Self-rechargeable cardiac pacemaker system with triboelectric nanogenerators.

Self-powered implantable devices have the potential to extend device operation time inside the body and reduce the necessity for high-risk repeated surgery. Without the technological innovation of in vivo energy harvesters driven by biomechanical energy, energy harvesters are insufficient and inconvenient to power titanium-packaged implantable medical devices. Here, we report on a commercial coin battery-sized high-performance inertia-driven triboelectric nanogenerator (I-TENG) based on body motion and gravity. We demonstrate that the enclosed five-stacked I-TENG converts mechanical energy into electricity at 4.9 µW/cm3 (root-mean-square output). In a preclinical test, we show that the device successfully harvests energy using real-time output voltage data monitored via Bluetooth and demonstrate the ability to charge a lithium-ion battery. Furthermore, we successfully integrate a cardiac pacemaker with the I-TENG, and confirm the ventricle pacing and sensing operation mode of the self-rechargeable cardiac pacemaker system. This proof-of-concept device may lead to the development of new self-rechargeable implantable medical devices.

Feasibility study on stereotactic radiotherapy for total pulmonary vein isolation in a canine model.

We tested the feasibility of pulmonary vein (PV) and left atrial (LA) posterior wall isolation using non-invasive stereotactic ablative body radiotherapy (SABR) and investigated pathological changes in irradiated lesions in a canine model. Seven male Mongrel dogs received single-fraction 33 Gy SABR. We designed the en-bloc circular target of total PVs and LA posterior wall to avoid the esophagus. The circular box lesion included the LA roof and ridge, low posterior wall, and posterior interatrial septum. At 6 weeks or 4 months post-SABR, electrical isolation of the SABR lesion was confirmed using LA posterior wall pacing, and histopathological review was performed. Electrical isolation of all PVs and the LA posterior wall was achieved in three of five dogs in the 4-month group. There was one target failure and one sudden death at 15 weeks. Although two dogs in the 6-week group failed to achieve electrical lesion isolation, the irradiated atrial myocardium showed diffuse hemorrhage with inflammatory cell infiltration. In successfully isolated 4-month model dogs, we observed transmural fibrotic scarring with extensive fibrosis on irradiated atrial tissue. The findings suggest that this novel circular box-design radiotherapy technique using SABR could be applied to humans after further studies are conducted to confirm safety.

Early Changes in Rat Heart After High-Dose Irradiation: Implications for Antiarrhythmic Effects of Cardiac Radioablation.

Background Noninvasive cardiac radioablation is employed to treat ventricular arrhythmia. However, myocardial changes leading to early-period antiarrhythmic effects induced by high-dose irradiation are unknown. This study investigated dose-responsive histologic, ultrastructural, and functional changes within 1 month after irradiation in rat heart. Methods and Results Whole hearts of wild-type Lewis rats (N=95) were irradiated with single fraction 20, 25, 30, 40, or 50 Gy and explanted at 1 day or 1, 2, 3, or 4 weeks' postirradiation. Microscopic pathologic changes of cardiac structures by light microscope with immunohistopathologic staining, ultrastructure by electron microscopy, and functional evaluation by ECG and echocardiography were studied. Despite high-dose irradiation, no myocardial necrosis and apoptosis were observed. Intercalated discs were widened and disrupted, forming uneven and twisted junctions between adjacent myocytes. Diffuse vacuolization peaked at 3 weeks, suggesting irradiation dose-responsiveness, which was correlated with interstitial and intracellular edema. CD68 immunostaining accompanying vacuolization suggested mononuclear cell infiltration. These changes were prominent in working myocardium but not cardiac conduction tissue. Intracardiac conduction represented by PR and QTc intervals on ECG was delayed compared with baseline measurements. ST segment was initially depressed and gradually elevated. Ventricular chamber dimensions and function remained intact without pericardial effusion. Conclusions Mononuclear cell-related intracellular and extracellular edema with diffuse vacuolization and intercalated disc widening were observed within 1 month after high-dose irradiation. ECG indicated intracardiac conduction delay with prominent ST-segment changes. These observations suggest that early antiarrhythmic effects after cardiac radioablation result from conduction disturbances and membrane potential alterations without necrosis.

Transcutaneous ultrasound energy harvesting using capacitive triboelectric technology.

A major challenge for implantable medical systems is the inclusion or reliable delivery of electrical power. We use ultrasound to deliver mechanical energy through skin and liquids and demonstrate a thin implantable vibrating triboelectric generator able to effectively harvest it. The ultrasound can induce micrometer-scale displacement of a polymer thin membrane to generate electrical energy through contact electrification. We recharge a lithium-ion battery at a rate of 166 microcoulombs per second in water. The voltage and current generated ex vivo by ultrasound energy transfer reached 2.4 volts and 156 microamps under porcine tissue. These findings show that a capacitive triboelectric electret is the first technology able to compete with piezoelectricity to harvest ultrasound in vivo and to power medical implants.

subchronic inhalation toxicity study of 1,3-dichloro-2-propanol in rats.

The subchronic toxicity of 1,3-dichloro-2-propanol (1,3-DCP) was investigated in Fischer 344 rats after 13 weeks of repeated, whole-body inhalation exposure. Groups of 10 rats of each sex were exposed to 1,3-DCP vapor by whole-body inhalation exposure at concentrations of 0, 5, 20 or 80 ppm for 6 h/day, 5 days/week for 13 weeks. All of the rats were sacrificed at the end of the treatment period. During the test period, clinical signs, mortality, body weights, food consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weights and histopathology were assessed. At 80 ppm, a decrease in the body weight gain, an increase in the urine protein and leukocyte counts and an increase in the liver and kidney weights were observed in both genders. Hematological and serum biochemical investigations revealed decreases in hemoglobin (HB), hematocrit (HCT), mean corpuscular volume (MCV) and mean corpuscular HB, as well as increases in the platelet (PLT) count, serum aspartate aminotransferase and alanine aminotransferase. The number of white blood cells was significantly lower in males than in controls, but this was not the case in females. Histopathological alterations included an increase in the incidence of multifocal necrosis, inflammation, pigmentation, biliary hyperplasia and the foci of cellular alteration of the liver and chronic nephropathy and protein cast of the kidney. At 20 ppm, decreases in HCT and MCV and increases in the liver and kidney weights were observed in both genders. A decrease in the HB of females and an increase in the PLT count of females were also observed. Histopathological alterations included slight increases in the incidences of hepatic necrosis, hepatic inflammation and chronic nephropathy. At 5 ppm, we found decreases in the MCV of males and the HB of females, as well as an increase in the liver weight of both genders. In the present experimental conditions, the target organs were determined to be the liver, kidney and blood cells in rats. The no-observed-adverse-effect level was considered to be <5 ppm/6 h/day and the low-observed-adverse-effect level was believed to be 5 ppm/6 h/day in rats.

Expression of tyrosine kinase A in the cerebral cortex of postnatal developing rat.

Tyrosine kinase A (TrkA) is an essential component of the high affinity nerve growth factor (NGF) receptor necessary to the mediate the biological effects of the neurotrophins, NGF. This study examined the distribution of TrkA-immunoreactivity (IR)cells in the postnatal rat cerebral cortex and the changes that occur in postnatal development as a result of the expression of this protein. TrkA-IR was detected at postnatal day (PD) 3, PD6, PD9 and PD15. Base upon their somatodendritic morphology, the most commonly labeled cell type was the pyramidal neurons. At PD3 and PD6, layer I, II, III and V was immunopositive for TrkA, at PD9, not only at layer I, II, III, and V but also at layer VI. At PD15, the TrkA-positive cells were distributed in all layers. These TrkA-positive cells were not detected at PD0. In contrast, there was significant increase in the percentage of cells exhibiting TrkA-IR with development and the highest level was detected at PD15. These results suggest that the cerebral cortex expresses TrkA strongly during the postnatal period. Moreover, the postnatal development-related increase in the expression of TrkA-cells shows that NGF may have a trophic effect on these cerebral cortex neurons from the postnatal period.

Distribution of trkA in cerebral cortex and diencephalon of the mongolian gerbil after birth.

TrkA is essential components of the high-affinity NGF receptor necessary to mediate biological effects of the neurotrophins NGF. Here we report on the expression of trkA in the cerebral cortex and diencephalon of mongolian gerbils during postnatal development. The expression of trkA was identified by immunohistochemical method. In parietal cortex and piriform cortex, higher levels of trkA IR (immunoreactivity) were detected at 3 days postnatal (P3) and at P9. Although trkA was not expressed till P3 in the parietal cortex, it was detectable at birth in the piriform cortex. Several regions, such as Layers I, IV & VI, did not show much expression. Layer I showed especially weak labeling. In the hippocampus, thalamus, and hypothalamus, higher levels of trkA IR were detected at P6 and P12 than earlier days. But trkA was not expressed at birth in the hippocampus, at P3 in the reticular thalamic nucleus (Rt), or neonatally in the dorsomedial hypothalamic nucleus (DM). This data shows that expression of trkA is developmentally regulated and suggests that high affinity neurotrophin-receptors mediate a transient response to neurotrophines in the cerebral cortex and diencephalon during mongolian gerbil brain ontogeny.

A histologic demonstration of siliceous materials in simian lung mite infected lung tissues by microincineration.

Approximately 90% of freshly imported macaques and other Old World Monkeys are known to be infected with respiratory mites. The lung associated pigments are integral components of pulmonary acariasis in Old World Monkeys; at least three distinctive pigmental bodies are identified in association with lung mite infection. Two major components of pigments are recently identified as silica by using elemental analysis using a high voltage electron microscope and an energy-dispersive X-ray analysis technique. Since a limited number of infected monkey lung tissues and associated pigments can be examined by this tedious procedure, it was important for us to examine much greater number of specimens to verify our initial observation. Ten microincineration technique described provided a unique and practical way to identify the mineral elements in as many 27 histologic sections within a short span of time. Silica and silicates are heat resistant whereas majority of organic materials including lung mite parasites disintegrated under the extreme temperature. Mineral elements were exclusively located within the polarizable white ash. More than 90% of total pigmental bodies identified were found to be related to siliceous materials in 20 incinerated infected monkey lung tissues whereas five noninfected lungs similarly examined did not reveal any pigmental bodies. Other than a small of fine granular mucin substances which were PAS positive, the majority of lung mite associated pigments such as large granules of hemosiderin, needle-like crystals and other fine granules engulfed by macrophages were identified to be siliceous materials as they have persisted even after microincineration. Mite parasites and other organic materials were completely disintegrated. Similar pigmental bodies examined by microscope X-ray analysis were positive for silicate. This finding suggests that lung mite infection in Old Monkeys apparently predisposed silicosis. Therefore, until the link between lung mite infection and silicosis is clarified, experimental inhalation toxicologic findings in mite-infected Old World monkeys should be interpreted cautiously.

A study on the spinoreticulocerebellar tract in chickens.

The spinoreticulocerebellar (SRC) tract is an indirect spinocerebellar tract formed by the reticular formation (RF), which is connected to the cerebellum and spinal cord. The RF receives ascending fibers to both the spinal enlargement and sends descending fibers to the cerebellum. This study demonstrated that the connectivity of the neurons in the RF is concerned to the cerebellum and spinal cord using the anterograde projection with biotinylated dextran amine (BDA) and retrograde labeling with wheatgerm agglutinin-horseradish peroxidase (WGA-HRP). Until now, a preliminary study in mammals has dealt with the afferent and efferent pathways in separating groups of neurons in the RF. There are only few reports on chickens. This study examined the SRC tract in chickens. Following bilateral injections we injected BDA into chicken spinal cord (lumbosacral enlargement) and WGA-HRP into the cerebellum. Both of single- and double-labeled cells were found within the RF. The spinoreticular axons were mainly distributed from the potomedullary junction to the rostral medulla in the rostro-caudally RF levels, for example, nucleus of reticularis (n. r.) pontis oralis,locus coeruleus, n. r. pontis caudalis, n. r. pars gigantocellularis, n. r. gigantocellularis and n. r. parvocellularis. Reticulocerebellar labeling by the WGA-HRP was found in the same place as well as that of the BDA-projection. We observed that the proportion and location of double labeling cells in the chicken were almost similar in each level, comparing to the rodents. These results suggest that the reticular formation is strongly related to the spinoreticulocerebellar tract in chickens.

Expression of aldose reductase in developing rat kidney.

Newborn rats are not capable of producing concentrated urine. With development of the concentrating system and a hypertonic medullary interstitium, intracellular osmolytes, such as sorbitol, accumulate in the renal medulla. Sorbitol is produced from glucose in a reaction catalyzed by aldose reductase (AR). The purpose of this study was to establish the time of expression and distribution of AR in the developing rat kidney. Kidneys from 16-, 18-, and 20-day-old fetuses and 1-, 3-, 4-, 5-, 7-, 14-, and 21-day-old pups were processed for immunohistochemistry and immunoblot analysis. In adult animals, AR was expressed only in the inner medulla, in which it was localized in ascending thin limbs (ATLs), inner medullary collecting ducts (IMCDs), and interstitial cells. AR immunoreactivity was not detected in fetal kidneys but was observed in the terminal part of the descending thin limb and IMCD in the renal papilla of 1-day-old pups. At birth, all of the loops of Henle are configured as short loops and there are no ATLs. After birth, papillary thick ascending limbs are gradually transformed into ATLs by a process that involves apoptotic deletion of cells from the thick ascending limb. During this time, AR immunoreactivity appeared in the cells undergoing transformation in the ascending limb, beginning at the papillary tip and ascending to the border between the outer medulla and the inner medulla. However, there was no labeling of apoptotic cells. The expression of AR in both the ATL and the IMCD gradually increased during kidney development. We conclude that AR expression in the inner medulla coincides with the increase in medullary tonicity that is known to occur during the first 3 wk after birth. On the basis of the observation that only AR-negative cells were deleted by apoptosis in the differentiating ATL, we propose that AR may protect ATL cells against apoptosis.

Immunohistochemical localization of nerve growth factor, glial fibrillary acidic protein and ciliary neurotrophic factor in mesencephalon, rhombencephalon, and spinal cord of developing mongolian gerbil.

The distribution of the nerve growth factor (NGF), the glial fibrillary acidic protein (GFAP) and the ciliary neurotrohic factor (CNTF) was performed in coronal sections of the mesencephalon, rhombencephalon and spinal cord in the developing Mongolian gerbils. Generally, NGF specifically recognizes neurons with the NGF receptor, whereas GFAP does the glia, and CNTF does the motor neurons. The receptor expression was examined separately in gerbils between embryonic days 15 (E15) and postnatal weeks 3 (PNW 3). The NGF-IR was first observed in the spinal cord at E21, which might be related to the maturation. The GFAP reactivity was peaked at the postnatal days 2 (PND2), while the highest CNTF-reaction was expressed at PNW 2. The GFAP stains were observed in the aqueduct and the spinal cord, which appeared to project laterally at E19. The CNTF was observed only after the birth and found in both the neurons and neuroglia of the substantia nigra, mesencephalon, cerebellum and the spinal cord from PND1 to PNW3. These results suggest that NGF, GFAP and CNTF are important for the development of the neurons and the neuroglia in the central nervous system at the late prenatal and postnatal stages.