The primary goals of tissue engineering scaffolds are to: o Provide guidance for anatomical tissue shape/volume o Provide temporary function within the tissue defect o Enhance tissue regeneration through mass transport and biologic delivery To achieve these goals, we must first define quantitative measures that characterize these goals. The first goal is general to all tissues and is readily defined by the shape of the tissue defect that needs to be filled. This defect is defined by CT or MR patient scanning. The next two goals are tissue specific and not as readily defined. Function could be mechanical, electrical, and/or chemical. Quantitative measures can be defined through constitutive models, including elastic or other mechanical coefficients, conductivity coefficients, or diffusion/permeability coefficients. However, there is little definition as to what coefficients are most relevant for which tissue, let alone the target values of these coefficients. In addition, since most scaffolds degrade over time, we must be able to characterize the time dependent nature of these constitutive coefficients. Still more nebulous is the definition of enhanced tissue regeneration. Many factors impact tissue regeneration, including mass transport, cell-surface interaction and biologics delivered from scaffolds, defined here as cells, proteins, and/or genes. Permeability and diffusion coefficients govern mass transport of proteins and other nutrients like oxygen to cells. Permeability and diffusion coefficients are also likely related to cell migration into the scaffold. Cell-surface interaction will be determined by ions and proteins on the cell surface as well as surface roughness. Biologic delivery will also depend upon material binding and surface characteristics. In summary, we can propose the following list of quantitative measures to characterize scaffold design and performance that is by no means complete: o Mass Transport/Enhanced Regeneration Measures: Permeability, Diffusivity, Hydrophilicity, Surface Roughness Defining the best scaffold for a particular reconstruction application depends on two important components. First, we must be able engineer scaffolds by combining hierarchical design with biomaterial fabrication to achieved desired properties. Second, we must experimentally test the engineered scaffolds in models ranging from in vitro cell models to large functional animal models to determine relevant and critical scaffold characteristics. This chapter will deal primarily with the first component, and will specifically focus on computational scaffold design and simulation of scaffold performance. To begin designing scaffolds, however, we must first recognize the important design and simulation issues:© Springer 2008.