Controllable nanotopography of lysine-branched self-assembling peptide hydrogels for tendon-bone insertion regeneration

Recent advances in tissue engineering have highlighted the critical roles of both mechanical and biochemical characteristics in tendon-bone insertion (TBI) regeneration. However, the influence of surface topography, particularly the development of biocompatible hydrogels with aligned nanotopographical structures while preserving intrinsic mechanical properties, remains insufficiently explored. Here, we engineered a lysine-branched self-assembling peptide hydrogels (Lys-SAPHs) to promote TBI healing. Compared with pristine SAPH, Lys-SAPHs exhibited distinctive aligned 3D groove-like topographies without compromising mechanical integrity or hemocompatibility. In vitro, Lys-SAPHs enhanced tendon stem cells (TSCs) and bone marrow mesenchymal stem cells (BMSCs) proliferation, migration, and tendonogenic differentiation, while promoting macrophage polarization toward a reparative M2 phenotype. In a rat TBI defect model, optimized Lys-SAPH (FEK17:FEK8 = 1:6) treatment facilitated superior tendon-bone regeneration, evidenced by reduced bone defect area on micro-CT, improved Achilles functional index (AFI), and increased fibrocartilage formation compared with SAPH and control groups. This study highlighted the critical role of nanotopography in directing stem cell fate and immune modulation and presented Lys-SAPHs as a versatile platform for designing next-generation self-assembling peptide hydrogels for tendon-bone repair and broader regenerative applications.