Concurrent Modeling: Nano Film Drug Delivery System

Faculty:  Adriana Compagnoni (Stevens), Matthew Libera (Stevens),

               Svetlana Sukhishvili (Stevens), Philippe Bidinger (Verimag),

               Eduardo Bonelli (UNQ)

Students: Yifei Bao (Stevens), Vishakha Sharma (Stevens)

                                                        

Research Overview

In this project we study the interactions and correlations between bacterial growth, pH change, and antibacterial agents release from pH responsive hydrogel thin films.

          Figure 1: Bio-triggered release of antibacterial agents from pH- responsive layer-by-layer hydrogel thin film.

Modeling

Our models include four objects: planktonic bacteria; ad- sorbed bacteria; gel-bound antibacterial agent (AmA); and released AmA. Each has attributes, many of which are inter- related. The bacteria, for example, can both metabolize, albeit at different rates. Metabolism is particularly significant for bound AmA, since acidic products will lower the local pH, reduce the strength of electrostatic AmA-gel binding, and enable the pH-release of bound AmAs. Released AmA can then diffuse and/or flow, and potentially kill bound or planktonic bacteria. Note that spatial coordinates and stochasticity are critical to understanding the interactions between different objects and with the substrate, because they all rely on proximity. Hence, existing process algebra modeling languages are insufficient. Furthermore, while there are now a number of models being developed to understanding the biofilm formation, none take into account the controllable properties of the substrate and pH and how this can influence bacterial adhesion, proliferation, and

phenotypic change.

In the following model, we run a controlled experiment where bacteria can attach to the substrate and grow freely. The view point is from the top. Blue dots represent bacteria in solution; bacteria attached to the substrate are green, and the light blue dots are hydrogen ions used to represent local pH.

The next simulation corresponds to a model with an AmA saturated substrate. Substrate bound drug molecules are purple, and released drug molecules in solution are red. Qualitatively we observe smaller and fewer colonies than in the previous model.

The following simulation results show an experiment starting with forty bacteria (green) and one hundred and fifty molecules of antibacterial agent (blue) embedded in the substrate. After a few seconds of computation we observe molecules released by pH change caused by bacterial growth and dead bacteria (red) killed by antibacterial molecules (blue). This simulation is a 3D version of b above.

The following is a validating experiment for our model. Optical micrographs of NJ 9709 S. epidermidis cultured on (A) as-synthesized and (B) L5-loaded (PMAA)10 gels. BioScape simulations with 40 bacteria and (C) an as-synthesized gel film and (D) an L5-loaded gel film.  Live bacteria are green, dead bacteria are red, and L5 molecules are small blue dots.