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Poly(lactic-co-glycolic acid) (PLGA) nanoparticle-based drug delivery systems are known to offer a plethora of potential therapeutic benefits. However, challenges related to large-scale manufacturing, such as the difficulty of reproducing complex formulations and high manufacturing costs, hinder their clinical and commercial development. In this context, a reliable manufacturing technique suitable for the scale-up production of nanoformulations without altering efficacy and safety profiles is highly needed. In this paper, we develop an inline sonication process and adapt it to the industrial scale production of immunomodulating PLGA nanovaccines developed using a batch sonication method at the laboratory scale. The investigated formulations contain three distinct synthetic peptides derived from the carcinogenic antigen New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) together with an invariant natural killer T-cell (iNKT) activator, threitolceramide-6 (IMM60). Process parameters were optimized to obtain polymeric nanovaccine formulations with a mean diameter of 150 ± 50 nm and a polydispersity index

Background: COVID-19 has caused a pandemic and is associated with significant mortality. The pathophysiology of COVID-19, affecting many organs and systems, is still being investigated. The hypothalamus, pituitary gland, and possibly adrenal glands are the targets of SARS-CoV-2 because of its angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) receptors expression. Hypocortisolemia can be seen in the postinfection period. COVID-19 infection tends to be severe in diabetic patients due to immune dysfunction. In this study, our aim was to investigate the relationship between basal cortisol levels and the course of COVID-19 infection in diabetic and non-diabetic patients. Methods: Our retrospective study included 311 PCR-positive COVID-19 patients over the age of 18 who were hospitalized in Ankara City Hospital Infectious Diseases Department or Intensive Care Unit (ICU) between 15 March 2020 and 15 May 2020. Serum basal cortisol, fasting plasma glucose (FPG), HbA1c values, and diabetes history were recorded within the first 24 h of hospitalization. The presence of pulmonary involvement was noted from the patients’ imaging records. Pregnant and breastfeeding women, patients with chronic liver disease or chronic kidney disease, and patients who were already using steroids or had started COVID-19 infection treatment within the 72 h before blood collection were excluded from the study. Results: Of the 311 patients, 100 had Type 2 Diabetes Mellitus (T2D), while 211 did not. The age, serum basal cortisol, and glucose levels of the patients with T2D (64.51 ± 12.29, 19.5 ± 13.12, and 143.5 (77–345)) were higher than those of the patients without T2D (46.67 ± 16.38, 15.26 ± 8.75, and 96 (65–202)), and the differences were statistically significant (p = 0.004, p = 0.004, and p < 0.001, respectively). The basal cortisol values of the ICU patients (27.89 (13.91–75)) were significantly higher than those of the ward patients (13.68 (1.48–51.93)) and patients who were transferred to the ICU from the ward due to worsening conditions (19.28 (7.74–55.21)) (p < 0.001 and p = 0.007, respectively). The factors affecting ICU admission were determined to be age, T2D history, basal cortisol, and elevation in FPG using univariate logistic regression analysis. In the multiple logistic regression analysis, age, basal cortisol level, and infiltrative involvement in thorax CT were determined to be the risk factors affecting intensive care admission. Conclusion: High basal cortisol levels in patients with T2D may predict the severity of COVID-19 infection or mortality. Although high basal cortisol levels are among the risk factors affecting ICU admission, patients with COVID-19 should also be evaluated in terms of clinical and laboratory findings and relative adrenal insufficiency.

Despite the efficacy and potential therapeutic benefits that poly(lactic-co-glycolic acid) (PLGA) nanomedicine formulations can offer, challenges related to large-scale processing hamper their clinical and commercial development. Major hurdles for the launch of a polymeric nanocarrier product on the market are batch-to-batch variations and lack of product consistency in scale-up manufacturing. Therefore, a scalable and robust manufacturing technique that allows for the transfer of nanomedicine production from the benchtop to an industrial scale is highly desirable. Downstream processes for purification, concentration, and storage of the nanomedicine formulations are equally indispensable. Here, we develop an inline sonication process for the production of polymeric PLGA nanomedicines at the industrial scale. The process and formulation parameters are optimized to obtain PLGA nanoparticles with a mean diameter of 150 ± 50 nm and a small polydispersity index (PDI < 0.2). Downstream processes based on tangential flow filtration (TFF) technology and lyophilization for the washing, concentration, and storage of formulations are also established and discussed. Using the developed manufacturing and downstream processing technologies, production of two PLGA nanoformulations encasing ritonavir and celecoxib was achieved at 84 g/h rate. As a measure of actual drug content, encapsulation efficiencies of 49.5 ± 3.2% and 80.3 ± 0.9% were achieved for ritonavir and celecoxib, respectively. When operated in-series, inline sonication and TFF can be adapted for fully continuous, industrial-scale processing of PLGA-based nanomedicines.

Discussions regarding the definition of Positive Energy Districts and the concept of a boundary are still being actively held. Even though there are certain initiatives working on the boundary limitations for PEDs, there is no methodology or tool developed for selecting peculiar spaces for future PED implementations. The paper focuses on a flexible GIS-based Multicriteria assessment method that identifies the most suitable areas to reach an annual positive non-renewable energy balance. For that purpose, a GIS-based tool is developed to indicate the boundary from an energy perspective harmonized with urban design and land-use planning. The method emphasizes evaluation through economic, social, political, legal, environmental, and technical criteria, and the results present the suitability of areas at macro and micro scales. The current study outlines macro-scale analyses in six European cities that represent Follower Cities under the MAKING-CITY H2020 project. Further research will be conducted for micro-scale analyses and the outcomes will pursue a technology selection process.

Polymeric particles made up of biodegradable and biocompatible polymers such as poly(lactic-co-glycolic acid) (PLGA) are promising tools for several biomedical applications including drug delivery. Particular emphasis is placed on the size and surface functionality of these systems as they are regarded as the main protagonists in dictating the particle behavior in vitro and in vivo. Current methods of manufacturing polymeric drug carriers offer a wide range of achievable particle sizes, however, they are unlikely to accurately control the size while maintaining the same production method and particle uniformity, as well as final production yield. Microfluidics technology has emerged as an efficient tool to manufacture particles in a highly controllable manner. Here, we report on tuning the size of PLGA particles at diameters ranging from sub-micron to microns using a single microfluidics device, and demonstrate how particle size influences the release characteristics, cellular uptake and in vivo clearance of these particles. Highly controlled production of PLGA particles with ~100 nm, ~200 nm, and >1000 nm diameter is achieved through modification of flow and formulation parameters. Efficiency of particle uptake by dendritic cells and myeloid-derived suppressor cells isolated from mice is strongly correlated with particle size and is most efficient for ~100 nm particles. Particles systemically administered to mice mainly accumulate in liver and ~100 nm particles are cleared slower. Our study shows the direct relation between particle size varied through microfluidics and the pharmacokinetics behavior of particles, which provides a further step towards the establishment of a customizable production process to generate tailor-made nanomedicines.

We propose a new type of CNT hydrogel that has unique conductive and reversible characteristics. We found in previous studies that CNT dispersions became gelatinous without any gelators when a specific CNT was combined with a specific dispersant. This hydrogel has conductive properties derived mainly from the CNTs it contains; and even after gelation, it can be returned to a liquid state by ultrasonic irradiation. Furthermore, the liquid is gelable again. In this study, we prepared several types of CNTs and several types of dispersants, experimentally verified the possibility of gelation by combining them, and geometrically investigated the gelation mechanism to determine how this unique hydrogel is formed. As a result, we found that the experimental results and the theory examined in this study were consistent with the combination of materials that actually become hydrogels. We expect that this study will allow us to anticipate whether or not an unknown combination of CNTs and dispersants will also become gelatinous.