A Cell-Engineered Small Intestinal Submucosa-Based Bone Mimetic Construct for Bone Regeneration

Extracellular matrix (ECM)-ornamented biomaterials have attracted attention due to their high potential to improve the biofunctionality of original materials. It is thought that ECM with a bone mimetic microenvironment generated by the specific induction of osteoblasts would be more beneficial for bone regeneration than a regular ECM. In this study, we developed an osteogenic and mineralized ECM construct (Os/M-ECM-SIS) under the guidance of osteoblasts on a small intestinal submucosa (SIS) scaffold cotreated with icariin and calcium. The generated Os/M-ECM-SIS scaffolds exhibited similar morphology and inorganic components as natural bone and higher mechanical strength than ECM-SIS. Cell adhesion, proliferation, and differentiation of osteoblasts and fibroblasts were also enhanced in the cells cultured on the Os/M-ECM-SIS scaffolds. The Os/M-ECM-SIS scaffolds even promoted transdifferentiation of fibroblasts with an upregulation of osteogenic differentiation markers. In a calvarial defect model, new bone formation was greatly enhanced in defects implanted with the Os/M-ECM-SIS scaffolds compared with ECM-SIS scaffolds. Further study showed that the Os/M-ECM-SIS scaffolds promoted bone regeneration in vitro and in vivo via the Bmp/Smad-signaling pathway. Thus, this work proposes a valuable method for generating a mineralized bone mimetic scaffold with SIS as off-the-shelf bone graft substitute that provides an excellent osteogenic microenvironment, making it suitable for application in bone tissue engineering.