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Implantable drug depots have the capacity to locally meet therapeutic requirements by maximizing local drug efficacy and minimizing potential systemic side effects. Tubular organs including the gastrointestinal tract, respiratory tract and vasculature all manifest with endoluminal disease. The anatomic distribution of localized drug delivery for these organs using existing therapeutic modalities is limited. Application of local depots in a circumferential and extended longitudinal fashion could transform our capacity to offer effective treatment across a range of conditions. Here we report the development and application of a kirigami-based stent platform to achieve this. The stents comprise a stretchable snake-skin-inspired kirigami shell integrated with a fluidically driven linear soft actuator. They have the capacity to deposit drug depots circumferentially and longitudinally in the tubular mucosa of the gastrointestinal tract across millimetre to multi-centimetre length scales, as well as in the vasculature and large airways. We characterize the mechanics of kirigami stents for injection, and their capacity to engage tissue in a controlled manner and deposit degradable microparticles loaded with therapeutics by evaluating these systems ex vivo and in vivo in swine. We anticipate such systems could be applied for a range of endoluminal diseases by simplifying dosing regimens while maximizing drug on-target effects through the sustained release of therapeutics and minimizing systemic side effects. A kirigami-inspired stent-based system has been developed for extended local drug delivery to the gastrointestinal and respiratory tracts as well as the vascular system.

A scalable, robust, and integrated differentiation platform for large‐scale production of human pluripotent stem cell‐cardiomyocyte (hPSC‐CM) in a stirred suspension bioreactor as a single‐unit operation was developed. This platform could become a valuable tool for mass production of functional hPSC‐CMs as a prerequisite for realizing their promising potential for therapeutic and industrial applications including drug discovery and toxicity assays. Recent advances in the generation of cardiomyocytes (CMs) from human pluripotent stem cells (hPSCs), in conjunction with the promising outcomes from preclinical and clinical studies, have raised new hopes for cardiac cell therapy. We report the development of a scalable, robust, and integrated differentiation platform for large‐scale production of hPSC‐CM aggregates in a stirred suspension bioreactor as a single‐unit operation. Precise modulation of the differentiation process by small molecule activation of WNT signaling, followed by inactivation of transforming growth factor‐β and WNT signaling and activation of sonic hedgehog signaling in hPSCs as size‐controlled aggregates led to the generation of approximately 100% beating CM spheroids containing virtually pure (∼90%) CMs in 10 days. Moreover, the developed differentiation strategy was universal, as demonstrated by testing multiple hPSC lines (5 human embryonic stem cell and 4 human inducible PSC lines) without cell sorting or selection. The produced hPSC‐CMs successfully expressed canonical lineage‐specific markers and showed high functionality, as demonstrated by microelectrode array and electrophysiology tests. This robust and universal platform could become a valuable tool for the mass production of functional hPSC‐CMs as a prerequisite for realizing their promising potential for therapeutic and industrial applications, including drug discovery and toxicity assays. Significance Recent advances in the generation of cardiomyocytes (CMs) from human pluripotent stem cells (hPSCs) and the development of novel cell therapy strategies using hPSC‐CMs (e.g., cardiac patches) in conjunction with promising preclinical and clinical studies, have raised new hopes for patients with end‐stage cardiovascular disease, which remains the leading cause of morbidity and mortality globally. In this study, a simplified, scalable, robust, and integrated differentiation platform was developed to generate clinical grade hPSC‐CMs as cell aggregates under chemically defined culture conditions. This approach resulted in approximately 100% beating CM spheroids with virtually pure (∼90%) functional cardiomyocytes in 10 days from multiple hPSC lines. This universal and robust bioprocessing platform can provide sufficient numbers of hPSC‐CMs for companies developing regenerative medicine technologies to rescue, replace, and help repair damaged heart tissues and for pharmaceutical companies developing advanced biologics and drugs for regeneration of lost heart tissue using high‐throughput technologies. It is believed that this technology can expedite clinical progress in these areas to achieve a meaningful impact on improving clinical outcomes, cost of care, and quality of life for those patients disabled and experiencing heart disease.

Current protocols for the scalable suspension culture of human pluripotent stem cells (hPSCs) are limited by multiple biological and technical challenges that need to be addressed before their use in clinical trials. To overcome these challenges, we have developed a novel bioprocess platform for large-scale expansion of human embryonic and induced pluripotent stem cell lines as three-dimensional size-controlled aggregates. This novel bioprocess utilizes the stepwise optimization of both static and dynamic suspension culture conditions. After screening eight xeno-free media in static suspension culture and optimizing single-cell passaging in dynamic conditions, the scale-up from a static to a dynamic suspension culture in the stirred bioreactor resulted in a two- to threefold improvement in expansion rates, as measured by cell counts and metabolic activity. We successfully produced size-specific aggregates through optimization of bioreactor hydrodynamic conditions by using combinations of different agitation rates and shear protectant concentrations. The expansion rates were further improved by controlling oxygen concentration at normoxic conditions, and reached a maximum eightfold increase for both types of hPSCs. Subsequently, we demonstrated a simple and rapid scale-up strategy that produced clinically relevant numbers of hPSCs (∼2×10 9 cells) over a 1-month period by the direct transfer of “suspension-adapted frozen cells” to a stirred suspension bioreactor. We omitted the required preadaptation passages in the static suspension culture. The cells underwent proliferation over multiple passages in the demonstrated xeno-free dynamic suspension culture while maintaining their self-renewal capabilities, as determined by marker expressions and in vitro spontaneous differentiation. In conclusion, suspension culture protocols of hPSCs could be used to mass produce homogenous and pluripotent undifferentiated cells by identification and optimization of key bioprocess parameters that are complemented by a simple and rapid scale-up platform.

The present study was set to develop a robust and economic biorefinery process for continuous co-production of ethanol and xylitol from rice straw in a membrane bioreactor. Acid pretreatment, enzymatic hydrolysis, detoxification, yeast strains selection, single and co-culture batch fermentation, and finally continuous co-fermentation were optimized. The combination of diluted acid pretreatment (3.5 %) and enzymatic conversion (1:10 enzyme (63 floating-point unit (FPU)/mL)/biomass ratio) resulted in the maximum sugar yield (81 % conversion). By concentrating the hydrolysates, sugars level increased by threefold while that of furfural reduced by 50 % (0.56 to 0.28 g/L). Combined application of active carbon and resin led to complete removal of furfural, hydroxyl methyl furfural, and acetic acid. The strains Saccharomyces cerevisiae NCIM 3090 with 66.4 g/L ethanol production and Candida tropicalis NCIM 3119 with 9.9 g/L xylitol production were selected. The maximum concentrations of ethanol and xylitol in the single cultures were recorded at 31.5 g/L (0.42 g/g yield) and 26.5 g/L (0.58 g/g yield), respectively. In the batch co-culture system, the ethanol and xylitol productions were 33.4 g/L (0.44 g/g yield) and 25.1 g/L (0.55 g/g yield), respectively. The maximum ethanol and xylitol volumetric productivity values in the batch co-culture system were 65 and 58 % after 25 and 60 h, but were improved in the continuous co-culture mode and reached 80 % (55 g/L) and 68 % (31 g/L) at the dilution rate of 0.03 L per hour, respectively. Hence, the continuous co-production strategy developed in this study could be recommended for producing value-added products from this hugely generated lignocellulosic waste.

Recently, application of ionic liquids due to their special solvency properties as a promising method of pretreatment for lignocellulosic biomass has received much attention. Chemical stability, temperature stability, non-flammability, low vapor pressure, wide liquidus range, and non-toxicity are among those unique properties. These solvents are also known as green solvents due to non-toxicity and low vapor pressure. The present study was set to compare the effect of five different ionic liquids namely, 1-ethyl-3-methyl imidazolium acetate, 1-ethyl-3-methyl imidazolium diethyl phosphate, 1-butyl-3-methyl imidazolium chlorides, 1,3-dimethyl imidazolium dimethyl phosphate, and 1-butyl-3-methylimidazolium-trifluoromethane sulfonate on barley straw in bioethanol production process. The performance of ionic liquids was evaluated based on the change observed in chemical structure, crystallinity index, and cellulose digestibility. Overall, 1-ethyl-3-methyl imidazolium acetate was found most effective in pretreating barely straw for bioethanol production. To the best of our knowledge, the present study reports different ionic liquids; some for the first time, for barely straw pretreatment.