Deep Eutectic Liquids as a Topical Vehicle for Tadalafil: Characterisation and Potential Wound Healing and Antimicrobial Activity.

Deep eutectic solvents (DESs) and ionic liquids (ILs) offer novel opportunities for several pharmaceutical applications. Their tunable properties offer control over their design and applications. Choline chloride (CC)-based DESs (referred to as Type III eutectics) offer superior advantages for various pharmaceutical and therapeutic applications. Here, CC-based DESs of tadalafil (TDF), a selective phosphodiesterase type 5 (PDE-5) enzyme inhibitor, were designed for implementation in wound healing. The adopted approach provides formulations for the topical application of TDF, hence avoiding systemic exposure. To this end, the DESs were chosen based on their suitability for topical application. Then, DES formulations of TDF were prepared, yielding a tremendous increase in the equilibrium solubility of TDF. Lidocaine (LDC) was included in the formulation with TDF to provide a local anaesthetic effect, forming F01. The addition of propylene glycol (PG) to the formulation was attempted to reduce the viscosity, forming F02. The formulations were fully characterised using NMR, FTIR and DCS techniques. According to the obtained characterisation results, the drugs were soluble in the DES with no detectable degradation. Our results demonstrated the utility of F01 in wound healing in vivo using cut wound and burn wound models. Significant retraction of the cut wound area was observed within three weeks of the application of F01 when compared with DES. Furthermore, the utilisation of F01 resulted in less scarring of the burn wounds than any other group including the positive control, thus rendering it a candidate formula for burn dressing formulations. We demonstrated that the slower healing process associated with F01 resulted in less scarring potential. Lastly, the antimicrobial activity of the DES formulations was demonstrated against a panel of fungi and bacterial strains, thus providing a unique wound healing process via simultaneous prevention of wound infection. In conclusion, this work presents the design and application of a topical vehicle for TDF with novel biomedical applications.

Multiple Particle Manipulation under Dielectrophoresis Effect: Modeling and Experiments.

The dissipative particle dynamics (DPD) technique was employed to design multiple microfluidic devices for investigating the motion of bioparticles at low Reynolds numbers. A DPD in-house FORTRAN code was developed to simulate the trajectories of two microparticles in the presence of hydrodynamic and transverse deflecting force fields via considering interparticle interaction forces. The particle-particle interactions were described by using a simplified version of the Morse potential. The transverse deflecting force considered in this microfluidic application was the dielectrophoresis (DEP) force. Multiple microfluidic devices with different configurations of microelectrodes were numerically designed to investigate the dielectrophoretic behavior of bioparticles for their trajectories and the focusing of bioparticles into a single stream in the middle of the microchannel. The DPD simulation results were verified and validated against previously reported numerical and experimental works in the literature. The computationally designed microdevices were fabricated by employing standard lithographic techniques, and experiments were conducted via taking red blood cells as the representative bioparticles. The experimental results for the trajectories and focusing showed good agreement with the numerical results.

Dissipative particle dynamics for modeling micro-objects in microfluidics: application to dielectrophoresis.

The dissipative particle dynamics (DPD) technique is employed to model the trajectories of micro-objects in a practical microfluidic device. The simulation approach is first developed using an in-house Fortran code to model Stokes flow at Reynolds number of 0.01. The extremely low Reynolds number is achieved by adjusting the DPD parameters, such as force coefficients, thermal energies of the particles, and time steps. After matching the numerical flow profile with the analytical results, the technique is developed further to simulate the deflection of micro-objects under the effect of a deflecting external force in a rectangular microchannel. A mapping algorithm is introduced to establish the scaling relationship for the deflecting force between the physical device and the DPD domain. Dielectrophoresis is studied as a case study for the deflecting force, and the trajectory of a single red blood cell under the influence of the dielectrophoretic force is simulated. The device is fabricated using standard microfabrication techniques, and the experiments involving a dilute sample of red blood cells are performed at two different cases of the actuation voltage. Good agreement between the numerical and experimental results is achieved.

Investigation of DPD transport properties in modeling bioparticle motion under the effect of external forces: Low Reynolds number and high Schmidt scenarios.

We have used a dissipative particle dynamics (DPD) model to study the movement of microparticles in a microfluidic device at extremely low Reynolds number (Re). The particles, immersed in a medium, are transported in the microchannel by a flow force and deflected transversely by an external force along the way. An in-house Fortran code is developed to simulate a two-dimensional fluid flow using DPD at Re ≥ 0.0005, which is two orders of magnitude less than the minimum Re value previously reported in the DPD literature. The DPD flow profile is verified by comparing it with the exact solution of Hagen-Poiseuille flow. A bioparticle based on a rigid spring-bead model is introduced in the DPD fluid, and the employed model is verified via comparing the velocity profile past a stationary infinite cylinder against the profile obtained via the finite element method. Moreover, the drag force and drag coefficient on the stationary cylinder are also computed and compared with the reported literature results. Dielectrophoresis (DEP) is investigated as a case study for the proposed DPD model to compute the trajectories of red blood cells in a microfluidic device. A mapping mechanism to scale the external deflecting force from the physical to DPD domain is performed. We designed and built our own experimental setup with the aim to compare the experimental trajectories of cells in a microfluidic device to validate our DPD model. These experimental results are used to investigate the dependence of the trajectory results on the Reynolds number and the Schmidt number. The numerical results agree well with the experiment results, and it is found that the Schmidt number is not a significant parameter for the current application; Reynolds numbers combined with the DEP-to-drag force ratio are the only important parameters influencing the behavior of particles inside the microchannel.

One-dimensional slow invariant manifolds for spatially homogenous reactive systems.

A reactive system's slow dynamic behavior is approximated well by evolution on manifolds of dimension lower than that of the full composition space. This work addresses the construction of one-dimensional slow invariant manifolds for dynamical systems arising from modeling unsteady spatially homogeneous closed reactive systems. Additionally, the relation between the systems' slow dynamics, described by the constructed manifolds, and thermodynamics is clarified. It is shown that other than identifying the equilibrium state, traditional equilibrium thermodynamic potentials provide no guidance in constructing the systems' actual slow invariant manifolds. The construction technique is based on analyzing the composition space of the reactive system. The system's finite and infinite equilibria are calculated using a homotopy continuation method. The slow invariant manifolds are constructed by calculating attractive heteroclinic orbits which connect appropriate equilibria to the unique stable physical equilibrium point. Application of the method to several realistic reactive systems, including a detailed hydrogen-air kinetics model, reveals that constructing the actual slow invariant manifolds can be computationally efficient and algorithmically easy.