Coacervate formation of human bone morphogenetic protein-2 fused with an extracellular matrix peptide with hyaluronic acid

Human bone morphogenetic protein-2 (hBMP-2) is a growth factor extensively used to promote bone regeneration. Nonetheless, challenges such as initial burst release, low solubility and aggregation under physiological conditions, and the requirement for high doses in clinical applications can limit its effectiveness and lead to adverse side effects. In this study, a simplified and efficient hBMP-2 formulation was developed by directly forming coacervates of hBMP-2 variants with hyaluronic acid (HA) without additional hBMP-2 encapsulation steps. Extracellular matrix (ECM) peptides such as RGD, PDSGR, and YIGSR were fused to hBMP-2 to create variants, in which the intrinsic disorder of ECM peptides facilitates the coacervation of hBMP-2 variants with HA. hBMP-2-YIGSR formed stable coacervates with HA and exhibited a controlled release profile on the coacervate-coated hydroxyapatite surfaces. Furthermore, the sustained release led to significantly enhanced alkaline phosphatase activity in preosteoblast MC3T3-E1 cells. This study highlights the stable coacervate formation of hBMP-2 fused with ECM peptides with HA and establishes the potential of this formulation to reduce the initial hBMP-2 burst release and provide a controlled release for extended hBMP-2 bioactivity in bone tissue engineering applications.