Modulation of host osseointegration during bone regeneration by controlling exogenous stem cell differentiation using a material approach

Stem cell-based tissue engineering for large bone defect healing has attracted enormous attention in regenerative medicine. However, sufficient osseointegration of the grafts combined with exogenous stem cells still remains a major challenge. Here, we developed a material approach to modulate the integration of the grafts to the host tissue when exogenous bone marrow stromal cells (BMSCs) were used as donor cells. Distinctive osseointegration of bone grafts was observed as we varied the content of hydroxyapatite (HA) in the tissue scaffolds implanted in a mouse femur model. More than 80% of new bone was formed in the first two weeks of implantation in high HA content scaffolds but host integration was poor, while only less than 5% of the new bone was formed during this time period in the No HA group but the host integration was good. Cell origin analysis leveraging the GFP reporter indicates new bone in the HA containing groups was mainly derived from donor BMSCs. In comparison, both host and donor cells were found on the new bone surface in the No HA groups which led to seamless bridging between host tissue and the scaffold. Most importantly, host integration during bone formation is closely dictated by the content of HA present in the scaffolds. Taken together, we demonstrate a material approach to modulate the osseointegration of bone grafts in the context of an exogenous stem cell-based bone healing strategy which might lead to fully functional bone tissue regeneration.