The role of matrix metalloproteinase (MMP)-9 and processing conditions of biodegradable polymer scaffolds has been investigated to optimize engineering vascular constructs. For a small diameter vascular construct, uniform 10 mm thickness of highly porous scaffolds were developed using a computer-controlled knife coater and exploiting phase transition properties of salts. The comparative study of fast vs. slow degrading three-dimensional scaffolds using a fast degrading poly D, L-lactic-glycolic acid co-polymer (PLGA) and a slow degrading poly e-caprolactone (PCL) indicated that fast degradation negatively affects cell viability and migration into the scaffold in vitro and in vivo, which is likely due to the fast polymer degradation mediated acidification of the local environment. MMP-9 was crucial for collagen remodeling process by smooth muscle cells (SMC). MMP-9 deficiency dramatically decreased inflammatory cell invasion as well as capillary formation within the scaffolds implanted in vivo. This study reports that the angiogenic response developed within the scaffolds in vivo was related to the presence of inflammatory response. Combinatorial polymer libraries fabricated from blended PLGA and PCL and processed at gradient annealing temperatures were utilized to investigate polymeric interactions with SMC. Surface roughness was also found to correlate with SMC adhesion. SMC aggregation, proliferation, and protein production, were highest in regions that exhibited increased surface roughness, reduced hardness, and decreased crystallinity of the PCL-rich phases. This study revealed a previously unknown processing temperature and blending compositions for two well-known polymers, which optimized SMC interactions.