•  Biomaterials-associated infections (BAI) are greatly influenced by the design and composition of the biomaterial implants. The complexity of such systems motivates the need of new methods like computational modeling to help treat such infections.

•  We designed BioScape, a concurrent language to build a computational model of anti-adhesive and antibacterial bifunctional polymers for surface coating.

•  BioScape is based on stochastic pi-calculus; a calculus suitable for modeling and simulating biological and biomaterials processes in a reactive environment. It also captures the spatial information by taking into account the movement, diffusion rate, shape and reaction distance associated with the species.

•  Our computational model is build for three different surfaces for the adhesion and the growth phase and yields the amount of dead and alive bacteria throughout the experiments and will help us in identifying the biological targets and materials to treat Biomaterials-associated infections (BAI) caused by biomedical devices like, implants. ! !!

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•  Biomaterials used for implants in the human body often lead to the development of the biofilm formation which are resistant to antibiotics and the immune system.

•  The current state of art lies in the design and composition of the biomaterials with antimicrobial agents.

•  Anti-adhesive and Antibacterial Bifunctional Polymers2 is one way to prevent biofilm growth. Currently the University of Groningen Medical Center is running experiments on bifunctional polymers. Such wet lab experiments are very costly and time consuming.

•  We designed a formal modeling language to simulate the behavior of these complex anti-adhesive and antibacterial bifunctional polymers named BioScape1.

•  The modeling and simulation framework helps in identifying biological targets and materials to treat bacterial infections.

/0$%+,-&$/+0'!0,'(+$/1!$/+0' )2!(3.)4'356789:;<.=>8?=@A'&89B6CDEA>'•  Pluronic-Lysozyme conjugates consists of a triblock copolymers (PEO-PPO-PEO) which are

made up of a central polypropylene oxide (PPO) block which is hydrophobic in nature and attaches to the hydrophobic surface. The PEO block is hydrophilic in nature and extend into the aqueous medium forming a polymer brush.

•  Polymer causes an osmotic pressure and repels any bacteria from adhering to the hydrophobic surface and results in the non-adhesive property of the surface.

•  An antimicrobial protein, lysozyme is attached to the end of the brushes which kill bacteria on contact even before they form a biofilm and are responsible for the antibacterial property of the surface.

%)#-.$#'• Adhesion Phase: 2 Hours

&+0&.-#/+0#'•  Build a computational model that yields the optimal surface that has the least total number of live and dead bacteria with the highest percentage of dead bacteria.

•  Build computational models using BioScape for multi-functional coatings for application in biomedical systems.

Figure 1:Bifunctional Polymers of Pluronic-Lysozyme Conjugate

Experiment 1: Pluronic Unmodified Experiment 2: 1% Pl-Lys Experiment 3: 100% Pl-Lys •  108 Binding Sites in 1 cm2. •  In Silico: We consider substrate of 100µmX100µm which has 104 Binding Site. •  Simulation time : 1 unit of simulation time corresponds to 10 minutes of wet

lab. •  Rate Parameters

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%)F)%)0&)#'1.  A. Compagnoni, V. Sharma, Y. Bao, P. Bidinger, L. Bioglio, E. Bonelli, M. Libera, and S. Sukhishvili. Bioscape: A

modeling and simulation language for bacteria-materials interactions. In the proceedings of 3rd International Workshop on Interactions between Computer Science and Biology (CS2Bio), 2012.

2.  A. K. Muszanska, H. J. Busscher, A. Herrmann, H.C. van der Mei and W. Norde. Pluronic-lysozyme conjugates as anti-adhesive and antibacterial bifunctional polymers for surface coating. Biomaterials, 32:6333-6341, 2011.

+0G+/0G'!0,'F-$-%)'H+%I'•  The simulation results obtained from BioScape for the adhesion phase

and the growth phase are validated with the wet lab experiments.

•  Spatial information helped us visualize the bacterial colonization and surface construction.

•  In silico experiments can greatly reduce the time and cost for wet lab experiments and can accelerate curing biomaterials associated infections (BAI).

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• Growth Phase: 18 Hours

•  Live/Dead % Bacteria and CFUs per unit in silico experiments

•  Summary of Wet Lab and In Silico experiments Adhesion Phase Growth Phase

•  Number of PEOs and Lysozymes in silico

Experiment 1: Pluronic Unmodified Experiment 2: 1% Pl-Lys Experiment 3: 100% Pl-Lys

Figure 4: Reaction radius and Reaction rates

What BioScape can do?

•  Model interactions/behavior •  Bacteria is killed by Lysozyme. •  Bacteria attaches to PEO. •  Bacteria multiplies.

•  Concurrency, Stochasticity and 3D Space •  Bacteria-biomaterials interactions are highly

concurrent. •  Wet lab experiments are stochastic. •  3D space has 3 new attributes: shape ("), step

(#) and movement space ($).

•  Process algebra •  Send/Receive Handshake (!/?)

Figure 2: Process Model

Figure 3: 3D Space