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Apatite crystals found in native bone are highly rich in citrate molecules.These citrate molecules are highly important in the mediation of bone development and overall bone load-bearing function.However, such understanding has not been translated into bone biomaterial design and bone stem cell culture.In this work, we developed osterix-up-regulating, biodegradable, and mechanically strong citrate-based polymer blend/hydroxyapatite (CBPBHA) composites for orthopedic tissue engineering applications.The role of citrate supplements in culture medium for stem cell culture was also investigated.CBPBHA composites consist of our newly developed osteoinductive citrate-based polymers, crosslinked urethane-doped polyester (CUPE), poly (octanediol citrate) (POC), and hydroxyapatite (HA).The results showed that a 10 wt% addition of POC into the mechanically strong CUPE/HA network produced materials similar in strength to that of human cortical bone with a compressive strength of 116.23 + 5.37 MPa.CBPBHA composites promoted in vitro mineralization, and greatly amplified C2C12 osterix (OSX) and alkaline phosphatase (ALP) gene expression in vitro.Composite samples implanted for 6 weeks in a rabbit lateral femoral condyle defect model demonstrated impressive complete osteointegration, no fibrous tissue encapsulation, and promoted bone remodeling.Another exciting finding was that citrate supplemented in bone marrow stromal cells (BMSCs) culture medium promoted calcium matrix formation in a dose-dependent manner.The discovery of CBPBHA composites and the exciting preliminary understanding on the role of citrate on stem cell differentiation bridges the gap in previous bone biomaterial designs and bone stem cell culture.