Biomimetic Scaffolds with Dual Gradients of Biological Effectors for Tendon-to-Bone Repair

Due to the complexspatial gradients in composition and structure at the native tendon-to-bone attachment, it remains a clinical challenge to repair rotator cuff tears. Herein, we describe a biomimetic scaffold with dual gradients in osteogenic and tendon enthesis effectors to regulate the graded differentiation of stem cells for tendon-to-bone repair. Funnel-shaped microchannels prompted stem cells to rapidly infiltrate into the scaffold to experience the dual gradients in biological effectors along the walls of each microchannel. The graded distributions of two different effectors-hydroxyapatite nanorods and hedgehog agonist-worked synergistically to promote the differentiation of stem cells into osteoblasts, chondrocytes, and tenocytes, reproducing the cell phenotypes present in the natural tendon enthesis. The new scaffold offers a versatile platform to address key requirements for successful repair/regeneration of the tendon-to-bone attachment while also presenting an innovative strategy for the repair of connective tissue interfaces in general.