Biodegradable polymeric scaffolds are being investigated as scaffolding materials for use in regenerative medicine. While the in vivo evaluation of various three-dimensional (3D), porous, biodegradable polymeric scaffolds has been reported, most studies are <= 3 months in duration, which is typically prior to bulk polymer degradation, a critical event that may initiate an inflammatory response and inhibit tissue formation. Here, a 6 month in vitro degradation and corresponding in vivo studies that characterized scaffold changes during complete degradation of an amorphous, 3D poly(lactide-co-glycolide) (3D-PLAGA) scaffold and near-complete degradation of a semi-crystalline 3D-PLAGA scaffold are reported. Using sintered microsphere matrix technology, constructs were fabricated in a tubular shape, with the longitudinal axis void and a median pore size that mimicked the architecture of native bone. Long-term quantitative measurements of molecular weight, mechanical properties, and porosity provided a basis for theorization of the scaffold degradation process. Following implantation in a critical size ulnar defect model, histological analysis and quantitative microCT indicated early solubilization of the semi-crystalline polymer created an acidic microenvironment that inhibited mineralized tissue formation. Thus, the use of amorphous over semi-crystalline PLAGA materials is advocated for applications in regenerative medicine.