Mathematical modeling of transdermal delivery of topical drug formulations in a dynamic microfluidic diffusion chamber in health and disease.

Mathematical models of epidermal and dermal transport are essential for optimization and development of products for percutaneous delivery both for local and systemic indication and for evaluation of dermal exposure to chemicals for assessing their toxicity. These models often help directly by providing information on the rate of drug penetration through the skin and thus on the dermal or systemic concentration of drugs which is the base of their pharmacological effect. The simulations are also helpful in analyzing experimental data, reducing the number of experiments and translating the in vitro investigations to an in-vivo setting. In this study skin penetration of topically administered caffeine cream was investigated in a skin-on-a-chip microfluidic diffusion chamber at room temperature and at 32°C. Also the transdermal penetration of caffeine in healthy and diseased conditions was compared in mouse skins from intact, psoriatic and allergic animals. In the last experimental setup dexamethasone, indomethacin, piroxicam and diclofenac were examined as a cream formulation for absorption across the dermal barrier. All the measured data were used for making mathematical simulation in a three-compartmental model. The calculated and measured results showed a good match, which findings indicate that our mathematical model might be applied for prediction of drug delivery through the skin under different circumstances and for various drugs in the novel, miniaturized diffusion chamber.

A Kinetic Finite Volume Discretization of the Multidimensional PIDE Model for Gene Regulatory Networks.

In this paper, a finite volume discretization scheme for partial integro-differential equations (PIDEs) describing the temporal evolution of protein distribution in gene regulatory networks is proposed. It is shown that the obtained set of ODEs can be formally represented as a compartmental kinetic system with a strongly connected reaction graph. This allows the application of the theory of nonnegative and compartmental systems for the qualitative analysis of the approximating dynamics. In this framework, it is straightforward to show the existence, uniqueness and stability of equilibria. Moreover, the computation of the stationary probability distribution can be traced back to the solution of linear equations. The discretization scheme is presented for one and multiple dimensional models separately. Illustrative computational examples show the precision of the approach, and good agreement with previous results in the literature.

Persistence and stability of generalized ribosome flow models with time-varying transition rates.

In this paper some important qualitative dynamical properties of generalized ribosome flow models are studied. Ribosome flow models known from the literature are generalized by allowing an arbitrary directed network structure between compartments, and by assuming general time-varying rate functions corresponding to the transitions. Persistence of the dynamics is shown using the chemical reaction network (CRN) representation of the system where the state variables correspond to ribosome density and the amount of free space in the compartments. The L1 contractivity of solutions is also proved in the case of periodic reaction rates having the same period. Further we prove the stability of different compartmental structures including strongly connected ones with entropy-like logarithmic Lyapunov functions through embedding the model into a weakly reversible CRN with time-varying reaction rates in a reduced state space. Moreover, it is shown that different Lyapunov functions may be assigned to the same model depending on the non-unique factorization of the reaction rates. The results are illustrated through several examples with biological meaning including the classical ribosome flow model on a ring.