Targeting Early Healing Phase with Titania Nanotube Arrays on Tunable Diameters to Accelerate Bone Regeneration and Osseointegration.

Blood coagulation and inflammation are the earliest biological responses to implant surfaces. Implant nano-surfaces can significantly impact the osseointegration through the influence on the early phase of bone regeneration. However, the interplay between blood clot property and inflammatory reaction on nanosurfaces is rarely understood. Herein, titania nanotube arrays (TNAs) with different diameters are fabricated on titanium. In vitro evaluation with the whole blood indicates that TNA with a diameter of 15 nm (TNA 15) enables noteworthy platelet activation resulting in distinct clot features compared with that of pure Ti and TNA with a diameter of 120 nm (TNA 120). Further co-culture with macrophages on the clot or in the clot-conditioned medium shows that the clot on TNA 15 downregulates the inflammation and manipulates a favorable osteoimmunomodulatory environment for osteogenesis. In vivo studies further demonstrate that TNA 15 could downregulate the inflammation-related genes while upregulating growth metabolism-related genes in an early healing hematoma. Additionally, TNA 15 promotes de novo bone formation with improved extending of osteocyte dendrites, demonstrating the desired osseointegration. These findings indicate that surface nano-dimensions can significantly influence clot formation and appropriate clot features can manipulate a favorable osteoimmunomodulatory environment for bone regeneration and osseointegration.