Functionally graded scaffold with M2 macrophage-derived LncRNA-Encoded peptide: Mechanistic and therapeutic evaluation for rotator cuff repair

The rotator cuff is prone to tear under degenerative changes or mechanical injury, leading to excessive inflammation, extracellular matrix degradation, and unsatisfactory prognosis. Interleukin-4 (IL-4) was used to induce macrophages polarization toward M2 phenotype. By mapping IL 4-activated pathways and applying peptidome profiling, macrophage-derived peptide 1 (MDP1) was identified and shown to promote the phosphorylation of STAT3 and STAT6, thereby inducing the polarization of M0 macrophages toward the anti-inflammatory M2 phenotype. A functionally graded scaffold woven from electrospun nanofiber yarns was developed, with MDP1 and hydroxyapatite (HA) loaded onto its corresponding interfaces. During rotator cuff repair process, the scaffold functioned as an augmentation patch, with mechanical properties (Young's modulus, ca. 280 MPa) comparable to native tendons, prevented rotator cuff re-tearing in an early stage. MDP1 was incorporated into scaffolds to modulate an excessive inflammatory response, while HA was used to enhance bio-mineralization for enhanced osteointegration. Through a multidimensional collaborative repair strategy, this functionally graded scaffold not only mimicked the tendon-bone interface, but also significantly suppressed local inflammation at the interface, as evidenced by a 60.6 % and 66.5 % reduction in IL-6-positive areas at 2 and 4 months, respectively, compared with the control group. Furthermore, it promoted tissue regeneration in the damaged region, resulting in a 32.6 % increase in Young's modulus, thereby ultimately enhancing rotator cuff performance. The multifunctionally graded scaffold may offer an invaluable solution to promote rotator cuff tear healing and potentially other related disciplines.