Polycaprolactone scaffolds promote a regeneration-supportive metabolic response attenuated in diabetes.

Scaffold-guided bone regeneration (SGBR) is a promising strategy for repairing large bone defects. However, its efficacy is markedly reduced in diabetes. Here, we used non-diabetic and diabetic Zucker Diabetic Fatty (ZDF) rats with sham-operated, empty-defect and scaffold-treated groups to examine how host metabolic state influences the regenerative performance of 3D-printed polycaprolactone (PCL) scaffolds in critical-sized femoral defects. Targeted metabolomics of plasma and femoral midshaft revealed a distinct diabetic signature that was characterized by carbohydrate accumulation and broad amino acid dysregulation. In non-diabetic rats, PCL scaffolds enhanced bone regeneration and were associated with a local metabolic response consistent with a regeneration-supportive increase in energy and substrate availability, including glutamate-related metabolism. In diabetic rats, empty defects showed elevated branched-chain amino acids (BCAAs) and reduced glutamine, together with limited bone regeneration. Although scaffold treatment partially normalized BCAAs in diabetic rats, glutamate was not restored and the regenerative benefit of scaffold implantation was lost. These data indicate that SGBR is associated with a regeneration-supportive metabolic response in non-diabetic bone defects, whereas this response is blunted in the diabetic host. This study underscores the need for biomaterial strategies better matched to metabolically compromised host conditions, such as diabetes, to enable effective scaffold-guided regeneration.