Effective Penetration of a Liposomal Formulation of Bleomycin through Ex-Vivo Skin Explants from Two Different Species.

Bleomycin is a chemotherapy agent that, when administered systemically, can cause severe pulmonary toxicity. Bleosome is a novel formulation of bleomycin encapsulated in ultra-deformable (UD) liposomes that may be applicable as a topical chemotherapy for diseases such as non-melanoma skin cancer. To date, the ability of Bleosome to effectively penetrate through the skin has not been evaluated. In this study, we investigated the ability of Bleosome to penetrate through ex vivo skin explants from dogs and horses. We visualized the penetration of UD liposomes through the skin by transmission electron microscopy. However, to effectively image the drug itself we fluorescently labeled bleomycin prior to encapsulation within liposomes and utilized multiphoton microscopy. We showed that UD liposomes do not penetrate beyond the stratum corneum, whereas bleomycin is released from UD liposomes and can penetrate to the deeper layers of the epidermis. This is the first study to show that Bleosome can effectively penetrate through the skin. We speculate that UD liposomes are penetration enhancers in that UD liposomes carry bleomycin through the outer skin to the stratum corneum and then release the drug, allowing diffusion into the deeper layers. Our results are comparative in dogs and horses and warrant further studies on the efficacy of Bleosome as topical treatment.

Front roughening of flames in discrete media.

The morphology of flame fronts propagating in reactive systems composed of randomly positioned, pointlike sources is studied. The solution of the temperature field and the initiation of new sources is implemented using the superposition of the Green's function for the diffusion equation, eliminating the need to use finite-difference approximations. The heat released from triggered sources diffuses outward from each source, activating new sources and enabling a mechanism of flame propagation. Systems of 40000 sources in a 200×200 two-dimensional domain were tracked using computer simulations, and statistical ensembles of 120 realizations of each system were averaged to determine the statistical properties of the flame fronts. The reactive system of sources is parameterized by two nondimensional values: the heat release time (normalized by interparticle diffusion time) and the ignition temperature (normalized by adiabatic flame temperature). These two parameters were systematically varied for different simulations to investigate their influence on front propagation. For sufficiently fast heat release and low ignition temperature, the front roughness [defined as the root mean square deviation of the ignition temperature contour from the average flame position] grew following a power-law dependence that was in excellent agreement with the Kardar-Parisi-Zhang (KPZ) universality class (ß=1/3). As the reaction time was increased, lower values of the roughening exponent were observed, and at a sufficiently great value of reaction time, reversion to a steady, constant-width thermal flame was observed that matched the solution from classical combustion theory. Deviation away from KPZ scaling was also observed as the ignition temperature was increased. The features of this system that permit it to exhibit both KPZ and non-KPZ scaling are discussed.

Influence of discrete sources on detonation propagation in a Burgers equation analog system.

An analog to the equations of compressible flow that is based on the inviscid Burgers equation is utilized to investigate the effect of spatial discreteness of energy release on the propagation of a detonation wave. While the traditional Chapman-Jouguet (CJ) treatment of a detonation wave assumes that the energy release of the medium is homogeneous through space, the system examined here consists of sources represented by δ functions embedded in an otherwise inert medium. The sources are triggered by the passage of the leading shock wave following a delay that is either of fixed period or randomly generated. The solution for wave propagation through a large array (10^{3}-10^{4}) of sources in one dimension can be constructed without the use of a finite difference approximation by tracking the interaction of sawtooth-profiled waves for which an analytic solution is available. A detonation-like wave results from the interaction of the shock and rarefaction waves generated by the sources. The measurement of the average velocity of the leading shock front for systems of both regular, fixed-period and randomized sources is found to be in close agreement with the velocity of the equivalent CJ detonation in a uniform medium, wherein the sources have been spatially homogenized. This result may have implications for the applicability of the CJ criterion to detonations in highly heterogeneous media (e.g., polycrystalline, solid explosives) and unstable detonations with a transient and multidimensional structure (e.g., gaseous detonation waves).

Propagation limits and velocity of reaction-diffusion fronts in a system of discrete random sources.

The effect of spatially randomizing a system of pointlike sources on the propagation of reaction-diffusion fronts is investigated in multidimensions. The dynamics of the reactive front are modeled by superimposing the solutions for diffusion from a single point source. A nondimensional parameter is introduced to quantify the discreteness of the system, based on the characteristic reaction time of sources compared to the diffusion time between sources. The limits to propagation and the average velocity of propagation are expressed as probabilistic quantities to account for the influence of the randomly distributed sources. In random systems, two- and three-dimensional fronts are able to propagate beyond a limit previously found for systems with regularly distributed sources, while a propagation limit in one dimension that is independent of domain size cannot be defined. The dimensionality of the system is seen to have a strong influence on the front propagation velocity, with higher dimensional systems propagating faster than lower dimensional systems. In a three-dimensional system, both the limit to propagation and average front velocity revert to a solution that assumes a spatially continuous source function as the discreteness parameter is increased to the continuum limit. The results indicate that reactive systems are able to exploit local fluctuations in source concentration to extend propagation limits and increase the velocity in comparison to regularly spaced systems.

Formation of a disordered solid via a shock-induced transition in a dense particle suspension.

Shock wave propagation in multiphase media is typically dominated by the relative compressibility of the two components of the mixture. The difference in the compressibility of the components results in a shock-induced variation in the effective volume fraction of the suspension tending toward the random-close-packing limit for the system, and a disordered solid can take form within the suspension. The present study uses a Hugoniot-based model to demonstrate this variation in the volume fraction of the solid phase as well as a simple hard-sphere model to investigate the formation of disordered structures within uniaxially compressed model suspensions. Both models are discussed in terms of available experimental plate impact data in dense suspensions. Through coordination number statistics of the mesoscopic hard-sphere model, comparisons are made with the trends of the experimental pressure-volume fraction relationship to illustrate the role of these disordered structures in the bulk properties of the suspensions. A criterion for the dynamic stiffening of suspensions under high-rate dynamic loading is suggested as an analog to quasi-static jamming based on the results of the simulations.

Reaction-diffusion fronts in media with spatially discrete sources.

The exact solution for a reaction-diffusion front propagating in a heterogeneous system of discrete, point-like sources is obtained without resorting to a representation of the sources by a spatially continuous function. When the reaction time is smaller than the characteristic diffusion time between neighboring sources, the front speed predicted by this discrete source model differs from the continuum theory based on the spatial averaging of the heterogeneities. Furthermore, when the sources are regularly distributed in space, discreteness introduces a limit and propagation beyond this limit is only possible in a system with randomly distributed sources via local fluctuations of the concentration. The discrete regime of front propagation is observed experimentally in suspensions of iron particles burning in oxygen-xenon mixtures.