Fn‐HMGB1 Adsorption Behavior Initiates Early Immune Recognition and Subsequent Osteoinduction of Biomaterials

Abstract Implantable biomaterials are widely used in bone tissue engineering, but little is still known about how they initiate early immune recognition and the initial dynamics. Herein, the early immune recognition and subsequent osteoinduction of biphasic calcium phosphate (BCP) after implantation to the protein adsorption behavior is attributed. By liquid chromatography tandem mass spectrometry (LC‒MS/MS) analysis, the biomaterial‐related molecular patterns (BAMPs) formed after BCP implantation are mapped, dominated by the highly expressed extracellular matrix protein fibronectin (Fn) and the high mobility group box 1 (HMGB1). Molecular dynamics simulations show that Fn has the ability to bind more readily to the BCP surface than HMGB1. The preferential binding of Fn provides a higher adsorption energy for HMGB1. Furthermore, multiple hydrogen bonding sites between HMGB1 and Fn are demonstrated using a molecular docking approach. Ultimately, the formation of BAMPs through HMGB1 antagonist glycyrrhizic acid (GA), resulting in impaired immune recognition of myeloid differentiation factor 88 (MYD88) mediated dendritic cells (DCs) and macrophages (Mφs), as well as failed osteoinduction processes is obstructed. This study introduces a mechanism for early immune recognition of implant materials based on protein adsorption, providing perspectives for future design and application of tissue engineering materials.