Metabolic Patterning on a Chip: Towards in vitro Liver Zonation of Primary Rat and Human Hepatocytes

An important number of healthy and diseased tissues shows spatial variations in their metabolic capacities across the tissue. The liver is a prime example of such heterogeneity where the gradual changes in various metabolic activities across the liver sinusoid is termed as “zonation” of the liver. Here, we introduce the Metabolic Patterning on a Chip (MPOC) platform capable of dynamically creating metabolic patterns across the length of a microchamber of liver tissue via actively enforced gradients of various metabolic modulators such as hormones and inducers. Using this platform, we were able to create continuous liver tissues of both rat and human origin with gradually changing metabolic activities. The gradients we have created in nitrogen, carbohydrate and xenobiotic metabolisms recapitulated an in vivo like zonation and zonal toxic response. Beyond its application in recapitulation of liver zonation in vitro as we demonstrate here, the MPOC platform can be used and expanded for a variety of purposes including better understanding of heterogeneity in many different tissues during developmental and adult stages

Progressive Hypoxia-on-a-chip: An In Vitro Oxygen Gradient Model for Capturing the Effects of Hypoxia on Primary Hepatocytes in Health and Disease

Oxygen is vital to the function of all tissues including the liver and lack of oxygen, that is, hypoxia can result in both acute and chronic injuries to the liver in vivo and ex vivo. Furthermore, a permanent oxygen gradient is naturally present along the liver sinusoid, which plays a role in the metabolic zonation and the pathophysiology of liver diseases. Accordingly, here, we introduce an in vitro microfluidic platform capable of actively creating a series of oxygen concentrations on a single continuous microtissue, ranging from normoxia to severe hypoxia. This range approximately captures both the physiologically relevant oxygen gradient generated from the portal vein to the central vein in the liver, and the severe hypoxia occurring in ischemia and liver diseases. Primary rat hepatocytes cultured in this microfluidic platform were exposed to an oxygen gradient of 0.3–6.9%. The establishment of an ascending hypoxia gradient in hepatocytes was confirmed in response to the decreasing oxygen supply. The hepatocyte viability in this platform decreased to approximately 80% along the hypoxia gradient. Simultaneously, a progressive increase in accumulation of reactive oxygen species and expression of hypoxia‐inducible factor 1α was observed with increasing hypoxia. These results demonstrate the induction of distinct metabolic and genetic responses in hepatocytes upon exposure to an oxygen (/hypoxia) gradient. This progressive hypoxia‐on‐a‐chip platform can be used to study the role of oxygen and hypoxia‐associated molecules in modeling healthy and injured liver tissues. Its use can be further expanded to the study of other hypoxic tissues such as tumors as well as the investigation of drug toxicity and efficacy under oxygen‐limited conditions

Extended mixed integer quadratic programming for simultaneous distributed generation location and network reconfiguration

Introduction. To minimise power loss, maintain the voltage within the acceptable range, and improve power quality in power distribution networks, reconfiguration and optimal distributed generation placement are presented. Power flow analysis and advanced optimization techniques that can handle significant combinatorial problems must be used in distribution network reconfiguration investigations. The optimization approach to be used depends on the size of the distribution network. Our methodology simultaneously addresses two nonlinear discrete optimization problems to construct an intelligent algorithm to identify the best solution. The proposed work is novel in that it the Extended Mixed-Integer Quadratic Programming (EMIQP) technique, a deterministic approach for determining the topology that will effectively minimize power losses in the distribution system by strategically sizing and positioning Distributed Generation (DG) while taking network reconfiguration into account. Using an efficient Quadratic Mixed Integer Programming (QMIP) solver (IBM ®), the resulting optimization problem has a quadratic form. To ascertain the range and impact of various variables, our methodology outperforms cutting-edge algorithms described in the literature in terms of the obtained power loss reduction, according to extensive numerical validation carried out on typical IEEE 33- and 69-bus systems at three different load factors. Practical value. Examining the effectiveness of concurrent reconfiguration and DG allocation versus sole reconfiguration is done using test cases. According to the findings, network reconfiguration along with the installation of a distributed generator in the proper location, at the proper size, with the proper loss level, and with a higher profile, is effective.  Вступ. Для мінімізації втрат потужності, підтримки напруги в допустимому діапазоні та покращення якості електроенергії у розподільчих мережах представлена реконфігурація та оптимальне розміщення розподіленої генерації. При дослідженнях реконфігурації розподільної мережі необхідно використовувати аналіз потоку потужності та передові методи оптимізації, які можуть вирішувати серйозні комбінаторні проблеми. Підхід до оптимізації, що використовується, залежить від розміру розподільної мережі. Наша методологія одночасно вирішує дві задачі нелінійної дискретної оптимізації, щоби побудувати інтелектуальний алгоритм для визначення найкращого рішення. Пропонована робота є новою, оскільки вона використовує метод розширеного змішано-цілочисельного квадратичного програмування (EMIQP), детермінований підхід до визначення топології, що ефективно мінімізує втрати потужності в системі розподілу за рахунок стратегічного визначення розмірів та позиціонування розподіленої генерації (DG) з урахуванням реконфігурації мережі. При використанні ефективного солвера Quadratic Mixed Integer Programming (QMIP) (IBM®) результуюча задача оптимізації має квадратичну форму. Щоб з'ясувати діапазон та вплив різних змінних, наша методологія перевершує передові алгоритми, описані в літературі, з точки зору одержаного зниження втрат потужності, згідно з великою числовою перевіркою, проведеною на типових системах з шинами IEEE 33 і 69 при трьох різних коефіцієнтах навантаження. Практична цінність. Вивчення ефективності одночасної реконфігурації та розподілу DG у порівнянні з єдиною реконфігурацією проводиться з використанням тестових прикладів. Відповідно до результатів, реконфігурація мережі разом із установкою розподіленого генератора в потрібному місці, належного розміру, з належним рівнем втрат і з більш високим профілем є ефективною

A Microfluidic Patterned Model of Non-Alcoholic Fatty Liver Disease: Applications to Disease Progression and Zonation

Non-alcoholic fatty liver disease (NAFLD) and its progressive form non-alcoholic steatohepatitis (NASH) affect 25% of the world population. NAFLD is predicted to soon become the main cause of liver morbidity and transplantation. The disease is characterized by a progressive increase of lipid accumulation in hepatocytes, which eventually induce fibrosis and inflammation, and can ultimately cause cirrhosis and hepatic carcinoma. Here, we created a patterned model of NAFLD on a chip using free fatty acid gradients to recapitulate a spectrum of disease conditions in a single continuous liver tissue. We established the NAFLD progression via quantification of intracellular lipid accumulation and transcriptional levels of fatty acid transporters and NAFLD pathogenesis markers. We then used this platform to create oxygen driven steatosis zonation mimicking the sinusoidal lipid distribution on a single continuous tissue and showed that this fat zonation disappears under progressed steatosis, in agreement with in vivo observations and recent computational studies. While we focus on free fatty acids and oxygen as the drivers of NAFLD, the microfluidic platform here is extensible to simultaneous use of other drivers

A Microfabricated Platform for Generating Physiologically-Relevant Hepatocyte Zonation

In vitro liver models have been important tools for more than 40 years for academic research and preclinical toxicity screening by the pharmaceutical industry. Hepatocytes, the highly metabolic parenchymal cells of the liver, are efficient at different metabolic chemistries depending on their relative spatial location along the sinusoid from the portal triad to the central vein. Although replicating hepatocyte metabolic zonation is vitally important for physiologically-relevant in vitro liver tissue and organ models, it is most often completely overlooked. Here, we demonstrate the creation of spatially-controlled zonation across multiple hepatocyte metabolism levels through the application of precise concentration gradients of exogenous hormone (insulin and glucagon) and chemical (3-methylcholanthrene) induction agents in a microfluidic device. Observed gradients in glycogen storage via periodic acid-Schiff staining, urea production via carbamoyl phosphatase synthetase I staining, and cell viability after exposure to allyl alcohol and acetaminophen demonstrated the in vitro creation of hepatocyte carbohydrate, nitrogen, alcohol degradation, and drug conjugation metabolic zonation. This type of advanced control system will be crucial for studies evaluating drug metabolism and toxicology using in vitro constructs

Extended mixed integer quadratic programming for simultaneous distributed generation location and network reconfiguration

Introduction. To minimise power loss, maintain the voltage within the acceptable range, and improve power quality in power distribution networks, reconfiguration and optimal distributed generation placement are presented. Power flow analysis and advanced optimization techniques that can handle significant combinatorial problems must be used in distribution network reconfiguration investigations. The optimization approach to be used depends on the size of the distribution network. Our methodology simultaneously addresses two nonlinear discrete optimization problems to construct an intelligent algorithm to identify the best solution. The proposed work is novel in that it the Extended Mixed-Integer Quadratic Programming (EMIQP) technique, a deterministic approach for determining the topology that will effectively minimize power losses in the distribution system by strategically sizing and positioning Distributed Generation (DG) while taking network reconfiguration into account. Using an efficient Quadratic Mixed Integer Programming (QMIP) solver (IBM ®), the resulting optimization problem has a quadratic form. To ascertain the range and impact of various variables, our methodology outperforms cutting-edge algorithms described in the literature in terms of the obtained power loss reduction, according to extensive numerical validation carried out on typical IEEE 33-and 69-bus systems at three different load factors. Practical value. Examining the effectiveness of concurrent reconfiguration and DG allocation versus sole reconfiguration is done using test cases. According to the findings, network reconfiguration along with the installation of a distributed generator in the proper location, at the proper size, with the proper loss level, and with a higher profile, is effective. References 24, table 4, figures 14

Size-controlled conformal nanofabrication of biotemplated three-dimensional TiO2 and ZnO nanonetworks

Cataloged from PDF version of article.A solvent-free fabrication of TiO2 and ZnO nanonetworks is demonstrated by using supramolecular nanotemplates with high coating conformity, uniformity, and atomic scale size control. Deposition of TiO2 and ZnO on three-dimensional nanofibrous network template is accomplished. Ultrafine control over nanotube diameter allows robust and systematic evaluation of the electrochemical properties of TiO2 and ZnO nanonetworks in terms of size-function relationship. We observe hypsochromic shift in UV absorbance maxima correlated with decrease in wall thickness of the nanotubes. Photocatalytic activities of anatase TiO2 and hexagonal wurtzite ZnO nanonetworks are found to be dependent on both the wall thickness and total surface area per unit of mass. Wall thickness has effect on photoexcitation properties of both TiO2 and ZnO due to band gap energies and total surface area per unit of mass. The present work is a successful example that concentrates on nanofabrication of intact three-dimensional semiconductor nanonetworks with controlled band gap energies

The design and fabrication of supramolecular semiconductor nanowires formed by benzothienobenzothiophene (BTBT)-conjugated peptides

π-Conjugated small molecules based on a [1]benzothieno[3,2-b]benzothiophene (BTBT) unit are of great research interest in the development of solution-processable semiconducting materials owing to their excellent charge-transport characteristics. However, the BTBT π-core has yet to be demonstrated in the form of electro-active one-dimensional (1D) nanowires that are self-assembled in aqueous media for potential use in bioelectronics and tissue engineering. Here we report the design, synthesis, and self-assembly of benzothienobenzothiophene (BTBT)–peptide conjugates, the BTBT–peptide (BTBT-C3–COHN-Ahx-VVAGKK-Am) and the C8-BTBT–peptide (C8-BTBT-C3–COHN-Ahx-VVAGKK-Am), as β-sheet forming amphiphilic molecules, which self-assemble into highly uniform nanofibers in water with diameters of 11–13(±1) nm and micron-size lengths. Spectroscopic characterization studies demonstrate the J-type π–π interactions among the BTBT molecules within the hydrophobic core of the self-assembled nanofibers yielding an electrical conductivity as high as 6.0 × 10−6 S cm−1. The BTBT π-core is demonstrated, for the first time, in the formation of self-assembled peptide 1D nanostructures in aqueous media for potential use in tissue engineering, bioelectronics and (opto)electronics. The conductivity achieved here is one of the highest reported to date in a non-doped state