Surface modified small intestinal submucosa membrane manipulates sequential immunomodulation coupled with enhanced angio- and osteogenesis towards ameliorative guided bone regeneration

Abstract Constructing bioactive guided bone regeneration (GBR) membranes that possess biological multifunctionality is becoming increasingly attractive and promising to meet higher requirements for bone healing. Given the biological responses following implantation, GBR process originates from an early inflammation-driven reaction adjacent to implanted membranes surface. However, to date there is relatively little attention paid to the critical immunoregulatory functions in traditionally designed GBR membranes. Herein, for the first time, we manipulate immunomodulatory properties of the widely-used native small intestinal submucosa (SIS) membrane by incorporating strontium-substituted nanohydroxyapatite coatings and/or IFN-γ to its surface. In vitro results reveal the obtained novel membrane SIS/SrHA/IFN-γ not only promote functions of endothelial cells and osteoblasts directly, but also energetically mediate a sequential M1-M2 macrophages transition to concurrently facilitate angiogenesis and osteogenesis. Moreover, in vivo outcomes of subcutaneous implantation and cranial defects repair further confirm its superior capacity to promote vascularization and in situ bone regeneration than pristine SIS through immunomodulation. These results demonstrate a sequential immunomodulatory strategy renders modified SIS membranes acting as a robust immunomodulator rather than a traditional barrier to significantly ameliorate in vivo GBR outcomes and hence provide important implications that may facilitate concerns on immunomodulatory properties for future GBR developments.