Cryogenically 3D printed biomimetic scaffolds containing decellularized small intestinal submucosa and Sr2+/Fe3+ co-substituted hydroxyapatite for bone tissue engineering

Currently, advanced bone biomaterials are preferred able to mimic the architecture/composition of natural bone and possess sufficient biological multifunctionality to chronologically dictate bone regeneration events. Such biomaterials are increasingly being researched and quite promising in bone tissue engineering. In this view, novel biomimetic scaffolds composed of decellularized small intestinal submucosa matrix (SIS-ECM) and Sr2+/Fe3+ co-substituted hydroxyapatite (SrFeHA) were constructed via extrusion cryogenic 3D printing method. The produced SIS/SrFeHA scaffolds revealed desirable 3D interconnected macro/micro-porous structures, rough microsurfaces and improved mechanical strength, along with appreciable synergic releasing of bioactive ECM components and Sr2+/Fe3+. These favorable physico-chemical properties rendered composite SIS/SrFeHA inducing a highly biomimetic bony environment which manipulated desired immunoregulation coupled with enhanced angiogenesis, osteogenesis, and biomineralization. Consistently, in vivo cranial defects and subcutaneous implantation outcomes yet affirmed the superior ability of SIS/SrFeHA to well dictate early immune reaction, neovascularization, and in vivo bone regeneration, suggesting the potent combined actions of SIS and SrFeHA to accelerate bone healing. Moreover, as examined by RNA sequencing assay, a new finding of up-regulated Amot(+)/YAP(-)/Hippo signaling pathway responsible for the enhanced angiogenesis in SIS/SrFeHA scaffolds was further clarified. Consequently, for the first time, present research highlights the considerable potential of SIS/SrFeHA scaffolds for inducing bone healing and simultaneously afford a new finding for better understanding underlying mechanism of bioactive SrFeHA components, thus may generating a new promising alternative for future bone tissue engineering.