Intelligente Drug-Delivery-Systeme zur Vermeidung Implantat-assoziierter Infektionen

All medical devices and implants are made of synthetic or natural, but usually not endogenous, materials. Implantation of such devices, into living tissue, is therefore subject to the risk of nosocomial infections, biofilm formation and may cause implant-associated infections. Microorganisms (including bacteria) that grow in biofilms and cause chronic inflammation are the typical source of these infections. Subsequently, they can lead to implant failure, requiring further surgical treatments. To prevent this, this study investigated and presented enzymatically degradable drug delivery systems that enable encapsulation and targeted release of an antibacterial agent triggered by an infection. To achieve this, the dissertation focused on the fabrication, characterization of suitable nanocarriers and their immobilization on implant surfaces such as titanium. To build a stable and degradable encapsulation system, different steps were established: 1) the integration of an enzyme-labile model peptide into two different polymer-based systems 2) generation of particles 3) coating of titanium surfaces with the particles 4) investigation of stability and degradability of those systems 5) the release of ciprofloxacin as a model substance. For this, two approaches have been tested. The first approach included the synthesis of chitosan‐g‐[peptide‐poly‐L‐caprolactone] and its self‐assembly into polymeric vesicles by the solvent shift method. For the second approach, nanogels dispersions were prepared by ionotropic gelation of the alginate with the poly-L-lysine, which was conjugated with ciprofloxacin via a copper-free 1,3-dipolar cycloaddition (click reaction).Alle medizinischen Geräte und Implantate bestehen aus synthetischen oder natürlichen, jedoch in der Regel aus nicht endogenen Materialien. Die Implantation solcher Geräte in lebendes Gewebe unterliegt daher dem Risiko nosokomialer Infektionen und der Bildung von Biofilmen und kann implantatassoziierte Infektionen verursachen. Mikroorganismen (einschließlich Bakterien), die in Biofilmen wachsen und chronische Entzündungen verursachen, sind die typische Quelle dieser Infektionen. Anschließend können sie zu einem Implantatversagen führen, was weitere chirurgische Behandlungen erforderlich macht. Um dies zu verhindern, untersuchte und ergab diese Studie enzymatisch abbaubare Arzneimittelabgabesysteme, die die Einkapselung und gezielte Freisetzung eines durch eine Infektion ausgelösten antibakteriellen Mittels ermöglichen. Um dies zu erreichen, konzentrierte sich die Dissertation auf die Herstellung und Charakterisierung geeigneter Nanoträger sowie deren Immobilisierung auf Implantatoberflächen wie Titan. Um ein stabiles und abbaubares Einkapselungssystem aufzubauen, wurden verschiedene Schritte festgelegt: 1) Integration eines enzymlabilen Modellpeptids in zwei verschiedene Systeme auf Polymerbasis 2) Erzeugung von Partikeln 3) Beschichtung von Titanoberflächen mit den Partikeln 4) Untersuchung von Stabilität und Abbaubarkeit dieser Systeme 5) Freisetzung von Ciprofloxacin als Modellsubstanz. Hierzu wurden zwei Ansätze getestet. Der erste Ansatz umfasste die Synthese von Chitosan-g-[Peptid-Poly-ε-Caprolacton] und dessen Selbstorganisation zu polymeren Vesikeln durch das Lösungsmittel-Verschiebungsverfahren. Für den zweiten Ansatz wurden Nanogeldispersionen durch ionotrope Gelierung des Alginats mit dem Poly-L-Lysin hergestellt, das über eine kupferfreie 1,3-dipolare Cycloaddition (Klickreaktion) mit Ciprofloxacin konjugiert wurde

Optimization of Critical Parameters for Carbodiimide Mediated Production of Highly Modified Chitosan

An optimization of the 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and hydroxy benzotriazole mediated conjugation of the polysaccharide chitosan with functional carboxylic acids was shown. Optimal parameters that enable resource-efficient synthesis of highly functionalized chitosan were identified. In particular, use of only catalytic instead of stoichiometric amounts of hydroxy benzotriazole and tight control of pH in reaction mixture resulted in highly efficient incorporation of the desired moieties as side chains in chitosan. As a result, the model reactant 4-azidobenzoic acid was incorporated resulting in a degree of substitution of over 30% with very high coupling efficacy of up to 90%. Similar results were obtained with other carboxylic acids such as methacrylic acid, 3-(2-furyl) propionic acid and 3-maleimido propionic acid, highlighting the broad applicability of our findings for the functionalization of chitosan

A Multiscale Kinetic-Fluid Solver with Dynamic Localization of Kinetic Effects

This paper collects the efforts done in our previous works [P. Degond, S. Jin, L. Mieussens, A Smooth Transition Between Kinetic and Hydrodynamic Equations, J. Comp. Phys., 209 (2005) 665--694.],[P.Degond, G. Dimarco, L. Mieussens, A Moving Interface Method for Dynamic Kinetic-fluid Coupling, J. Comp. Phys., Vol. 227, pp. 1176-1208, (2007).],[P. Degond, J.G. Liu, L. Mieussens, Macroscopic Fluid Model with Localized Kinetic Upscaling Effects, SIAM Multi. Model. Sim. 5(3), 940--979 (2006)] to build a robust multiscale kinetic-fluid solver. Our scope is to efficiently solve fluid dynamic problems which present non equilibrium localized regions that can move, merge, appear or disappear in time. The main ingredients of the present work are the followings ones: a fluid model is solved in the whole domain together with a localized kinetic upscaling term that corrects the fluid model wherever it is necessary; this multiscale description of the flow is obtained by using a micro-macro decomposition of the distribution function [P. Degond, J.G. Liu, L. Mieussens, Macroscopic Fluid Model with Localized Kinetic Upscaling Effects, SIAM Multi. Model. Sim. 5(3), 940--979 (2006)]; the dynamic transition between fluid and kinetic descriptions is obtained by using a time and space dependent transition function; to efficiently define the breakdown conditions of fluid models we propose a new criterion based on the distribution function itself. Several numerical examples are presented to validate the method and measure its computational efficiency.Comment: 34 page

A hybrid method for hydrodynamic-kinetic flow - Part I -A particle-gridmethod for reducing stochastic noise in kinetic regimes

In this work we present a hybrid particle-grid Monte Carlo method for the Boltzmann equation, which is characterized by a significant reduction of the stochastic noise in the kinetic regime. The hybrid method is based on a first order splitting in time to separate the transport from the relaxation step. The transport step is solved by a deterministic scheme, while a hybrid DSMC-based method is used to solve the collision step. Such a hybrid scheme is based on splitting the solution in a collisional and a non-collisional part at the beginning of the collision step, and the DSMC method is used to solve the relaxation step for the collisional part of the solution only. This is accomplished by sampling only the fraction of particles candidate for collisions from the collisional part of the solution, performing collisions as in a standard DSMC method, and then projecting the particles back onto a velocity grid to compute a piecewise constant reconstruction for the collisional part of the solution. The latter is added to a piecewise constant reconstruction of the non-collisional part of the solution, which in fact remains unchanged during the relaxation step. Numerical results show that the stochastic noise is significantly reduced at large Knudsen numbers with respect to the standard DSMC method. Indeed in this algorithm, the particle scheme is applied only on the collisional part of the solution, so only this fraction of the solution is affected by stochastic fluctuations. But since the collisional part of the solution reduces as the Knudsen number increases, stochastic noise reduces as well at large Knudsen number

Notice d'utilisation du logiciel BOL2D pour la simulation bidimensionnelle de l'equation de Boltzmann

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Enzyme-Responsive Nanoparticles and Coatings Made from Alginate/Peptide Ciprofloxacin Conjugates as Drug Release System

Infection-controlled release of antibacterial agents is of great importance, particularly for the control of peri-implant infections in the postoperative phase. Polymers containing antibiotics bound via enzymatically cleavable linkers could provide access to drug release systems that could accomplish this. Dispersions of nanogels were prepared by ionotropic gelation of alginate with poly-L-lysine, which was conjugated with ciprofloxacin as model drug via a copper-free 1,3-dipolar cy-cloaddition (click reaction). The nanogels are stable in dispersion and form films which are stable in aqueous environments. However, both the nanogels and the layers are degraded in the presence of an enzyme and the ciprofloxacin is released. The efficacy of the released drug against Staphylococcus aureus is negatively affected by the residues of the linker. Both the acyl modification of the amine nitrogen in ciprofloxacin and the sterically very demanding linker group with three annel-lated rings could be responsible for this. However the basic feasibility of the principle for enzyme-triggered release of drugs was successfully demonstrated

Calcul du buckling associé à une équation de transport de neutrons dans un milieu périodique

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Numerical extraction of a macroscopic pde and a lifting operator from a lattice Boltzmann model

Lifting operators play an important role in starting a lattice Boltzmann model from a given initial density. The density, a macroscopic variable, needs to be mapped to the distribution functions, mesoscopic variables, of the lattice Boltzmann model. Several methods proposed as lifting operators have been tested and discussed in the literature. The most famous methods are an analytically found lifting operator, like the Chapman-Enskog expansion, and a numerical method, like the Constrained Runs algorithm, to arrive at an implicit expression for the unknown distribution functions with the help of the density. This paper proposes a lifting operator that alleviates several drawbacks of these existing methods. In particular, we focus on the computational expense and the analytical work that needs to be done. The proposed lifting operator, a numerical Chapman-Enskog expansion, obtains the coefficients of the Chapman-Enskog expansion numerically. Another important feature of the use of lifting operators is found in hybrid models. There the lattice Boltzmann model is spatially coupled with a model based on a more macroscopic description, for example an advection-diffusion-reaction equation. In one part of the domain, the lattice Boltzmann model is used, while in another part, the more macroscopic model. Such a hybrid coupling results in missing data at the interfaces between the different models. A lifting operator is then an important tool since the lattice Boltzmann model is typically described by more variables than a model based on a macroscopic partial differential equation.Comment: submitted to SIAM MM

A Unified Analysis of Balancing Domain Decomposition by Constraints for Discontinuous Galerkin Discretizations

The BDDC algorithm is extended to a large class of discontinuous Galerkin (DG) discretizations of second order elliptic problems. An estimate of C(1 + log(H/h))2 is obtained for the condition number of the preconditioned system where C is a constant independent of h or H or large jumps in the coefficient of the problem. Numerical simulations are presented which confirm the theoretical results. A key component for the development and analysis of the BDDC algorithm is a novel perspective presenting the DG discretization as the sum of element-wise “local” bilinear forms. The element-wise perspective allows for a simple unified analysis of a variety of DG methods and leads naturally to the appropriate choice for the subdomain-wise local bilinear forms. Additionally, this new perspective enables a connection to be drawn between the DG discretization and a related continuous finite element discretization to simplify the analysis of the BDDC algorithm.Boeing CompanyMassachusetts Institute of Technology (Zakhartchenko Fellowship

Variational formulation and algorithm for trace operation in domain decomposition calculations

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