a fear for hurting it. To evaluate the healing process of needle puncture biologic vascular grafts, a canine study was performed. Canine carotid arteries were obtained and treated with polyepoxy compound. Under general anesthesia, the grafts were implanted into the carotid artery position of 16 dogs. The grafts were punctured 5 times using a 18G needle. The grafts were evaluated macroscopically and microscopically from 1 hour to 191 days. At day 3, the bleeding was still observed through the wall. At day 7, fibrinolysis was noticed in the thrombus. At day 30, cell infiltration was minimum and it was from the adventitia side. At day 81, a mushroom shaped organized tissue, which was endothelialized, was formed. At day 191, some puncture sites had a thrombus and not healed. Healing process was delayed at the puncture sites. These results suggest that needle puncture of vascular grafts is not recommended and use a small needle, when it is necessary.

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A miniaturised Clark-type invasive catheter-tip oxygen sensor has been constructed with a tip diameter 1mm using bi-lumen segmented polyurethane (SPU) tube and a gas-permeable membrane was dip-coated with the same material. Comprehesive tests of the sensor in in vitro performance have been done, and the results showed that the device has a linear response between cathodic current and pO2 in phosphate buffered solution at 37°C and a response time of lOsec. To improve haemocompatibility of the sensor surface, a highly biocompatible biomaterial developed by us, 2-methacryloyloxyethyl phosphorylcholine (MPC), was adopted and two kinds of MPC copolymer, i. e. PME and PMC, were newly synthesised; PMC is which copolymer with cyclohexylmethacrylate and PME with 2-ethyl-hexylmethacrylate, expecting high affinity to hard and soft segment of SPU, respectively. From the results obtained, it is clearly demonstrated that both PMC and PME are highly effective for improving haemocompatibility of SPU keeping its mechanical property almost in the original level, and that both polymers could be useful materials not only for the sensor membrane, but also for coating the SPU bi-lumen tube.

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The oxygen unloading capacity and in vitro biocompatibilities to blood components of Neo Red Cells (NRC) were examined. NRC showed an extremely increased P50 value (over 50mmHg). Complement and karikurein-kinin systems were either marginally activated or not affected by NRC, however blood coagulation was slightly prolonged by the addition of a large amount of NRC. Platlet number and functions were not affected. The pinocytosis of NRC particles was observed by polymononuclear cells and monocytes. In addition, whether stroma-free hemoglobin and NRC were contaminated with hepatitis B and C viruses was examined. The PCR method demonstrated the absence of both viruses. This study was performed as a part of works by the comettee for the preclinical evaluation found by the Society of Blood Substitutes, Japan. These efforts were expected to contribute not only to the investigative validation of NRC but also to the overall progress in the development of blood substitutes.

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