Mixed Poloxamer Nanomicelles for the Anticonvulsant Lamotrigine Drug: Solubility, Micellar Characterization, and In-Vitro Release Studies

Recently the applications of Poloxamers in drug development is promising as it facilitated the drug molecule for delivering to the correct place, at the correct time and in the correct amount. Poloxamers can form nanomicelles to encapsulate hydrophobic drugs in order to increase solubility, stability and facilitate delivery at target. In this context, the solubilization of anticonvulsant lamotrigine (LMN) drug in a chain of Poloxamers containing different polyethylene oxide and polypropylene oxide noieties were examined. The results showed better solubilization of LMN in Poloxamers contain low CMTs while poor with Poloxamers having high CMTs. Systematic investigation of two mixed Poloxamer nanomicelles (P407:P403 and P407:P105) for LMN bioavailability at body temperature (37 °C) were investigated. The solubility of LMN was enhanced in mixed P407:P403 nanomicelles with the amount of P403 and reduced in mixed P407:P105 nanomicelles with the amount of P105. LMN encapsulated mixed Poloxamer nanomicelles were found spherical in shape with ~25 nm Dh sizes. The In-Vitro release profiles of mixed Poloxamer nanomicelles demonstrated the biphasic model with initial burst release and then slowly release of LMN. Better biocompatibility of LMN in the mixed P407:P403 nanomicelles was confirmed with stability data. The results of this work were proven the mixed P407:P403 nanomicelles as efficient nanocarriers for LMN.

Caspase inhibition prolongs inflammation by promoting a signaling complex with activated RIPK1

Activation of inflammation by lipopolysaccharide (LPS) is an important innate immune response. Here we investigated the contribution of caspases to the LPS-mediated inflammatory response and discovered distinctive temporal roles of RIPK1 in mediating proinflammatory cytokine production when caspases are inhibited. We propose a biphasic model that differentiates the role of RIPK1 in early versus late phase. The early production of proinflammation cytokines stimulated by LPS with caspase inhibition is mediated by the NF-κB pathway that requires the scaffold function of RIPK1 but is kinase independent. Autocrine production of TNFα in the late phase promotes the formation of a novel TNFR1-associated complex with activated RIPK1, FADD, caspase-8, and key mediators of NF-κB signaling. The production of proinflammatory cytokines in the late phase can be blocked by RIPK1 kinase inhibitor Nec-1s. Our study demonstrates a mechanism by which the activation of RIPK1 promotes its own scaffold function to regulate the NF-κB–mediated proinflammatory cytokine production that is negatively regulated by caspases to restrain inflammatory signaling.

Comparison of the Trueness of Fits of the Biphasic Transverse Isotropic and Kelvin Models to the Tensile Behavior of Temporomandibular Joint Disc

This technical brief explores the validity and trueness of fit for using the transverse isotropic biphasic and Kelvin models (first and second order generalized) for characterization of the viscoelastic tensile properties of the temporomandibular joint (TMJ) discs from pigs and goats at a strain rate of 10 mm/min. We performed incremental stress-relaxation tests from 0 to 12% strain, in 4% strain steps on pig TMJ disc samples. In addition, to compare the outcomes of these models between species, we also performed a single-step stress-relaxation test of 10% strain. The transverse isotropic biphasic model yielded reliable fits in reference to the least root mean squared error method only at low strain, while the Kelvin models yielded good fits at both low and high strain, with the second order generalized Kelvin model yielding the best fit. When comparing pig to goat TMJ disc in 10% strain stress-relaxation test, unlike the other two Kelvin models, the transverse isotropic model did not fit well for this larger step. In conclusion, the second order Kelvin model showed the best fits to the experimental data of both species. The transverse isotropic biphasic model did not fit well with the experimental data, although better at low strain, suggesting that the assumption of water flow only applies while uncrimping the collagen fibers. Thus, it is likely that the permeability from the biphasic model is not truly representative, and other biphasic models, such as the poroviscoelastic model, would likely yield more meaningful outputs and should be explored in future works.

Model order reduction for deformable porous materials in thin domains via asymptotic analysis

We study fluid-saturated porous materials that undergo poro-elastic deformations in thin domains. The mechanics in such materials are described using a biphasic model based on the theory of porous media (TPM) and consisting of a system of differential equations for material’s displacement and fluid’s pressure. These equations are in general strongly coupled and nonlinear, such that exact solutions are hard to obtain and numerical solutions are computationally expensive. This paper reduces the complexity of the biphasic model in thin domains with a scale separation between domain’s width and length. Based on standard asymptotic analysis, we derive a reduced model that combines two sub-models. Firstly, a limit model consists of averaged equations that describe the fluid pore pressure and displacement in the longitudinal direction of the domain. Secondly, a corrector model re-captures the mechanics in the transverse direction. The validity of the reduced model is finally tested using a set of numerical examples. These demonstrate the computational efficiency of the reduced model, while maintaining reliable solutions in comparison with original biphasic TPM model in thin domain.

A biphasic multilayer computational model of human skin

The present study investigates the layer-specific mechanical behavior of human skin. Motivated by skin’s histology, a biphasic model is proposed which differentiates between epidermis, papillary and reticular dermis, and hypodermis. Inverse analysis of ex vivo tensile and in vivo suction experiments yields mechanical parameters for each layer and predicts a stiff reticular dermis and successively softer papillary dermis, epidermis and hypodermis. Layer-specific analysis of simulations underlines the dominating role of the reticular dermis in tensile loading. Furthermore, it shows that the observed out-of-plane deflection in ex vivo tensile tests is a direct consequence of the layered structure of skin. In in vivo suction experiments, the softer upper layers strongly influence the mechanical response, whose dissipative part is determined by interstitial fluid redistribution within the tissue. Magnetic resonance imaging-based visualization of skin deformation in suction experiments confirms the deformation pattern predicted by the multilayer model, showing a consistent decrease in dermal thickness for large probe opening diameters.

Numerical Study of Lymph Mechanics

Methods taken from engineering and computer science were applied to the lymphatic system. Starting with a 3D analysis of a single subject-specific lymphatic valve. A mechanism was presented to explain previous experimental results showing the effect of trans-mural pressure on the pressure required to close lymphatic valves. The impor-tance of wall motion in future FSI studies of lymphatic valve dynamics were identified. Previous approaches to lumped modelling of the lymphatic system were considered and modifications were proposed. A less-idealised valve model, incorporating trans-mural dependent bias, was proposed as well as a method of allowing self-organised contrac-tion through a stretch-dependent frequency of contraction. A network of the superficial lymphatics of the upper-limb was reconstructed from an anatomical sketch. The net-work was used in conjunction with the lumped model to produce a 421 vessel lymphatic model consisting of 17,706 lymphangions. Several issues which impede large network scale modelling of the lymphatic system are identified. A simplified patient-specific biphasic model of lymphoedema was proposed and used to develop a novel shape-based metric for lymphoedema. A statistically significant relationship between the metric and the presence of lymphoedema was found.

Incorporating environmental factors to describe wild radish (Raphanus raphanistrum) seedling emergence and plant phenology

Wild radish (Raphanus raphanistrum L.) is a weed found globally in agricultural systems. The facultative winter annual nature of this plant and high genetic variability makes modeling its growth and phenology difficult. In the present study, R. raphanistrum natural seedbanks exhibited a biphasic pattern of emergence, with emergence peaks occurring in both fall and spring. Traditional sigmoidal models were inadequate to fit this pattern, regardless of the predictive environmental variable, and a corresponding biphasic model (sigmoidal + Weibull) was used to describe emergence based on the best parameters. Each best-fit chronological, thermal, and hydrothermal model accounted for at least 85% of the variation of the validation data. Observations on phenology progression from four cohorts were used to create a common model that described all cohorts adequately. Different phenological stages were described using chronological, thermal, hydrothermal, daylength-dependent thermal time, and daylength-dependent hydrothermal time. Integrating daylength and temperature into the models was important for predicting reproductive stages of R. raphanistrum.

Biomechanical modelling of spinal tumour anisotropic growth

Biomechanical abnormalities of solid tumours involve stiffening of the tissue and accumulation of mechanical stresses. Both abnormalities affect cancer cell proliferation and invasiveness and thus, play a crucial role in tumour morphology and metastasis. Even though, it has been known for more than two decades that high mechanical stresses reduce cancer cell proliferation rates driving growth towards low-stress regions, most biomechanical models of tumour growth account for isotropic growth. This cannot be valid, however, in tumours that grow within multiple host tissues of different mechanical properties, such as the spine. In these cases, structural heterogeneity would result in anisotropic growth of tumours. To this end, we present a biomechanical, biphasic model for anisotropic growth of spinal tumours. The model that accounts for both the fluid and the solid phase of the tumour was used to predict the evolution of solid stress and interstitial fluid pressure in intramedullary spinal tumours and highlight the differences between isotropic and anisotropic growth. Varying the degree of anisotropy, we found considerable differences in the shape of the tumours, leading to tumours of more realistic ellipsoidal shapes.

Kinetics of ascorbic acid loss during thermal treatment in different pH buffer solutions and the presence of oxygen

Ascorbic acid stability is greatly influenced by temperature, oxygen content. Both exposures to oxygen and prolonged heating in the presence of oxygen destroy ascorbic acid. Thermal degradation kinetics of ascorbic acid in sodium acetate buffer (0.2 M, pH 5.0) and sodium phosphate buffer (0.1 M, pH 7.0) were studied at the temperature range of 80 to 100°C and the different molar ratio between oxygen and ascorbic acid. The obtained results showed that the decrease in AA concentration as a function of time at constant temperature occurred in two phases. The biphasic model was used to describe the loss of AA in aqueous solution due to thermal treatment. The AA degradation had occurred during thermal processing probably due to oxidation (aerobic degradation). When the oxygen was totally used up, the anaerobic degradation dominated and took place much more slowly than aerobic degradation. At low AA concentration (≈0.28 mM) and an oxygen concentration of 0.25 mM, most of the degradation of AA occurred under aerobic conditions, however, AA was further degraded through an anaerobic pathway at a higher ratio of AA to oxygen concentration [0.57:0.25 (mM:mM) and 1.42:0.25 (mM:mM)]. The estimated activated energy Ea values, the temperature sensitivity of the kvalues was lower at pH 7.0 than at pH 5.0. Studying the degradation of ascorbic in a model system is essential in order to fully understood and applied effectively in food products processing.