Transport phenomena; bioactive surfaces; biological pores; transdermal transport
507 Furnas Hall
Buffalo NY, 14260
Phone: (716) 645-1182
Research addresses fundamental problems in the transport of molecules and particles in pores, near surfaces and in other types of heterogeneous environments, and the application of such basic theory to mechanistic understanding and technological development in biology and biomedical engineering.
Basic research focuses on the dynamics (“kinetic theory”) of configurational diffusion (rotation, stretching, bending) for nonspherical and flexible molecules. These types of Brownian motion have a particularly rich structure, both geometrically and physicochemically, when they occur in pores or near surfaces, and when they involve intermolecular forces, binding interactions or chemically reactive species. Specific problems studied are: (i) what is the macroscopically observable rate of diffusion and binding of a solute through a medium with a microscopically heterogeneous distribution of binding sites; (ii) how is the rate of a site-specific reaction affected when one of the reacting molecules is immobilized on a surface; and (iii) how do attractive and repulsive interactions with the wall affect the equilibrium distribution and diffusion of nonspherical and flexible molecules within fine pores?
The first biological application is a collaboration with Prof. Bruce J. Nicholson (Department of Biochemistry, University of Texas Health Sciences Center at San Antonio) aimed at understanding the permeability and selectivity properties of key intercellular pores called gap junctions, which are the primary means by which cells in the body exchange metabolites and signals. Although these pores were once thought to be simple aqueous conduits, it is now clear that they can, in fact, be highly selective in allowing different molecules to pass through them at different rates. Macroscopic modeling of intercellular diffusion is making it possible to convert macroscopic measurements of fluorescent dye transfer between cells into absolute values of permeability of individual channels. Microscopic theory of ion flow and molecular diffusion through these pores is being developed to explain the derived data on pore permeability.
The second application is related to theory for a collaborative investigation being pursued with Prof. Gerald B. Kasting (College of Pharmacy, University of Cincinnati) on drug and chemical transport through skin. The goal is to understand how fast applied agents pass through the skin, especially the outermost stratum corneum (barrier) layer, how and where they distribute themselves within tissue layers below the surface, and how fast they are absorbed into the blood stream through skin capillaries. Improved theoretical knowledge of these processes is key to the engineering of topical and transdermal drug delivery, as well as risk assessment of chemical exposure. Detailed diffusion models incorporating realistic representations of tissue microstructure, ultrastructure and physiochemical parameters are being developed to describe and predict: (i) permeability of the stratum corneum barrier; (ii) drug/chemical distribution in the epidermis, dermis and subcutaneous fat layers; (iii) systemic uptake by dermal capillaries; and (iv) drug distribution around hair follicles, and dermal permeability associated with follicles and other skin appendages.
Prof. Johannes M. Nitsche’s research is addressing two areas of pressing need in the field of dermal absorption — the study of how drugs and chemicals pass through the skin. The first area relates to the stark reality that models still cannot predict the time evolution of most drug/chemical applications and exposures to the skin, in part because the diffusional transients usually considered are inextricably intertwined with the kinetics of solute binding to intracellular keratin protein, which occurs ubiquitously on a comparable time scale and has never been characterized in any comprehensive way. Thus, pivotally important parameters including lag time and the so-called reservoir capacity (or depot effect) of the barrier layer of skin are as yet mired in uncertainty. The second area of need is a general inability to model and predict the dermal absorption of numerous drug formulations that dry down on the skin from water or another volatile solvent or solvent mixture. This inability continues to vex topical drug and cosmetic product development with baffling dependences of absorption on solute lipophilicity and order-of-magnitude differences in absorption rates of ostensibly similar molecules.