DESCRIPTION (provided by applicant): While skeletal tissue engineering is ideally based on transition from scaffold function to shared bone/scaffold function to completely natural bone, almost no information exists on designing scaffolds to optimize this transition. A simplified starting point is to associate scaffold function with mechanical modulus and tissue regeneration with scaffold porosity/permeability. The fundamental scaffold design question becomes "What is the right balance between modulus and interconnected porosity/permeability such that the scaffold can bear load until the regenerate tissue can bear load?". To answer this critical question we must be able to design scaffold architectures with specific modulus porosity relationships, fabricate these complex scaffolds from bone engineering materials, and test these scaffolds in a well characterized in vivo load bearing model. Our global hypothesis is that a minimally stiff scaffold (stiff equates to modulus) capable of load bearing coupled with the highest interconnected porosity/permeability will achieve optimal bone regeneration. Our goal is to define "minimally stiff' and "highest porosity/permeability" in an in vivo functional load bearing site. We will test this hypothesis through the following three specific aims: Specific Aim 1. Use computational topology optimization techniques to design scaffold architectures with four modulus/porosity ratios that span the theoretical Hashin-Shtrikman bounds initially and after degradation. Specific Aim 2. Fabricate designed scaffold architectures from PPF/TCP using Solid Free-Form Fabrication techniques. Micro-CT scaffolds to examine architecture and measure scaffold permeability. Specific Aim 3.Test scaffolds in minipig mandibular condyle load bearing site that has known bone regeneration dynamics. Determine how modulus/porosity ratios correlate with bone regeneration at 4 and 8 weeks using 3D quantitative micro-CT, mechanical testing, and histology. The results will provide quantitative information as to what modulus is necessary for load bearing and how designed porosity/permeability influence bone regeneration. This information will provide guidelines for designing scaffolds to optimize transition from scaffold load bearing to bone regeneration and load bearing.