Principle and basic property of the sequential flow pump.

In the emergency care field, early treatment of acute heart or respiratory failure has been a global concern. In severe cases, patients are frequently required to be on an extracorporeal membrane oxygenator (ECMO) life support. To make the ECMO system more compact and portable, we proposed a sequential flow-type centrifugal pump named the sequential flow pump (SFP). In this study, principle and basic properties of this novel blood pump were examined by computational fluid dynamic (CFD) analysis and an experimental model. In the SFP, fluid is given centrifugal force sequentially twice with a single closed impeller. This sequential pressurization mechanism enables high-pressure output without high impeller speed. To realize easy integration of a blood pump with an artificial lung, the inlet and outlet ports are located at lateral side and center of the pump, respectively, which is the reverse configuration of conventional centrifugal pumps. The computational model was composed for CFD analysis and the experimental model was developed for the experiment of the actual pump. For both models, dimension of the impeller and volute was designed to be equal. In the CFD analysis, the SFP could generate higher performance than the single pressurization model with the same rotational speed of the impeller. Basic property of the experimental model was very similar to that of the computational model. The results showed the possibility that the SFP would be more suitable for the compact ECMO system than conventional centrifugal pumps.

Appropriate control time constant in relation to characteristics of the baroreflex vascular system in 1/R control of the total artificial heart.

1/R control is a physiological control method of the total artificial heart (TAH) with which long-term survival was obtained with animal experiments. However, 1/R control occasionally diverged in the undulation pump TAH (UPTAH) animal experiment. To improve the control stability of the 1/R control, appropriate control time constant in relation to characteristics of the baroreflex vascular system was investigated with frequency analysis and numerical simulation. In the frequency analysis, data of five goats in which the UPTAH was implanted were analyzed with first Fourier transform technique to examine the vasomotion frequency. The numerical simulation was carried out repeatedly changing baroreflex parameters and control time constant using the elements-expanded Windkessel model. Results of the frequency analysis showed that the 1/R control tended to diverge when very low frequency band that was an indication of the vasomotion frequency was relative high. In numerical simulation, divergence of the 1/R control could be reproduced and the boundary curves between the divergence and convergence of the 1/R control varied depending on the control time constant. These results suggested that the 1/R control tended to be unstable when the TAH recipient had high reflex speed in the baroreflex vascular system. Therefore, the control time constant should be adjusted appropriately with the individual vasomotion frequency.

Histopathology Image Analysis in Two Long-Term Animal Experiments with Helical Flow Total Artificial Heart.

Histopathological analysis can provide important information in long-term experiments with total artificial heart (TAH). Recently, a new type of blood pump, the helical flow total artificial heart (HF-TAH) was developed. This study aimed to investigate the changes in selected vital organs in animal experiments with implanted HF-TAH. Samples from lung, liver, and kidneys from two female goats (No. 1301 and No. 1304) with implanted HF-TAH were analyzed. Tissue samples were fixed in 10% formaldehyde and 4 µm thick transverse sections were stained with hematoxylin-eosin (HE). Additional staining was done for detection of connective tissue (Masson-Goldner stain) and for detection of iron (hemosiderin) deposits (Perls stain). Sections were scanned at 100× and 500× magnification with a light microscope. Experiment no. 1301 survived 100 days (cause of termination was heavy damage of the right pump); experimental goat no.1304 survived 68 days and was sacrificed due to severe right hydrodynamic bearing malfunction. Histopathological analysis of liver samples proved signs of chronic venostasis with limited focal necrotic zones. Dilated tubules, proteinaceous material in tubular lumen, and hemosiderin deposits were detected in kidney samples. Contamination of the organs by embolized micro-particles was suspected at the autopsy after discovery of visible damage (scratches) of the pump impeller surface (made from titanium alloy) in both experiments. Sporadic deposits of foreign micro-particles (presumably titanium) were observed in most of the analyzed parenchymal organs. However, the described deposits were not in direct connection with inflammatory reactions in the analyzed tissues. Histopathological analysis showed the presence of minimal contamination of the lung, kidney, and liver tissue samples by foreign material (titanium very likely). The analysis showed only limited pathological changes, especially in liver and kidneys, which might be attributed to the influence of artificial perfusion often observed in chronic TAH experiments.

Viscosity-adjusted estimation of pressure head and pump flow with quasi-pulsatile modulation of rotary blood pump for a total artificial heart.

Estimation of pressure and flow has been an important subject for developing implantable artificial hearts. To realize real-time viscosity-adjusted estimation of pressure head and pump flow for a total artificial heart, we propose the table estimation method with quasi-pulsatile modulation of rotary blood pump in which systolic high flow and diastolic low flow phased are generated. The table estimation method utilizes three kinds of tables: viscosity, pressure and flow tables. Viscosity is estimated from the characteristic that differential value in motor speed between systolic and diastolic phases varies depending on viscosity. Potential of this estimation method was investigated using mock circulation system. Glycerin solution diluted with salty water was used to adjust viscosity of fluid. In verification of this method using continuous flow data, fairly good estimation could be possible when differential pulse width modulation (PWM) value of the motor between systolic and diastolic phases was high. In estimation under quasi-pulsatile condition, inertia correction was provided and fairly good estimation was possible when the differential PWM value was high, which was not different from the verification results using continuous flow data. In the experiment of real-time estimation applying moving average method to the estimated viscosity, fair estimation could be possible when the differential PWM value was high, showing that real-time viscosity-adjusted estimation of pressure head and pump flow would be possible with this novel estimation method when the differential PWM value would be set high.

Animal Experiments of the Helical Flow Total Artificial Heart.

Severe cardiac failure patients require a total artificial heart (TAH) to save life. To realize a TAH that can fit a body of small stature and has high performance, high durability, good anatomical fitting, good blood compatibility, and physiological control, we have been developing the helical flow TAH (HFTAH) with two helical flow pumps with hydrodynamic levitation impeller. Animal experiments of the HFTAH were conducted to perform in vivo studies. The HFTAH was implanted in 13 adult female goats weighing 45.0-64.0 kg. After surgery, neither anti-coagulant nor anti-platelet medication was given systemically. The HFTAH was usually driven with a quasi-pulsatile mode. The 1/R control or ΔP control was applied to control the circulation. The ΔP control is a new method using simplified equation of the 1/R control. The HFTAH could be implanted in all goats with good anatomical fitting. Two goats survived for a long time (100 and 68 days). Major causes of termination were device failure and surgical complications. In the device failure, trouble with hydrodynamic bearing was conspicuous. In the two long-term survived goats, experiments were terminated with bearing instability that was probably caused by the suction effect. In these goats, hemolysis occurred on postoperative day 88 and 44, which was considered to be relevant to the bearing trouble. Thrombus was found at the broken right bearing of the 100-day survived goat. However, antithrombogenicity of the pump is expected to be good unless bearing trouble occurs. In two long-term survived goats, the 1/R control or ΔP control worked appropriately to prevent the elevation of right atrial pressure. In both goats, hemodynamic parameters changed with the condition of the animals, liver and kidney functions remained almost normal except when recovering from surgery and during hemolysis, and total protein recovered 2 weeks after surgery. Although instability of the hydrodynamic bearing should be improved, performance of the HFTAH with physiological control could be demonstrated.

Hydrodynamic characteristics of the helical flow pump.

The helical flow pump (HFP) was invented to be an ideal pump for developing the TAH and the helical flow TAH (HFTAH) using two HFPs has been developed. However, since the HFP is quite a new pump, hydrodynamic characteristics inside the pump are not clarified. To analyze hydrodynamic characteristics of the HFP, flow visualization study using the particle image velocimetry and computational fluid dynamics analysis were performed. The experimental and computational models were developed to simulate the left HFP of the HFTAH and distributions of flow velocity vectors, shear stress and pressure inside the pump were examined. In distribution of flow velocity vectors, the vortexes in the vane were observed, which indicated that the HFP has a novel and quite unique working principle in which centrifugal force rotates the fluid in the helical volutes and the fluid is transferred from the inlet to the outlet helical volutes according to the helical structure. In distribution of shear stress, the highest shear stress that was considered to be occurred by the shunt flow across the impeller was found around the entrance of the inlet helical volute. However, it was not so high to cause hemolysis. This shunt flow is thought to be improved by redesigning the inlet and outlet helical volutes. In distribution of pressure, negative pressure was found near the entrance of the inlet helical volute. However, it was not high. Negative pressure is thought to be reduced with an improvement in the design of the impeller or the vane shape.

Computational fluid dynamics analysis of the pump parameters in the helical flow pump.

The helical flow pump (HFP) was invented to develop a total artificial heart at the University of Tokyo in 2005. The HFP consists of the multi-vane impeller involving rotor magnets, a motor stator and pump housing having double-helical volutes. To investigate the characteristics of the HFP, computational fluid dynamics analysis was performed. Validation of the computational model was performed with the data of the actual pump. A control computational model in which the vane area corresponded approximately to that of the actual pump was designed for the parametric study. The parametric study was performed varying the vane height, vane width and helical volute pitch. When the vane height was varied from 0.5 to 1.5 times that of the control computational model, the H-Q (pressure head vs. flow) and efficiency curves were translated in parallel with the vane height. When the vane height was two and three times that of the control computational model, the profile of these curves changed. From the results, the best proportion for the vane was considered to be a vane height between 1.5 and 2 times the vane width. The effect of vane width was not very strong compared to that of the vane height. A similar tendency in vane height was observed by varying the helical volute pitch. The best helical volute-pitch size is considered to be between 1.5 and 2 times the vane width. Although further study is necessary to determine the best values for these parameters, the characteristics of the pump parameters in the HFP could be approximately clarified.

Concept of left atrial pressure estimation using its pulsatile amplitude in the helical flow total artificial heart.

The total artificial heart (TAH) requires physiological control to respond to the metabolic demand of the body. To date, 1/R control is a single physiological control method that can control venous pressure. To realize an implantable 1/R control system, we are developing a new pressure measuring method using absolute pressure sensor. To find a method for absolute pressure sensor, which went well without calibration, concept of left atrial pressure (LAP) estimation using its pulsatile amplitude was proposed. Its possibility was investigated with two long-term survived goats whose hearts were replaced with the helical flow TAHs. In manual control condition, there existed a positive relation between mean LAP (mLAP) and normalized pulsatile amplitude (NPA). Percent systole revealed not to affect the relationship between mLAP and NPA. Dispersion was observed between different pulse rates. As for cardiac output difference (QLD) that is the difference of flow rate between systolic and diastolic phases, similar results were obtained except in low QLDs. In the 1/R control condition, relatively high correlation between mLAP and NPA could be obtained. In estimation of mLAP using the correlating function of individual goat, fairly good correlation was obtained between measured mLAP and estimated mLAP. Despite that further studies are necessary, it was demonstrated that the concept of the LAP estimation could be possible.

Development of normal-suction boundary control method based on inflow cannula pressure waveform for the undulation pump ventricular assist device.

It is desirable to obtain the maximum assist without suction in ventricular assist devices (VADs). However, high driving power of a VAD may cause severe ventricle suction that can induce arrhythmia, hemolysis, and pump damage. In this report, an appropriate VAD driving level that maximizes the assist effect without severe systolic suction was explored. The target driving level was set at the boundary between low driving power without suction and high driving power with frequent suction. In the boundary range, intermittent mild suction may occur. Driving power was regulated by the suction occurrence. The normal-suction boundary control method was evaluated in a female goat implanted with an undulation pump ventricular assist device (UPVAD). The UPVAD was driven in a semipulsatile mode with heartbeat synchronization control. Systolic driving power was adjusted using a normal-suction boundary control method developed for this study. We confirmed that driving power could be maintained in the boundary range. Occurrences of suction were evaluated using the suction ratio. We defined this ratio as the number of suction occurrences divided by the number of heartbeats. The suction ratio decreased by 70% when the normal-suction boundary control method was used.

The helical flow pump with a hydrodynamic levitation impeller.

The helical flow pump (HFP) is a novel rotary blood pump invented for developing a total artificial heart (TAH). The HFP with a hydrodynamic levitation impeller, which consists of a multi-vane impeller involving rotor magnets, stator coils at the core position, and double helical-volute pump housing, was developed. Between the stator and impeller, a hydrodynamic bearing is formed. Since the helical volutes are formed at both sides of the impeller, blood flows with a helical flow pattern inside the pump. The developed HFP showed maximum output of 19 l/min against 100 mmHg of pressure head and 11 % maximum efficiency. The profile of the H-Q (pressure head vs. flow) curve was similar to that of the undulation pump. Hydrodynamic levitation of the impeller was possible with higher than 1,000 rpm rotation speed. The normalized index of the hemolysis ratio of the HFP to centrifugal pump (BPX-80) was from 2.61 to 8.07 depending on the design of the bearing. The HFP was implanted in two goats with a left ventricular bypass method. After surgery, hemolysis occurred in both goats. The hemolysis ceased on postoperative days 14 and 9, respectively. In the first experiment, no thrombus was found in the pump after 203 days of pumping. In the second experiment, a white thrombus was found in the pump after 23 days of pumping. While further research and development are necessary, we are expecting to develop an excellent TAH with the HFP.

Results of animal experiments with the fourth model of the undulation pump total artificial heart.

Animal experiments using a total artificial heart in a goat are not easy to perform. The fourth model of the undulation pump total artificial heart (UPTAH4), which was designed to perform a long-term physiological experiment including pulsatile and nonpulsatile TAH operations with a conductance- and arterial pressure-based control method named 1/R control, was implanted in 31 goats weighing 38.5 to 60.4 kg (average of 46.8 kg). The 1/R control is a physiological flow control method of TAH developed with a conductance (1/R: reciprocal of a resistance) parallel circuit model. The survival periods were from 0.1 to 153 days (average of 14.5 days). The causes of termination were postoperative bleeding in eight goats, respiratory failure in five goats, device failure in 14 goats, dissected aneurysm in two goats, and thrombus in one goat. The thrombus case was the longest surviving goat. The respiratory failure tended to occur when the extracorporeal circulation time was prolonged. Autotransfusion was effective for the prolongation of survival time. The left-right balance control and the suction control were performed successfully in all goats. The 1/R control was performed for a long time in five goats that survived for more than 1 month. With three goats that survived for 48, 52, and 53 days mainly with the pulsatile mode, the 1/R control was stable. With a goat that survived for 73 days, the nonpulsatile mode with the 1/R control could be tested for 3 weeks. With the longest surviving goat that was maintained mainly with the pulsatile mode, the 1/R control was unstable, possibly due to the mismatching of the response time of the control system between the computer and the body. However, liver and kidney functions were almost normal, and the total protein level recovered. Further study to stabilize the 1/R control in the UPTAH is necessary.

Automatic calibration of the inlet pressure sensor for the implantable continuous-flow ventricular assist device.

Significant progress in the development of implantable ventricular assist devices using continuous-flow blood pumps has been made recently. However, a control method has not been established. The blood pressure in the inflow cannula (inlet pressure) is one of the candidates for performing an adequate control. This could also provide important information about ventricle sucking. However, no calibration method for an inlet pressure sensor exists. In this study, an automatic calibration algorithm of the inlet pressure sensor from the pressure waveform at the condition of ventricle sucking was proposed. The calibration algorithm was constructed based on the consideration that intrathoracic pressure could be substituted for atmospheric pressure because the lung is open to air. We assumed that the inlet pressure at the releasing point of the sucking would represent the intrathoracic pressure, because the atrial pressure would be low owing to the sucking condition. A special mock circulation system that can reproduce ventricle sucking was developed to validate the calibration algorithm. The calibration algorithm worked well with a maximum SD of 2.1 mmHg for 3-min measurement in the mock circulation system. While the deviation was slightly large for an elaborate calibration, it would still be useful as a primitive calibration. The influence of the respiratory change and other factors as well as the reliability of the calibration value should be investigated with an animal experiment as a next step.

Use of in vivo insert molding to form a jellyfish valve leaflet.

We developed an in vivo insert molding technique to form tissue-derived biomaterials into the desired shape, and with sufficient strength and durability, for use in artificial organs. Molds of acrylic resin with inserted velour cloth were implanted under the skin of goats to form a circular leaflet for a jellyfish valve. The valve leaflets were successfully produced in the molds after 17-60 days. Dense connective tissue covered the velour cloth, and loose connective tissue was formed within it. Tissue was radially formed from the hole in the mold. The tissue was simultaneously formed and shrunk. It is necessary to increase the connected portion between the tissue inside and outside the mold so that the tissue can completely cover the inserted materials without shrinkage.

Measurement of optical reflection and temperature changes after blood occlusion using a wearable device.

Early detection of compromised circulation is essential for postoperative monitoring of free flap. Hourly clinical check-ups such as inspection and palpation still result in a delay in detection. Conversely, optical reflection and temperature measurement are useful alternatives for detecting blood circulation. However, conventional methods that verify ischemia and congestion within a short period have not been reported. In this study, we measured short-term changes in optical reflection and temperature in a rat flap using a wearable flexible sensor probe previously developed in our laboratory. Five ischemia and five congestion groin flap models were measured using a sensor probe and reference devices. Curve fitting was performed on transition signals to evaluate changes in signals and their time constants. The optical reflection signal decreased after venous ligation and increased after arterial ligation. The parameters of the fitted curves indicate a significant difference between congestion and ischemia at p < 0.01 (probability value), which was detected within a few minutes after ligation. However, insufficient significance was observed in the temperature signal. Our method gives supporting information to verify ischemia and congestion, and has the potential to rapidly detect compromised circulation.

Development of Magnetic Probe for Sentinel Lymph Node Detection in Laparoscopic Navigation for Gastric Cancer Patients.

New laparoscopic sentinel lymph node navigation using a dedicated magnetic probe and magnetic nanoparticle tracer for gastric cancer patients allows minimally invasive surgeries. By identifying the sentinel lymph nodes containing magnetic nanoparticles, patients can avoid excessive lymph node extraction without nuclear facilities and radiation exposure. This paper describes the development of the laparoscopic magnetic probe, ACDC-probe, for laparoscopic sentinel lymph node identification utilizing the nonlinear response of the magnetic nanoparticles magnetized by an alternating magnetic field with a static magnetic field. For highly sensitive detection, the ratio of static to alternating magnetic fields was optimized to approximately 5. The longitudinal detection length was approximately 10 mm for 140 µg of iron, and the detectable amount of iron was approximately 280 ng at a distance of 1 mm. To demonstrate the feasibility of laparoscopic detection using the ACDC-probe and magnetic tracers, an experiment was performed on a wild swine. The gastric sentinel lymph node was clearly identified during laparoscopic navigation. These results suggest that the newly developed ACDC-probe is useful for laparoscopic sentinel lymph node detection and this magnetic technique appears to be a promising method for future sentinel lymph node navigation of gastric cancer patients.

A nonpulsatile total artificial heart with 1/R control.

A total artificial heart (TAH) using continuous flow pumps is promising for size reduction of the device; however, the role of pulsatility in TAHs has been a subject of great debate. Additionally, it is unclear whether, in a nonpulsatile TAH, a physiological control method such as 1/R control can keep the experimental animal in good condition. To realize a nonpulsatile TAH with 1/R control, the artificial valves were removed from undulation pump total artificial hearts (UPTAHs), which can produce both pulsatile and nonpulsatile flows using a single device. The UPTAHs were implanted into 18 goats, and 4 goats survived for more than 1 month. Three weeks of long-term nonpulsatile TAH operation could be tested in the goat that survived for 72 days, and it was proved that 1/R control is possible not only with a pulsatile TAH but also with a nonpulsatile TAH. The general condition of the goat and its organ function did not change on the application of nonpulsatile mode. Cardiac output and arterial pressure changed with the condition of the goat in pulsatile and also in nonpulsatile modes, and the changes seemed almost identical. However, the sucking effect of the atria was very significant in nonpulsatile mode, resulting in hemolysis. Therefore, nonpulsatile TAHs under 1/R control are considered to be inadequate unless some pulsatility can be introduced to avoid fatal sucking effects and to ensure sufficient inflow. During nonpulsatile operation, regular fluctuations were sometimes found in the aortic pressure, and these were caused by the periodic sucking effect in the left atrium that was possibly influenced by respiratory changes.

Nonthrombogenic, stretchable, active multielectrode array for electroanatomical mapping.

High-precision monitoring of electrophysiological signals with high spatial and temporal resolutions is one of the most important subjects for elucidating physiology functions. Recently, ultraflexible multielectrode arrays (MEAs) have been fabricated to establish conformal contacts with the surface of organs and to measure propagation of electrophysiological signals with high spatial-temporal resolution; however, plastic substrates have high Young's modulus, causing difficulties in creating appropriate stretchability and blood compatibility for applying them on the dynamically moving and surgical bleeding surface of the heart. Here, we have successfully fabricated an active MEA that simultaneously achieves nonthrombogenicity, stretchability, and stability, which allows long-term electrocardiographic (ECG) monitoring of the dynamically moving hearts of rats even with capillary bleeding. Because of the active data readout, the measured ECG signals exhibit a high signal-to-noise ratio of 52 dB. The novel stretchable MEA is carefully designed using state-of-the-art engineering techniques by combining extraordinarily high gain organic electrochemical transistors processed on microgrid substrates and a coating of poly(3-methoxypropyl acrylate), which exhibits significant antithrombotic properties while maintaining excellent ionic conductivity.

Handheld magnetic probe with permanent magnet and Hall sensor for identifying sentinel lymph nodes in breast cancer patients.

The newly developed radioisotope-free technique based on magnetic nanoparticle detection using a magnetic probe is a promising method for sentinel lymph node biopsy. In this study, a novel handheld magnetic probe with a permanent magnet and magnetic sensor is developed to detect the sentinel lymph nodes in breast cancer patients. An outstanding feature of the probe is the precise positioning of the sensor at the magnetic null point of the magnet, leading to highly sensitive measurements unaffected by the strong ambient magnetic fields of the magnet. Numerical and experimental results show that the longitudinal detection length is approximately 10 mm, for 140 µg of iron. Clinical tests were performed, for the first time, using magnetic and blue dye tracers-without radioisotopes-in breast cancer patients to demonstrate the performance of the probe. The nodes were identified through transcutaneous and ex-vivo measurements, and the iron accumulation in the nodes was quantitatively revealed. These results show that the handheld magnetic probe is useful in sentinel lymph node biopsy and that magnetic techniques are widely being accepted as future standard methods in medical institutions lacking nuclear medicine facilities.

Acute and chronic consequences of non-pulsatile blood flow pattern in long-term total artificial heart experiment.

Vessel pulsation is presumably a key physiological function for the optimal supply of peripheral tissues and vital organs by oxygen and nutrients. The absence of pulsatility might impair the peripheral perfusion stability and trigger microvascular dysfunction of vital organs. The main purpose of this study was to investigate the influence of non-pulsatile flow on the microcirculation in experimental goat with implanted undulation pump total artificial heart (UPTAH). A microscopic system (Keyence, Japan) for the direct observation of the microcirculation of bulbar conjunctiva was used. Following the acute flow pattern change (from pulsatile to non-pulsatile one), the number of perfused capillaries decreased significantly (from 34.7+/-6.3 to 19.7+/-4.1 number of capillaries/mm; P<0.05). The velocity of erythrocytes dropped (from 526+/-83 to 132+/-41mum/s; P<0.05). The velocity of erythrocytes and capillary density were only partly recovered, when the pulsatile flow mode was restored. Histopathological analysis after 33 days of pumping in non-pulsatile mode revealed the presence of chronic venostasis, tissue edema, hemorrhages, hypoxia and ischemic necroses in the tissue samples from liver, kidneys and lung. These findings could be regarded as a direct effect of the chronic non-pulsatile pumping mode and inadequate blood supply. We conclude that the presence of pulsatile flow should be considered as a vital condition for a successful long-term survival after total artificial heart implantation.

Multipoint Tissue Circulation Monitoring with a Flexible Optical Probe.

Compromised circulation is a potential complication during the postoperative period following tissue transplantation. The use of a monitoring device allows physicians to detect compromised circulation immediately. Such monitoring devices need to be continuously usable, wearable, and area-detectable. However, existing devices fail to satisfy all of these requirements simultaneously. We developed a wearable, multipoint pulse wave-monitoring device. An array of reflective optical sensors implemented on a thin film substrate was used as a lightweight and flexible probe. As a model of tissue transplantation, an inguinal flap in a Wistar rat was dissected and freed from all subcutaneous tissue. By ligating the artery or vein, ischemia or congestion was induced in the tissue. In a human study, ischemia or congestion was induced in the palm by pressing the feeding artery or cutaneous vein, respectively. The amplitude of the pulse wave was evaluated using the power spectrum of Fourier transformed signals. Pulse wave amplitude significantly decreased under compromised circulation in both animal and human models. Moreover, we accomplished 1 week of continuous wireless monitoring in healthy subjects. These results demonstrated the potential utility of the developed device in postoperative blood-flow monitoring to improve the rescue rate of transplanted tissue.