Sphingosine 1-phosphate (S1P) receptor modulators can influence bone regeneration owing to their positive impact on osteoblast differentiation and neovascularisation. While previous studies have utilised non-specific S1P and fingolimod, this study aims to design and characterise a controlled release vehicle to deliver the specific S1P1 & 5 receptor modulator siponimod and test its effectiveness in rat critical cranial defects.Electrospun scaffolds of poly lactide-co-glycolide (PLGA) were loaded with siponimod at drug:polymer mass ratios of 0.5:100 to 2:100. Where indicated, collagen was co-spun at a collagen:polymer mass ratio of 2:100. Thereafter, scaffolds underwent in vitro physicochemical characterisation and in vivo assessment using a rat cranial defect model. Drug-loaded scaffolds showed controlled release of siponimod, -cytocompatibility with endothelial and osteoblast cells in vitro, and furthermore, showed that released siponimod stimulated osteoblast differentiation and endothelial cell migration. The in vivo cranial defect repair study showed regeneration was occurring in the defect, although there was no significant difference in the extent of mineralisation between scaffold experimental groups. To our knowledge, this is the first study investigating siponimod in bone regeneration. In vitro studies confirm a positive impact on key cells involved in bone regeneration, however, the scaffolds did not result in significant repair of critical cranial defects.