Automatic irrigation system with a fiber-optic pressure sensor regulating intrapelvic pressure for flexible ureteroscopy.

Increased intrapelvic pressure (IPP) due to irrigation during flexible ureteroscopy (f-URS) can pose a risk of postoperative severe urinary tract infection associated with pyelovenous backflow. An automatic regulation system for maintaining safe IPP levels could enable surgeons to perform f-URS safely without postoperative complications. This study aimed to assess the measurement accuracy of an ultra-miniature fiber-optic pressure sensor incorporated into a small-caliper ureteroscope for assessing IPP and to develop an automatic irrigation system linked to this sensor. A porcine kidney was used for the ex vivo experiment. The nephrostomy catheter, connected to the conventional pressure transducer, was placed on the renal pelvis to evaluate the actual IPP (a-IPP). For measuring IPP using the fiber-optic pressure sensor (fo-IPP) built into the f-URS, a diaphragm pressure sensor of Φ250 µm was used. To establish an irrigation system, the optimal proportional-integral-derivative (PID) controller was explored to accurately adjust the irrigation pump flow rate. A high correlation between a-IPP and fo-IPP was confirmed across irrigation pressure values of 60-180 mbar (all, r ≥ 0.7, p < 0.001). When performing bolus irrigation, although fo-IPP showed relatively a higher peak value than a-IPP, the response time of fo-IPP was equivalent to that of a-IPP. After PID parameter optimization, our automatic irrigation system based on fo-IPP smoothly and accurately regulated the intended IPP set in the 5-20 mmHg range without overshooting. We successfully developed and demonstrated an automatic irrigation system regulating IPP based on the PID controller for f-URS, utilizing a fiber-optic pressure sensor. Further research, including in vivo studies, will be needed to assess clinical feasibility.

Development of modified laser Doppler flowmetry device for real-time monitoring of esophageal mucosal blood flow: a preclinical assessment with an animal model.

This study aimed to modify a laser Doppler flowmeter designed and assembled at our institute. After measuring sensitivity evaluation in ex vivo experiments, we confirmed the efficacy of this new device for monitoring real-time esophageal mucosal blood flow changes after thoracic stent graft implantation by simulating various clinical situations in an animal model. Thoracic stent graft implantation was performed in a swine model (n = 8). Esophageal mucosal blood flow decreased significantly from baseline (34.1 ± 18.8 ml/min/100 g vs. 16.7 ± 6.6 ml/min/100 g, P < 0.05) in the lower esophagus (Th6-Th8) where the stent graft covered the aorta. In the hemorrhagic shock model (shock index ≥ 1.0), esophageal mucosal blood flow showed a remarkable change from baseline in the upper esophagus (Th1-Th3), where the stent graft did not cover the aorta (20.8 ± 9.8 ml/min/100 g vs. 12.9 ± 8.6 ml/min/100 g, P < 0.01); however, it returned to the baseline value within a 30-min period. Mucosal blood flow remained stable in the esophagus, where the stent graft did not cover the aorta. After elevating the mean blood pressure to > 70 mmHg with continuous intravenous noradrenaline infusion, esophageal mucosal blood flow increased significantly in both regions; however, the reaction was different between the two regions. Our newly developed laser Doppler flowmeter could measure real-time esophageal mucosal blood flow changes in various clinical situations during thoracic stent graft implantation in a swine model. Hence, this device can be applied in many medical fields by downsizing it.

Design and kinematics of a tube-shaped multidirectional bending robotic device using slackened SMA wires for transurethral ureterolithotripsy.

PURPOSE: The complex and elaborate structure of the urinary system presents surgeons with difficulty in using a ureteroscope with a fixed optical fiber to reach the targeted calculus. To address this challenge, a robotic device is required to control the direction of laser irradiation position independently in ureteroscopes. METHOD: A continuum robotic device was designed and fabricated. The device is constructed with three slackened shape memory alloy (SMA) wires to control the laser irradiation position of the optical fiber combined with the view of the camera on the tip of the ureteroscope. Kinematics analysis and experimental evaluation reveal the capability of the device. RESULTS: The structure of the device is the same as a single-joint continuum robot. This device is unique because of the tiny diameter of 1.1 mm which can be used inside the ureteroscope through a Ø1.2 mm inner channel into the kidney for transurethral ureterolithotripsy. Kinematic analysis revealed the relationship among space coordinates, angles of bending, and direction and SMA wires length. The maximum bending angle was around 25° when the current value was 350 mA on a single SMA wire. The device could achieve multi-directional bending by allocating the values of current on SMA wires, separately. CONCLUSION: This device offers a major advancement in small size and dexterity in medical robotics. Combined with a proper control system, this device could simplify the operation and improve the efficiency of the transurethral ureterolithotripsy.

Effects of salicylate derivatives on localization of p.H723R allele product of SLC26A4.

OBJECTIVE: Pendrin is a transmembrane protein encoded by the SLC26A4 gene that functions in maintaining ion concentrations in the endolymph of the inner ear, most likely by acting as a chloride/bicarbonate transporter. Variants in the SLC26A4 gene are responsible for sensorineural hearing loss. Although pendrin localizes to the plasma membrane, we previously identified that 8 missense allele products of SLC26A4 were retained in the intracellular region and lost their anion exchange function. We also found that 10 mM salicylate induced the translocation of 4 out of 8 allele products from the intracellular region to the plasma membrane and restored their anion exchanger activity. However, since 10 mM salicylate exhibits cytotoxicity, the use of chemical compounds with less cell toxicity is needed. In the present study, therefore, salicylate derivatives were used as the chemical compounds and their effects on the p.H723R allele products of SLC26A4 were investigated. METHODS: HEK293 cells were transfected with the cDNA of p.H723R. Cell proliferation, viability and toxicity assays were performed to investigate the response and health of cells in culture after treatment with four types of salicylate derivatives, i.e., 2-hydroxybenzyl alcohol, 2,3-dihydroxybenzoic acid, 2'-hydroxyacetophenone and methyl salicylate. The effects of these salicylate derivatives on the localization of the p.H723R were investigated by immunofluorescence microscopy. RESULTS: The application of 10 mM salicylate showed an increase in cell toxicity and decrease in cell viability, leading to a significant decrease in cell proliferation. In contrast, the application of 1 mM salicylate derivatives did not show any significant increase in cell toxicity and decrease in cell viability, corresponding to a logarithmic increase in cell concentration with an increase in culture time. Immunofluorescence experiments showed that the p.H723R retained in the endoplasmic reticulum (ER). Among the salicylate derivatives applied, 2-hydroxybenzyl alcohol induced the translocation of p.H723R from the ER to the plasma membrane 3 h after its application. CONCLUSION: The results obtained showed that 2-hydroxybenzyl alcohol restored the localization of the p.H723R allele products of SLC26A4 from the ER to the plasma membrane at a concentration of 1 mM by 3 h after its administration with less cytotoxicity than 10 mM salicylate.

Treatment strategy for pediatric giant mucinous cystadenoma: A case report.

Because of their rarity, the treatment strategy for pediatric ovarian epithelial tumors is controversial, especially for a giant cystadenoma. We report the largest mucinous cystadenoma (MCA) case in the pediatric literature thus far. A 12-year-old girl had abdominal distention and visited our hospital. She had a multilocular cyst with some protuberance on the inside and high values of CA 19-9 and CA-125. We diagnosed her with a left MCA and performed a left oophorectomy. The tumor was the stage IA borderline malignant MCA and weighed 11.8 kg. Five years have passed, the patient has not experienced recurrence or metastasis. The resection of giant tumors can affect respiration and circulation. However, pre- or intra-operative drainage may lead to dissemination and adhesion. When we treat pediatric giant ovarian epithelial tumors, we must understand the findings that suggest the possibility of malignancy to decide appropriately as to whether drainage should be performed.

Focused Ultrasound PC-6 Stimulation Effects on Blood Flow Volume, Skin Temperature, and Coldness of the Finger and Toe.

INTRODUCTION: Focused ultrasound can stimulate a specific point of tissue and can be a noninvasive method for acupoint stimulation. The aim of this study was to clarify the effects of acupoint stimulation by focused ultrasound on blood flow volume and coldness of the fingers and toes. MATERIALS AND METHODS: Forty healthy volunteers were included in this experiment. The blood flow volume and the skin temperature of a finger and toe were measured before and after stimulation of the pericardium 6 acupuncture point (PC-6) by focused ultrasound. Subjective coldness of the fingers and toes was also assessed using a visual analog scale (VAS) before and after stimulation. RESULTS: The maximum blood flow volumes of the finger and toe were significantly larger (p < 0.01) than those before stimulation. The maximum skin surface temperatures of the fingers were significantly higher (p < 0.01) than those before stimulation. The VAS scores for subjective coldness of the toes after stimulation were significantly higher (p < 0.01). CONCLUSION: The blood flow volume and skin temperature tended to increase after PC-6 stimulation. The VAS scores also indicated a tendency toward a warmer sensation in the toes after stimulation.

Viscosity measurement of Xanthan-Poly(vinyl alcohol) mixture and its effect on the mechanical properties of the hydrogel for 3D modeling.

Biomodels made of poly(vinyl alcohol) (PVA) are demanded because they can represent the geometries and mechanical properties of human tissues realistically. Injecting and molding, commonly used in three-dimensional (3D) modeling, help to represent the blood vessels accurately. However, these techniques sometimes require higher pressures than the upper pressure limit of the dispensers for pouring in high viscosity materials; the material viscosity should therefore be lower. Moreover, the mechanical properties of the biomodels should be reproduced. This study proposes a PVA solution through the addition of xanthan gum (XG) for 3D modeling, which lowers liquid viscosity while maintaining the mechanical properties of biomodels. XG is known to facilitate the achievement of non-Newtonian fluidity; however, the effects of XG on a PVA solution and PVA hydrogel (PVA-H) are not confirmed. The viscosity measurement using 15 wt% PVA with XG solution (PVA/XG) shows that it will provide easier pouring than 17 wt% PVA solution. The tensile test using the PVA-H of PVA(15 wt%)/XG(0.2 wt%) reveals that the gel is comparable in Young's modulus to 17 wt% PVA-H. X-ray diffraction shows the crystalline structures of the PVA/XG gel and PVA-H are identical. Thus, this PVA/XG would be useful for fabricating biomodels using injection molding techniques.

Fabrication and Packaging of CMUT Using Low Temperature Co-Fired Ceramic.

This paper presents fabrication and packaging of a capacitive micromachined ultrasonic transducer (CMUT) using anodically bondable low temperature co-fired ceramic (LTCC). Anodic bonding of LTCC with Au vias-silicon on insulator (SOI) has been used to fabricate CMUTs with different membrane radii, 24 µm, 25 µm, 36 µm, 40 µm and 60 µm. Bottom electrodes were directly patterned on remained vias after wet etching of LTCC vias. CMUT cavities and Au bumps were micromachined on the Si part of the SOI wafer. This high conductive Si was also used as top electrode. Electrical connections between the top and bottom of the CMUT were achieved by Au-Au bonding of wet etched LTCC vias and bumps during anodic bonding. Three key parameters, infrared images, complex admittance plots, and static membrane displacement, were used to evaluate bonding success. CMUTs with a membrane thickness of 2.6 µm were fabricated for experimental analyses. A novel CMUT-IC packaging process has been described following the fabrication process. This process enables indirect packaging of the CMUT and integrated circuit (IC) using a lateral side via of LTCC. Lateral side vias were obtained by micromachining of fabricated CMUTs and used to drive CMUTs elements. Connection electrodes are patterned on LTCC side via and a catheter was assembled at the backside of the CMUT. The IC was mounted on the bonding pad on the catheter by a flip-chip bonding process. Bonding performance was evaluated by measurement of bond resistance between pads on the IC and catheter. This study demonstrates that the LTCC and LTCC side vias scheme can be a potential approach for high density CMUT array fabrication and indirect integration of CMUT-IC for miniature size packaging, which eliminates problems related with direct integration.

A new manometry device for evaluating the sphincter of Oddi using a fiber-optic pressure sensor.

INTRODUCTION: Although measuring the pressure of the sphincter of Oddi and the bile duct is considered to be an important examination, called Sphincter of Oddi manometry (SOM), some complications related to the SOM device remain unsolved. MATERIAL AND METHODS: To decrease adverse complications, we developed a 0.46 mm manometry and we performed some in vitro studies. RESULTS: We successfully developed a 0.46 mm SOM. The diameter is the thinnest size used in endoscopic examinations. The results of in vitro studies show the suitability as SOM. CONCLUSION: This device will decrease the risks related to SOM examination. To confirm the safety and feasibility, further studies including in vivo studies will be needed.

Oesophageal mucosal blood flow changes after thoracic endovascular stent graft implantation using a novel sensor probe.

OBJECTIVES: Secondary aorto-oesophageal fistula is a rare, lethal complication occurring after thoracic endovascular aneurysmal repair. The cause of secondary aorto-oesophageal fistula is unknown, but a reduction in local oesophageal mucosal blood flow (OMBF) may be a basis for such a devastating sequela. Our study aims to develop a novel blood flow sensor probe to detect changes in OMBF after thoracic stent graft implantation in an experimental swine model. METHODS: A novel laser Doppler flowmetry sensor probe incorporating an optical fibre sensor within a nasogastric tube was developed using microelectromechanical system technology. OMBF was measured at various levels using this sensor probe, to test its feasibility before and after thoracic endovascular stent graft implantation covering Th4-Th8 vertebral levels in 6 swine. RESULTS: In the middle oesophagus (Th5-Th7), where the aorta was covered with a stent graft, the measured OMBFs were significantly decreased after thoracic endovascular stent graft implantation than those of baseline (8.6 ± 2.7 vs 18.4 ± 7.9 ml/min/100 g, P < 0.0001), followed by a plateau period for at least 2 h after stent grafting (8.7 ± 3.3 ml/min/100 g, P < 0.0001 vs baseline). OMBFs in the upper (Th1-Th3) and lower (Th9-Th11) oesophagus, where the aorta was not covered with a stent graft, were unaffected by thoracic endovascular stent grafting. CONCLUSIONS: The novel laser Doppler flowmetry sensor probe was useful to monitor precise changes of OMBF in a swine model, demonstrating a significant reduction in OMBF after thoracic endovascular stent graft implantation.

Lactate and glucose measurement in subepidermal tissue using minimally invasive microperfusion needle.

Knowing the concentrations of biological substances can help ascertain physiological and pathological states. In the present study, a minimally invasive microperfusion needle was developed for measuring the concentrations of biological substances in subepidermal tissue. The microperfusion needle has a flow channel with a perforated membrane through which biological substances from subepidermal tissue are extracted. Since this device uses a thin steel acupuncture needle as the base substrate, it has sufficient rigidity for insertion through the skin. The efficacy of the needle was examined by measuring lactate and glucose concentrations in mice. Lactate was injected intraperitoneally, and changes in lactate concentrations in subepidermal tissue over time were measured using the device. Lactate concentrations of blood were also measured as a reference. Lactate was successfully collected using the microperfusion needle, and the lactate concentration of perfused saline was significantly correlated with blood lactate concentration. Glucose solution was administered orally, and the glucose concentration of perfused saline was also correlated with blood glucose concentration. The newly developed microperfusion needle can be used for minimally invasive monitoring of the concentrations of biological substances.

Intraparenchymal ultrasound application and improved distribution of infusate with convection-enhanced delivery in rodent and nonhuman primate brain.

OBJECT Convection-enhanced delivery (CED) is an effective drug delivery method that delivers high concentrations of drugs directly into the targeted lesion beyond the blood-brain barrier. However, the drug distribution attained using CED has not satisfactorily covered the entire targeted lesion in tumors such as glioma. Recently, the efficacy of ultrasound assistance was reported for various drug delivery applications. The authors developed a new ultrasound-facilitated drug delivery (UFD) system that enables the application of ultrasound at the infusion site. The purpose of this study was to demonstrate the efficacy of the UFD system and to examine effective ultrasound profiles. METHODS The authors fabricated a steel bar-based device that generates ultrasound and enables infusion of the aqueous drug from one end of the bar. The volume of distribution (Vd) after infusion of 10 ml of 2% Evans blue dye (EBD) into rodent brain was tested with different frequencies and applied voltages: 252 kHz/30 V; 252 kHz/60 V; 524 kHz/13 V; 524 kHz/30 V; and 524 kHz/60 V. In addition, infusion of 5 mM gadopentetate dimeglumine (Gd-DTPA) was tested with 260 kHz/60 V, the distribution of which was evaluated using a 7-T MRI unit. In a nonhuman primate (Macaca fascicularis) study, 300 µl of 1 mM Gd-DTPA/EBD was infused. The final distribution was evaluated using MRI. Two-sample comparisons were made by Student t-test, and 1-way ANOVA was used for multiple comparisons. Significance was set at p < 0.05. RESULTS After infusion of 10 µl of EBD into the rat brain using the UFD system, the Vds of EBD in the UFD groups were significantly larger than those of the control group. When a frequency of 252 kHz was applied, the Vd of the group in which 60 V was applied was significantly larger than that of the group in which 30 V was used. When a frequency of 524 kHz was applied, the Vd tended to increase with application of a higher voltage; however, the differences were not significant (1-way ANOVA). The Vd of Gd-DTPA was also significantly larger in the UFD group than in the control group (p < 0.05, Student t-test). The volume of Gd-DTPA in the nonhuman primate used in this study was 1209.8 ± 193.6 mm(3). This volume was much larger than that achieved by conventional CED (568.6 ± 141.0 mm(3)). CONCLUSIONS The UFD system facilitated the distribution of EBD and Gd-DTPA more effectively than conventional CED. Lower frequency and higher applied voltage using resonance frequencies might be more effective to enlarge the Vd. The UFD system may provide a new treatment approach for CNS disorders.

Real-time monitoring of spinal cord blood flow with a novel sensor mounted on a cerebrospinal fluid drainage catheter in an animal model.

OBJECTIVE: The aim of our study was to develop a novel monitoring system for spinal cord blood flow (SCBF) to test the efficacy of the SCBF sensor in an animal model. METHODS: The sensor system consisted of 2 optical fibers, a pedestal for fiber fixation, and a mirror for the laser reflection and was incorporated into a cerebrospinal fluid drainage catheter. In vivo studies were performed in a swine model (n=10) to measure SCBF during spinal cord ischemia induced by clamping the descending thoracic aorta and supra-aortic neck vessels, when necessary. A temporary low cardiac output model was also created by inflow clamping of the inferior vena cava to analyze the quantitative changes in SCBF during this maneuver. RESULTS: The developed SCBF monitoring catheter placed intrathecally could detect SCBF in all the swine. The SCBF after aortic crossclamping at the fourth intercostal level exhibited diverse changes reproducibly among the swine, with a >25% reduction in SCBF in 5 pigs, an increase in 3, and no significant changes in 2. Consistent reductions were recorded during inferior vena cava occlusion. The mean SCBF decreased by 32% after inferior vena cava occlusion when the cardiac output had decreased by 27%. CONCLUSIONS: We have developed a novel SCBF sensor that could detect real-time changes in spinal cord perfusion in a swine model. The device holds promise to detect imminent ischemia or ensure acceptable blood perfusion in the spinal cord and could further enhance our understanding of spinal cord circulation.

Brief effect of acupoint stimulation using focused ultrasound.

BACKGROUND: Acupuncture is used worldwide in medical treatment. However, needle insertion damages the skin and patients sometimes feel pain. To avoid such drawbacks, an acupoint stimulation device using focused ultrasound has been developed. Ultrasound stimulation does not damage the skin like acupuncture does because ultrasound can deliver vibration energy to soft tissues noninvasively. OBJECTIVES: The aim of this study was to clarify the effect of acupoint stimulation using focused ultrasound. SUBJECTS: Fifty (50) healthy volunteers (40 males and 10 females) were included in this experiment. DESIGN: Subjects were randomly assigned to two groups. LR-3 was stimulated bilaterally for 36 seconds by focused ultrasound and conventional acupuncture. Brachial artery blood flow volume was monitored by an ultrasound with an echo-tracking system. The hemodynamic parameters were measured before, during, and 30, 60, 180 seconds after stimulation. RESULTS: During stimulation, the blood flow volume of the acupuncture stimulation group decreased significantly (p<0.05) compared with resting value, but that of the focused ultrasound stimulation group did not decrease. Blood flow volume of both groups increased gradually and showed significant increase at 180 seconds after stimulation (p<0.05). CONCLUSIONS: Blood flow volume was increased significantly by both focused ultrasound stimulation and conventional acupuncture. Although a significant decrease of blood flow volume during acupuncture stimulation was observed, no such decrease was observed during ultrasound stimulation. Findings of the present study show that noninvasive stimulation of acupoints by focused ultrasound is as effective as conventional acupuncture in blood flow volume of the brachial artery.

Salicylate restores transport function and anion exchanger activity of missense pendrin mutations.

The SLC26A4 gene encodes the transmembrane protein pendrin, which is involved in the homeostasis of the ion concentration of the endolymph of the inner ear, most likely by acting as a chloride/bicarbonate transporter. Mutations in the SLC26A4 gene cause sensorineuronal hearing loss. However, the mechanisms responsible for such loss have remained unknown. Therefore, in this study, we focused on the function of ten missense pendrin mutations (p.P123S (Pendred syndrome), p.M147V (NSEVA), p.K369E (NSEVA), p.A372V (Pendred syndrome/NSEVA), p.N392Y (Pendred syndrome), p.C565Y (NSEVA), p.S657N (NSEVA), p.S666F (NSEVA), p.T721M (NSEVA) and p.H723R (Pendred syndrome/NSEVA)) reported in Japanese patients, and analyzed their cellular localization and anion exchanger activity using HEK293 cells transfected with each mutant gene. Immunofluorescent staining of the cellular localization of the pendrin mutants revealed that p.K369E and p.C565Y, as well as wild-type pendrin, were transported to the plasma membrane, while 8 other mutants were retained in the cytoplasm. Furthermore, we analyzed whether salicylate, as a pharmacological chaperone, restores normal plasma membrane localization of 8 pendrin mutants retained in the cytoplasm to the plasma membrane. Incubation with 10 mM of salicylate of the cells transfected with the mutants induced the transport of 4 pendrin mutants (p.P123S, p.M147V, p.S657Y and p.H723R) from the cytoplasm to the plasma membrane and restored the anion exchanger activity. These findings suggest that salicylate might contribute to development of a new method of medical treatment for sensorineuronal hearing loss caused by the mutation of the deafness-related proteins, including pendrin.

Minimally invasive diagnostics and treatment using micro/nano machining.

Several medical tools with various functions have been developed for minimally invasive diagnostics and treatment. Microfabrication techniques such as MEMS technology are useful for the realization of high-performance multifunctional minimally invasive medical tools with small sizes. An ultra-miniature pressure sensor and an intravascular ultrasonic forward-viewing imager have been developed as microsensors for use in the human body. Active bending catheters have been developed for steering catheter tips without using traction of wires from outside the body. An ultrasonic therapeutic tool for sonodynamic therapy and sonoporation, and a micro scanner for precise laser treatment have been developed as therapeutic tools for use in the human body. High-functionalized endoscopic tools and catheters will enable more precise and safe diagnostics and therapy, as well as novel diagnostics and treatment which have been impossible to date.

Artificial myocardium with an artificial baroreflex system using nano technology.

Where is the place which should be helped in a patient with congestive heart failure? The answer may be contraction of the heart. At Tohoku University, development research of "the artificial myocardium" has been conducted, using a ball screw type electromagnetic motor. Furthermore, super-miniaturization is being attempted at present. Thus, a system with shape memory alloy is being developed. The cooling speed problem was solved by the application of the Peltier element. A drive at a speed equal to that of a heartbeat was realized by the application of this system. At present, a ventricular assist device is used for patients waiting for a heart transplant in Japan. An air driven type system disturbs a patient's QOL remarkably because it is connected to the drive device. With our concept, energy is provided by using the electromagnetic force from outside of the body by the use of transcutaneous energy transmission system. Magnetic shielding by amorphous fibers was used at Tohoku University to improve the total efficiency. A natural heart can alter the cardiac output corresponding to the demand. Artificial internal organs must participate in the system of the living body, too. Tohoku University has developed a resistance based artificial heart control algorithm, which simulated a baroreflex system to cope with every demand. Nano level sensing equipment is now under development at Tohoku University. At present, development is being conducted aiming at an "intelligent artificial myocardium".