Even though degradation products of biodegradable polymers are known to be largely non-cytotoxic, little detailed information is available regarding the degradation rate-dependent acidic byproduct effect of the scaffold. In vitro and in vivo scaffold degradation rate could be differentiated using a fast degrading polymer (e.g., poly D, L-lactic-glycolic acid co-polymer, PLGA, 50:50) and a slow degrading polymer (e.g., poly epsilon-caprolactone, PCL). We applied a new method to develop uniform 10 microm thickness of high porous scaffolds using a computer-controlled knife coater with a motion stage and exploiting phase transition properties of a combination of salts and water in salt-leaching method. We then verified in vitro the effect of fast degradation by assessing the viability of primary mouse aortic smooth muscle cell cultured in the three-dimensional scaffolds. We found that cell viability was inversely related to degradation rate and was dependent on the depth from the seeding (upper) surface toward the lower surface. The pH measurement of culture medium using fluorescence probes showed time-dependent decrease in pH in the PLGA scaffolds, corresponding to PLGA degradation, and closely related to cell viability. In vivo analysis of scaffolds implanted subcutaneously into the back of mice, showed significant differences in inflammation and cell invasion into PLGA vs. PCL. Importantly, these were correlated with the degree of the functional angiogenesis within the scaffolds. Again, PLGA scaffolds demonstrated less cell mobilization and less angiogenesis, further supporting the negative effect of the acidic environment created by the degradation of biocompatible polymers.