Norbert Siedow

Cochlear Pharmacokinetics with Local Inner Ear Drug Delivery Using a Three-Dimensional Finite-Element Computer Model

Hypothesis: Cochlear fluid pharmacokinetics can be better represented by three-dimensional (3D) finite-element simulations of drug dispersal. Background: Local drug deliveries to the round window membrane are increasingly being used to treat inner ear disorders. Crucial to the development of safe therapies is knowledge of drug distribution in the inner ear with different delivery methods. Computer simulations allow application protocols and drug delivery systems to be evaluated, and may permit animal studies to be extrapolated to the larger cochlea of the human. Methods: A finite-element 3D model of the cochlea was constructed based on geometric dimensions of the guinea pig cochlea. Drug propagation along and between compartments was described by passive diffusion. To demonstrate the potential value of the model, methylprednisolone distribution in the cochlea was calculated for two clinically relevant application protocols using pharmacokinetic parameters derived from a prior one-dimensional (1D) model. In addition, a simplified geometry was used to compare results from 3D with 1D simulations. Results: For the simplified geometry, calculated concentration profiles with distance were in excellent agreement between the 1D and the 3D models. Different drug delivery strategies produce very different concentration time courses, peak concentrations and basal-apical concentration gradients of drug. In addition, 3D computations demonstrate the existence of substantial gradients across the scalae in the basal turn. Conclusion: The 3D model clearly shows the presence of drug gradients across the basal scalae of guinea pigs, demonstrating the necessity of a 3D approach to predict drug movements across and between scalae with larger cross-sectional areas, such as the human, with accuracy. This is the first model to incorporate the volume of the spiral ligament and to calculate diffusion through this structure. Further development of the 3D model will have to incorporate a more accurate geometry of the entire inner ear and incorporate more of the specific processes that contribute to drug removal from the inner ear fluids. Appropriate computer models may assist in both drug and drug delivery system design and can thus accelerate the development of a rationale-based local drug delivery to the inner ear and its successful establishment in clinical practice.

An iterative algorithm for optimal mould design in high-precision compression moulding

Abstract The mould design for the manufacturing of high-precision glass parts remains a challenging task. This motivates the present study which proposes an optimization technique to identify the mould design that yields the desired glass piece profile at the end of the compression moulding process with an accuracy of the order of 1 μm. The intuitive, yet very efficient method consists in computing at each optimization loop the mismatch between the deformed and desired glass piece geometries and using this information to update the mould design. The deformed glass piece geometry is computed using the commercial finite element package ABAQUS. This package is well suited to model the multistage forming process, the complex rheology of the glass, and the varying mechanical contact between the parts involved. The feasibility of the method is demonstrated in theory by designing the required mould for a convex-concave lens, where an accuracy of the order of 1 μm is achieved.

Numerical and Experimental Investigations on the Residual Stresses at the Centre of Flat Glass Disks After Thermal Tempering

Flat glass disks are thermally tempered by air-cooling with two air jets at the centre of their surfaces. Numerical modelling and photoelasticity measurements are proposed to analyze the distribution of the residual stresses through the glass thickness at the centre of the tempered disks. For the modelling, glass properties dependent of the temperature are used for the conductive heat transfer. Radiation is modelled by an improved approximation method. By taking both structural and stress relaxations into account, the transient and residual stresses are computed along the disk thickness. For experimentation, a complete procedure is proposed to access to the stress state in the centre of the disks using a scattered light polariscope. The average distribution of the residual stresses is deduced from stress profile measurements taking four radial orientations at the disk centre into consideration. Comparison between numerical and experimental values is finally discussed for the residual surface and half-thickness stresses at the disk centre.

Simulation and Visualization of Medical Application to the Inner Ear of the Guinea Pig to Reduce Animal Experiments

We present a novel approach to simulate drug application to the inner ear of the guinea pig with the goal to reduce animal experiments and to increase the accuracy of measurements. The framework is based on a tetrahedral grid representing the individual compartments of the cochlea, associated with a finite element model used to simulate medical diffusion and clearance. In a first simulation scenario, we were able to compute transfer coefficients between the inner compartments of the ear, validating experiments from the literature, and to prove the existence of clearance at the inner scala tympani. In a second scenario, the cochlea was unwound to obtain a one-dimensional model for efficient simulation-based transfer coefficient identification. These coefficients are useful to predict the impact of novel medication application systems.