Bone regeneration remains a major challenge in modern medicine. Silk Fibroin (SF), a natural biopolymer derived from Bombyx mori is gaining an increasing attention due to its remarkable biological properties. The combination of SF with calcium-based (CaP) fillers such as hydroxyapatite (HAp),F062-tricalcium phosphate (F062-TCP), octacalcium phosphate (OCP), amorphous calcium phosphate (ACP), and others, allows the production of 3D composite scaffolds with enhanced osteogenic properties.This systematic review aims to critically evaluate the current literature on the use of SF-based 3D scaffolds implemented with calcim-based fillers for bone tissue engineering.A comprehensive search of PubMed, Science Direct and Scopus databases has been conducted according to PRISMA guidelines. Preclinical in vitro and in vivo results published in the last decade were included and data concerning scaffold fabrication methods, composition, structural and mechanical properties, in vitro and in vivo regenerative outcomes were extracted.A total of 19 studies met the inclusion criteria. Most scaffolds were fabricated via freeze-drying, salt-leaching, lyophilisation and electrospinning techniques, alone or combined. In the majority of cases, the incorporation of CaP-based fillers significantly improved scaffold bioactivity, mechanical strength, hence promoting osteoblasts proliferation and differentiation in vitro, while in vivo models demonstrated an enhanced bone formation.SF-based scaffolds enriched with CaP fillers may therefore represent a concrete and valuable solution for the treatment of critical sized bone defects, allowing the overcoming of clinical limitations linked to the classic surgical treatments. However, further studies and clinical trials are essential to validate and translate these results in humans.
