APOE mediated neuroinflammation and neurodegeneration in Alzheimer\u27s disease

Neuroinflammation is a central mechanism involved in neurodegeneration as observed in Alzheimer\u27s disease (AD), the most prevalent form of neurodegenerative disease. Apolipoprotein E4 (APOE4), the strongest genetic risk factor for AD, directly influences disease onset and progression by interacting with the major pathological hallmarks of AD including amyloid-β plaques, neurofibrillary tau tangles, as well as neuroinflammation. Microglia and astrocytes, the two major immune cells in the brain, exist in an immune-vigilant state providing immunological defense as well as housekeeping functions that promote neuronal well-being. It is becoming increasingly evident that under disease conditions, these immune cells become progressively dysfunctional in regulating metabolic and immunoregulatory pathways, thereby promoting chronic inflammation-induced neurodegeneration. Here, we review and discuss how APOE and specifically APOE4 directly influences amyloid-β and tau pathology, and disrupts microglial as well as astroglial immunomodulating functions leading to chronic inflammation that contributes to neurodegeneration in AD

Investigating the particle to fibre transition threshold during electrohydrodynamic atomization of a polymer solution

Electrohydrodynamic atomization (EHDA) is a key research area for producing micro and nano-sized structures. This process can be categorized into two main operating regimes: electrospraying for particle generation and electrospinning for fibre production. Producing particles/fibres of the desired size or morphology depends on two main factors; properties of the polymeric solution used and the processing conditions including flow rate, applied voltage and collection distance. In this work the particle-fibre transition region was analyzed by changing the polymer concentration of PLGA poly (lactic-co-glycolic acid) in acetone between 2 and 25wt%. Subsequently the processing conditions were adjusted to study the optimum transition parameters. Additionally the EHDA configuration was also modified by adding a metallic plate to observe the deposition area. The diameter and the distance of the plate from the capillary tip were adjusted to investigate variations in particle and fibre morphologies as well. It was found that complete transition from particles to fibres occurs at 20wt% indicating concentration to be the dominant criterion. Low flow rates yielded fibres without beads. However the applied voltage and distance between the tip of the nozzle jetting the polymer solution and collector (working distance) did not yield definitive results. Reducing the collector distance and increasing applied voltages produces smooth as well as beaded fibres. Addition of a metal plate reduces particle size by ~1μm; the fibre size increases especially with increasing plate diameter while bead density and size reduces when the disc is fixed closer to the capillary tip. Additionally, the deposition area is reduced by 70% and 57% with the addition of metal plates of 30mm and 60mm, respectively. The results indicate that a metal plate can be utilized further to tune the particle/fibre size and morphology and this also significantly increases the yield of EHDA process which is currently a limitation in adopting it as a mass production technique

Combining microfluidic devices with coarse capillaries to reduce the size of monodisperse microbubbles

In this work we report a significant advance for the preparation of monodispersed microbubbles, which are increasingly used and have become a key constituent in many advanced technologies. A new device comprising of two T-junctions containing coarse capillaries and operating in series was assembled. Microbubble generation was facilitated by using bovine serum albumin solution and nitrogen as the liquid and the gas phase, respectively. The effect of operating parameters such as gas pressure and liquid flow rate on the size of the microbubbles generated were investigated for the two T-junction systems and the results were compared with a single T-junction process. The experimental results showed that microbubbles produced via the double T-junction setup were smaller at any given gas pressure for both liquid flow rates of 100 and 200 μm studied in this work. A predictive model is developed from the experimental data, and the number of T-junctions was incorporated into this scaling model. It was demonstrated that the diameter of the monodisperse microbubbles generated can be tailored using multiple T-junctions while the operating parameters such as gas pressure and liquid flow rates were kept constant. The stability of the microbubbles produced was also examined and indicated that microbubbles produced through the double T-junction were more stable

Micro- and Nanomanufacturing for Biomedical Applications and Nanomedicine: A Perspective

Almost a century's dedicated research into micro- and nanomaterials has yielded fruitful development of preparation methods, achieving fine control over product properties among a broad spectrum of materials. One critical application of these materials lies within the healthcare sector for diagnostic, prophylactic, and therapeutic purposes. However, bench-to-bedside translations are still hindered by some unmet demands, especially the scaling-up from lab-scale preparation to industry-level production. The current review recapitulates the strategies of micro- and nanomaterial preparation from a holistic viewpoint. The similarities in synthesis and processing methods for various types of materials are highlighted. Furthermore, patents of commercialized nanomedicines are revisited to reveal a solid progress of micro- and nanomanufacturing in the last decade. In conclusion, further interdisciplinary research between fields in materials manufacturing is beneficial for the clinical translation and eventually unleashing the power of materials at small dimensions

Preparation of monodisperse microbubbles in a capillary embedded T-Junction device and the influence of process control parameters on bubble size and stability

The main goal for this work was to produce microbubbles for a wide range of applications with sizes ranging between 10 to 300 μm in a capillary embedded Tjunction device. Initially the bubble formation process was characterized and the factors that affected the bubble size; in particular the parameters that reduce it were determined. In this work, a polydimethylsiloxane (PDMS) block (100 x 100 x 10 mm3) was used, in which the T-shaped junction was created by embedded capillaries of fixed outer diameter. The effect of the inner diameter was investigated by varying all the inlet and outlet capillaries’ inner diameter at different stages. In addition, the effect of changes in the continuous phase viscosity and flow rate (Ql) as well as the gas pressure (Pg) on the resulting bubble size was studied. Aqueous glycerol solutions were chosen for the liquid phase, as they are widely used in experimental studies of flow phenomena and provide a simple method of varying properties through dilution. In addition, the viscosity could be varied without significantly changing the surface tension and density of the solutions. The experimental data were then compared with empirical data derived from scaling models proposed in literature, which is widely used and accepted as a basis of comparison among investigators. While the role of liquid viscosity was investigated by these authors, it was not directly incorporated in the scaling models proposed and therefore the effect of viscosity was also studied experimentally. It was found that bubble formation was influenced by both the ratio of liquid to gas flow rate and the capillary number. Furthermore, the effect of various surfactant types and concentrations on the bubble formation and stability were investigated. Preliminary studies with the current T-junction set-up indicated that producing microbubbles with size ranging from 50-300 μm was achievable. Subsequently, the study progressed to optimise the junction to produce smaller bubbles (~ 20 μm) by directly introducing an electric field to the T-junction set-up and assisting the bubble breakup with the combination of microfluidic and electrohydrodynamic focusing techniques. Finally, in this thesis, a novel method that combines microfluidics with electrohydrodynamic (EHD) processing to produce porous BSA scaffolds from microbubble templates with functional particles and/or fibres incorporated into the scaffolds’ structure is presented

Novel preparation of controlled porosity particle/fibre loaded scaffolds using a hybrid micro-fluidic and electrohydrodynamic technique.

The purpose of this research was to produce multi-dimensional scaffolds containing biocompatible particles and fibres. To achieve this, two techniques were combined and used: T-Junction microfluidics and electrohydrodynamic (EHD) processing. The former was used to form layers of monodispersed bovine serum albumin (BSA) bubbles, which upon drying formed porous scaffolds. By altering the T-Junction processing parameters, bubbles with different diameters were produced and hence the scaffold porosity could be controlled. EHD processing was used to spray or spin poly(lactic-co-glycolic) (PLGA), polymethysilsesquioxane (PMSQ) and collagen particles/fibres onto the scaffolds during their production and after drying. As a result, multifunctional BSA scaffolds with controlled porosity containing PLGA, PMSQ and collagen particles/fibres were obtained. Product morphology was studied by optical and scanning electron microscopy. These products have potential applications in many advanced biomedical, pharmaceutical and cosmetic fields e.g. bone regeneration, drug delivery, cosmetic cream lathers, facial scrubbing creams etc

Polymeric Nanocomposite Structures Based on Functionalized Graphene with Tunable Properties for Nervous Tissue Replacement

Electroconductive scaffolds can be a promising approach to repair conductive tissues when natural healing fails. Recently, nerve tissue engineering constructs have been widely investigated due to the challenges in creating a structure with optimized physiochemical and mechanical properties close to the native tissue. The goal of the current study was to fabricate graphene-containing polycaprolactone/gelatin/polypyrrole (PCL/gelatin/PPy) and polycaprolactone/polyglycerol-sebacate/polypyrrole (PCL/PGS/PPy) with intrinsic electrical properties through an electrospinning process. The effect of graphene on the properties of PCL/gelatin/PPy and PCL/PGS/PPy were investigated. Results demonstrated that graphene incorporation remarkably modulated the physical and mechanical properties of the scaffolds such that the electrical conductivity increased from 0.1 to 3.9 ± 0.3 S m–1 (from 0 to 3 wt % graphene) and toughness was found to be 76 MPa (PCL/gelatin/PPy 3 wt % graphene) and 143.4 MPa (PCL/PGS/PPy 3 wt % graphene). Also, the elastic moduli of the scaffolds with 0, 1, and 2 wt % graphene were reported as 210, 300, and 340 kPa in the PCL/gelatin/PPy system and 72, 85, and 92 kPa for the PCL/PGS/PPy system. A cell viability study demonstrated the noncytotoxic nature of the resultant scaffolds. The sum of the results presented in this study suggests that both PCL/gelatin/PPy/graphene and PCL/PGS/PPy/graphene compositions could be promising biomaterials for a range of conductive tissue replacement or regeneration applications

Core/shell microencapsulation of indomethacin/paracetamol by co-axial electrohydrodynamic atomization

Core/shell microparticles for development of drug delivery systems were prepared using co-axial electrohydrodynamic atomization technique in order to develop fixed dose combined formulations incorporating paracetamol and indomethacin as model drugs. The developed drug delivery systems offered successful co-encapsulation of paracetamol and indomethacin with high drug encapsulation efficiencies of 54% and 69% for paracetamol and indomethacin, respectively. The developed formulations were further characterised with respect to their morphology, drug release profile and possible interactions. In comparison to the release rate of the free indomethacin, the developed formulation resulted in enhanced dissolution rate of indomethacin. This study demonstrates a versatile polymeric platform where multiple drug encapsulation and co-delivery is made possible by utilizing co-axial electrohydrodynamic atomization. The proposed system offered high processing yield of 60–70%, as a single-step platform for preparation of fixed dose formulations for oral drug delivery, particularly in geriatric therapy

Latest developments in innovative manufacturing to combine nanotechnology with healthcare

Nanotechnology has become increasingly important in advancing the frontiers of many key areas of healthcare, for example, drug delivery and tissue engineering. To fully harness the many benefits of nanotechnology in healthcare, innovative manufacturing is necessary to mass produce nanoparticles and nanofibers, the two major types of nanofeatures currently sought after and of immense utilitarian value in healthcare. For example, nanoparticles are a key drug delivery enabler, the structural and mechanical mimicry are important attributes of nanofiber which are increasingly used as biomimetic agents

Grade Uncertainty and its Impact on Ore Grade Reconciliation between the Resource Model and the Mine

Major differences between estimated grade and actual grade are a usual problem in many open pit mines. The estimated grade is predicted in exploration stage from data obtained from boreholes, whereas the actual grade would be determined only after the mining operation. The poor reconciliation between the values of estimated and actual grades can cause major economic losses to the mining industry. Many different factors affect the reconciliation process in a mining operation. The nature of the orebody, the random uncertainty and the systematic errors are three main sources affecting the reconciliation process in exploration stage of the orebody. In this paper each source of uncertainty is studied and a probabilistic model is presented to determine the role of each item in total uncertainty of the grade parameter. The model ability was investigated in the study of real data taken from an iron open pit mine in Iran. The results showed the systematic uncertainty, the nature of the orebody and the random uncertainty are the main causes of poor reconciliation in the case study respectively