Performance Optimization of Pb0.97La0.03Sc0.45Ta0.45Ti0.1O3 Ceramics by Annealing Process.

The annealing effects on Pb0.97La0.03Sc0.45Ta0.45Ti0.1O3 (PLSTT) ceramics prepared by the solid-state reaction method are systemically investigated using experimental and theoretical techniques. Comprehensive studies are performed on the PLSTT samples by varying annealing time (AT) from t (=0, 10, 20, 30, 40, 50 and 60) h. The properties involving ferroelectric polarization (FP), electrocaloric (EC) effect, energy harvesting performance (EHP) and energy storage performance (ESP) are reported, compared and contrasted. All these features are seen to gradually improve with the increase in AT, and they all reach the climaxed-shaped values and then decrease by further increasing the AT. For t = 40 h, the maximum FP (23.2 µC/cm2) is attained at an electric field of 50 kV/cm, while the high EHP effects (0.297 J/cm3) and positive EC are achieved (for ΔT~0.92 K and ΔS~0.92 J/(K·kg)) at 45 kV/cm. The EHP value of the PLSTT ceramics increased by 21.7% while the polarization value was enhanced by 33.3%. At t = 30 h, the ceramics have attained the best ESP value of 0.468 J/cm3 with an energy loss of 0.05 J/cm3. We strongly believe that the AT plays a crucial role in the optimization of different traits of the PLSTT ceramics.

Adaptive multi-degree-of-freedom in situ bioprinting robot for hair-follicle-inclusive skin repair: A preliminary study conducted in mice.

Skin acts as an essential barrier, protecting organisms from their environment. For skin trauma caused by accidental injuries, rapid healing, personalization, and functionality are vital requirements in clinical, which are the bottlenecks hindering the translation of skin repair from benchside to bedside. Herein, we described a novel design and a proof-of-concept demonstration of an adaptive bioprinting robot to proceed rapid in situ bioprinting on a full-thickness excisional wound in mice. The three-dimensional (3D) scanning and closed-loop visual system integrated in the robot and the multi-degree-of-freedom mechanism provide immediate, precise, and complete wound coverage through stereotactic bioprinting, which hits the key requirements of rapid-healing and personalization in skin repair. Combined with the robot, epidermal stem cells and skin-derived precursors isolated from neonatal mice mixed with Matrigel were directly printed into the injured area to replicate the skin structure. Excisional wounds after bioprinting showed complete wound healing and functional skin tissue regeneration that closely resembling native skin, including epidermis, dermis, blood vessels, hair follicles and sebaceous glands etc. This study provides an effective strategy for skin repair through the combination of the novel robot and a bioactive bioink, and has a promising clinical translational potential for further applications.

An Internal-Electrostatic-Field-Boosted Self-Powered Ultraviolet Photodetector.

Self-powered photodetectors are of significance for the development of low-energy-consumption and environment-friendly Internet of Things. The performance of semiconductor-based self-powered photodetectors is limited by the low quality of junctions. Here, a novel strategy was proposed for developing high-performance self-powered photodetectors with boosted electrostatic potential. The proposed self-powered ultraviolet (UV) photodetector consisted of an indium tin oxide and titanium dioxide (ITO/TiO2) heterojunction and an electret film (poly tetra fluoroethylene, PTFE). The PTFE layer introduces a built-in electrostatic field to highly enhance the photovoltaic effect, and its high internal resistance greatly reduces the dark current, and thus remarkable performances were achieved. The self-powered UV photodetector with PTFE demonstrated an extremely high on-off ratio of 2.49 × 105, a responsivity of 76.87 mA/W, a response rise time of 7.44 ms, and a decay time of 3.75 ms. Furthermore, the device exhibited exceptional stability from room temperature to 70 °C. Compared with the conventional ITO/TiO2 heterojunction without the PTFE layer, the photoresponse of the detector improved by 442-fold, and the light-dark ratio was increased by 8.40 × 105 times. In addition, the detector is simple, easy to fabricate, and low cost. Therefore, it can be used on a large scale. The electrostatic modulation effect is universal for various types of semiconductor junctions and is expected to inspire more innovative applications in optoelectronic and microelectronic devices.

Perirenal adipose afferent nerves sustain pathological high blood pressure in rats.

Hypertension is a pathological condition of persistent high blood pressure (BP) of which the underlying neural mechanisms remain obscure. Here, we show that the afferent nerves in perirenal adipose tissue (PRAT) contribute to maintain pathological high BP, without affecting physiological BP. Bilateral PRAT ablation or denervation leads to a long-term reduction of high BP in spontaneous hypertensive rats (SHR), but has no effect on normal BP in control rats. Further, gain- and loss-of-function and neuron transcriptomics studies show that augmented activities and remodeling of L1-L2 dorsal root ganglia neurons are responsible for hypertension in SHR. Moreover, we went on to show that calcitonin gene-related peptide (CGRP) is a key endogenous suppressor of hypertension that is sequestered by pro-hypertensive PRAT in SHRs. Taken together, we identify PRAT afferent nerves as a pro-hypertensive node that sustains high BP via suppressing CGRP, thereby providing a therapeutic target to tackle primary hypertension.

The RAISE Trial: A Novel Device and First-in-Man Trial.

BACKGROUND: Currently, standard medical therapies have limited effects on heart failure with preserved ejection fraction (HFpEF), which impacts on the life quality and survival of patients. This study aimed to evaluate the safety and efficacy of the percutaneous radiofrequency ablation-based interatrial shunting for HFpEF with a novel atrial septostomy device. METHODS: A preclinical study in 11 normal domestic pigs and the first-in-man study in 10 patients with HFpEF were performed. The major safety events and interatrial shunt performance were evaluated at baseline, 1 month, 3 months, and 6 months post-procedure in both animals and human patients. The clinical functional status was also assessed in the first-in-man study. RESULTS: Percutaneous radiofrequency ablation-based interatrial shunting therapy was performed successfully both in animals and patients. In the animal study, a left-to-right interatrial shunt was created with a mean defect size of 5.5±2.2 mm without procedure-related safety events. Seven pigs showed the continuous shunting with a mean defect size of 4.1±1.5 mm at 6 months. In the first-in-man study, a median interatrial defect diameter of 5.0 (4.0-6.0) mm was measured immediately. No major safety events including death and thromboembolism were observed. The continuous shunting with the defect size of 4.0 (3.0-4.0) mm could still be observed in 7 patients at 6 months. The clinical status was significantly improved with NT-proBNP (N-terminal pro-B-type natriuretic peptide) reduced by 2149 pg/mL ([95% CI, 204-3301] P=0.028), with 6-minute walk distance increased by 88 m ([95% CI, 50-249] P=0.008) and with New York Heart Association class improved in 8 patients at 6 months. CONCLUSIONS: The present results showed that percutaneous radiofrequency ablation-based interatrial shunting was a safe and potentially effective therapy for HFpEF, providing a nonpharmacological and nonimplanted option for HFpEF management. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR1900027664.

Electrospun poly (L-lactic acid)/gelatine membranes loaded with doxorubicin for effective suppression of glioblastoma cell growth in vitro and in vivo.

Electrospun membranes are attracting interest as a drug delivery system because of their material composition flexibility and versatile drug loading. In this study, the electrospun membrane was loaded with doxorubicin (DOX) via electrostatic adsorption for long-term drug delivery. DOX loading process was optimized by varying temperature, time, drug concentration, pH and ionic strength of solutions. The loading process did not impair the structural properties of the membrane. Next, we investigated the drug release kinetics using spectroscopic techniques. The composite membranes released 22% of the adsorbed DOX over the first 48 h, followed by a slower and sustained release over 4 weeks. The DOX release was sensitive to acidic solutions that the release rate at pH 6.0 was 1.27 times as that at pH 7.4. The DOX-loaded membranes were found to be cytotoxic to U-87 MG cells in vitro that decreased the cell viability from 82.92% to 25.49% from 24 to 72 h of co-incubation. These membranes showed strong efficacy in suppressing tumour growth in vivo in glioblastoma-bearing mice that decreased the tumour volume by 77.33% compared with blank membrane-treated group on Day 20. In conclusion, we have developed an effective approach to load DOX within a clinically approved poly (L-lactic acid)/gelatine membrane for local and long-term delivery of DOX for the treatment of glioblastoma.

Association of Omental Adipocyte Hypertrophy and Fibrosis with Human Obesity and Type 2 Diabetes.

OBJECTIVE: Morphological alterations including adipocyte hypertrophy and fibrosis deposition are important surrogate markers of visceral adipose tissue function, but the relationships between these morphological changes and type 2 diabetes mellitus (T2DM) and impaired insulin sensitivity are poorly defined. METHODS: Omental adipose tissue was obtained from 66 individuals with obesity but without T2DM (OB group), 93 individuals with both obesity and T2DM (T2DM group), and 15 individuals with normal BMI and normal glucose tolerance (NGT group). Adipocyte diameter and volume were measured through pathological section analysis. Pericellular and perilobular fibrosis was determined through picrosirius red staining and immunochemistry, while fibrosis-related genes were tested through gene expression and hydroxyproline content. RESULTS: Compared with the NGT and OB groups, individuals from the T2DM group displayed increased adipocyte diameter and volume levels. Increased adipocyte size (diameter and volume) was positively associated with hyperglycemia and insulin resistance and inversely correlated with insulin sensitivity (using the Matsuda whole-body insulin sensitivity index assessment of insulin sensitivity) and ß-cell function (disposition index 30 and disposition index 120). The fibrosis levels of the OB group were the highest out of the three groups, whereas the fibrosis levels of T2DM individuals were lower than the OB group but higher than the NGT group. Although fibrosis was negatively correlated with T2DM, fibrosis deposition was not remarkably associated with impaired systemic insulin sensitivity and glucose metabolism. CONCLUSIONS: Compared with fibrosis deposition, adipocyte hypertrophy is more closely associated with T2DM and impaired systemic insulin sensitivity.

Inkjet Bioprinting of Biomaterials.

The inkjet technique has the capability of generating droplets in the picoliter volume range, firing thousands of times in a few seconds and printing in the noncontact manner. Since its emergence, inkjet technology has been widely utilized in the publishing industry for printing of text and pictures. As the technology developed, its applications have been expanded from two-dimensional (2D) to three-dimensional (3D) and even used to fabricate components of electronic devices. At the end of the twentieth century, researchers were aware of the potential value of this technology in life sciences and tissue engineering because its picoliter-level printing unit is suitable for depositing biological components. Currently inkjet technology has been becoming a practical tool in modern medicine serving for drug development, scaffold building, and cell depositing. In this article, we first review the history, principles and different methods of developing this technology. Next, we focus on the recent achievements of inkjet printing in the biological field. Inkjet bioprinting of generic biomaterials, biomacromolecules, DNAs, and cells and their major applications are introduced in order of increasing complexity. The current limitations/challenges and corresponding solutions of this technology are also discussed. A new concept, biopixels, is put forward with a combination of the key characteristics of inkjet printing and basic biological units to bring a comprehensive view on inkjet-based bioprinting. Finally, a roadmap of the entire 3D bioprinting is depicted at the end of this review article, clearly demonstrating the past, present, and future of 3D bioprinting and our current progress in this field.

Distribution, Morphological Characterization, and Resiniferatoxin-Susceptibility of Sensory Neurons That Innervate Rat Perirenal Adipose Tissue.

Perirenal adipose tissue (PrAT) is a visceral adipose tissue involved in the pathogenesis of obesity and cardiovascular diseases via neural pathways. However, the origins, morphological characterization, and resiniferatoxin (RTX)-susceptibility of sensory neurons that innervate rat PrAT are yet unclear. Using neural tracing, an injection of DiI (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate) into PrAT revealed that sensory neurons that innervate PrAT reside in T9-L3 dorsal root ganglia (DRG). Peak labeling occurred in T13 and L1 DRGs. Two distinct peaks were observed in cross-sectional areas of the labeled soma, and the mean cross-sectional area was 717.1 ± 27.7 µm2. Immunofluorescence staining for transient receptor potential cation channel subfamily V member 1 (TRPV1) separated DiI-positive neurons into three subpopulations: small TRPV1-negative, small TRPV1-positive, and large TRPV1-negative. Furthermore, the injection of RTX into PrAT reduced labeled cells by 36.7% where TRPV1-positive cells were the main target of RTX denervation. These novel findings provide a structural basis for future TRPV1-dependent and TRPV1-independent studies on the sensory innervation of PrAT, which may be of interest for future therapeutic obesity treatment and intervention.

Perirenal Fat: A Unique Fat Pad and Potential Target for Cardiovascular Disease.

Although visceral obesity is recognized as a risk factor for cardiovascular diseases (CVDs), the efficacy of omental fat removal in CVD treatment is still controversial. There is a need to identify other visceral fat depots for CVD management. This review aims to provide a summary on perirenal fat as an important risk factor for CVD. Studies on epidemiology, anatomy, and function of perirenal fat were reviewed. Observational studies in humans suggest that excessive perirenal fat increases the risk of hypertension and coronary heart disease. Anatomy studies prove that perirenal fat is unique compared to other connective tissues in that it is well vascularized, innervated, and drains into the lymphatic system. Other special morphological features include a complete fascia border, sympathetic-independent development of architecture, and proximity to the kidneys. Based on these anatomical features, perirenal fat regulates the cardiovascular system presumably via neural reflex, adipokine secretion, and fat-kidney interaction. These new insights suggest that perirenal fat may constitute a promising target for CVD management.

A Novel Strategy for Creating Tissue-Engineered Biomimetic Blood Vessels Using 3D Bioprinting Technology.

In this work, a novel strategy was developed to fabricate prevascularized cell-layer blood vessels in thick tissues and small-diameter blood vessel substitutes using three-dimensional (3D) bioprinting technology. These thick vascularized tissues were comprised of cells, a decellularized extracellular matrix (dECM), and a vasculature of multilevel sizes and multibranch architectures. Pluronic F127 (PF 127) was used as a sacrificial material for the formation of the vasculature through a multi-nozzle 3D bioprinting system. After printing, Pluronic F127 was removed to obtain multilevel hollow channels for the attachment of human umbilical vein endothelial cells (HUVECs). To reconstruct functional small-diameter blood vessel substitutes, a supporting scaffold (SE1700) with a double-layer circular structure was first bioprinted. Human aortic vascular smooth muscle cells (HA-VSMCs), HUVECs, and human dermal fibroblasts⁻neonatal (HDF-n) were separately used to form the media, intima, and adventitia through perfusion into the corresponding location of the supporting scaffold. In particular, the dECM was used as the matrix of the small-diameter blood vessel substitutes. After culture in vitro for 48 h, fluorescent images revealed that cells maintained their viability and that the samples maintained structural integrity. In addition, we analyzed the mechanical properties of the printed scaffold and found that its elastic modulus approximated that of the natural aorta. These findings demonstrate the feasibility of fabricating different kinds of vessels to imitate the structure and function of the human vascular system using 3D bioprinting technology.

Alamandine attenuates hypertension and cardiac hypertrophy in hypertensive rats.

Oral administration of the peptide alamandine has antihypertensive and anti-fibrotic effects in rats. This work aimed to determine whether subcutaneous alamandine injection would attenuate hypertension and cardiac hypertrophy, and improve the function of a major target of hypertension-related damage, the left ventricle (LV), in spontaneously hypertensive rats (SHRs). This was examined in vivo in SHRs and normotensive rats subjected to 6-week subcutaneous infusion of alamandine or saline control, and in vitro in H9C2-derived and primary neonatal rat cardiomyocytes treated with angiotensin (Ang) II to model cardiac hypertrophy. Tail artery blood pressure measurement and transthoracic echocardiography showed that hypertension and impaired LV function in SHRs were ameliorated upon alamandine infusion. Alamandine administration also decreased the mass gains of heart and lung in SHRs, suppressed cardiomyocyte cross-sectional area expansion, and inhibited the mRNA levels of atrial natriuretic peptide and brain natriuretic peptide. The expression of alamandine receptor Mas-related G protein-coupled receptor, member D was increased in SHR hearts and in cardiomyocytes treated with Ang II. Alamandine inhibited the increases of protein kinase A (PKA) levels in the heart in SHRs and in cardiomyocytes treated with Ang II. In conclusion, the present study showed that alamandine administration attenuates hypertension, alleviates cardiac hypertrophy, and improves LV function. PKA signaling may be involved in the mechanisms underlying these effects.

Alamandine injected into the paraventricular nucleus increases blood pressure and sympathetic activation in spontaneously hypertensive rats.

Alamandine is a newly discovered new component of the renin-angiotensin (Ang) system (RAS) that has been shown to exert vasoactive effects in some areas of the nervous system. The present study investigated whether administration of alamandine to the hypothalamic paraventricular nucleus (PVN) modulates blood pressure and sympathetic activity. Mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) were recorded in anaesthetized rats. PVN microinjection of alamandine increased MAP and RSNA both in Wistar-Kyoto (WKY) rats and in spontaneously hypertensive rats (SHRs), but to a greater extent in SHRs. Moreover, these effects were blocked by pretreatment with alamandine receptor Mas-related G-protein-coupled receptor, member D (MrgD) antagonist D-Pro7-Ang-(1-7), adenylyl cyclase (AC) inhibitor SQ22536, and protein kinase A (PKA) inhibitor rp-adenosine-3',5'-cyclic monophosphorothionate (Rp-cAMP). Treatment with D-Pro7-Ang-(1-7), SQ22536, or Rp-cAMP alone in PVN decreased MAP and RSNA in the SHRs. Conversely cAMP alone increased MAP and RSNA, and pretreatment with cAMP enhanced alamandine's effects. These results indicate that microinjection of alamandine into the PVN increases blood pressure and sympathetic outflow via MrgD and the cAMP-PKA pathway.