Structure, ingredient, and function-based biomimetic scaffolds for accelerated healing of tendon-bone interface.

Background: Tendon-bone interface (TBI) repair is slow and challenging owing to its hierarchical structure, gradient composition, and complex function. In this work, enlightened by the natural characteristics of TBI microstructure and the demands of TBI regeneration, a structure, composition, and function-based scaffold was fabricated. : The biomimetic scaffold was designed based on the "tissue-inducing biomaterials" theory: (1) a porous scaffold was created with poly-lactic-co-glycolic-acid, nano-hydroxyapatite and loaded with BMP2-gelatin to simulate the bone (BP); (2) a hydrogel was produced from sodium alginate, type I collagen, and loaded with TGF-β3 to simulate the cartilage (CP); (3) the L-poly-lactic-acid fibers were oriented to simulate the tendon (TP). The morphology of tri-layered constructs, gelation kinetics, degradation rate, release kinetics and mechanical strength of the scaffold were characterized. Then, bone marrow mesenchymal stem cells (MSCs) and tenocytes (TT-D6) were cultured on the scaffold to evaluate its gradient differentiation inductivity. A rat Achilles tendon defect model was established, and BMSCs seeded on scaffolds were implanted into the lesionsite. The tendon-bone lesionsite of calcaneus at 4w and 8w post-operation were obtained for gross observation, radiological evaluation, biomechanical and histological assessment.

Results: The hierarchical microstructures not only endowed the scaffold with gradual composition and mechanical properties for matching the regional biophysical characteristics of TBI but also exhibited gradient differentiation inductivity through providing regional microenvironment for cells. Moreover, the scaffold seeded with cells could effectively accelerate healing in rat Achilles tendon defects, attributable to its enhanced differentiation performance.

Conclusion: The hierarchical scaffolds simulating the structural, compositional, and cellular heterogeneity of natural TBI tissue performed therapeutic effects on promoting regeneration of TBI and enhancing the healing quality of Achilles tendon.

The Translational Potential Of This Article: The novel scaffold showed the great efficacy on tendon to bone healing by offering a structural and compositional microenvironment. The results meant that the hierarchical scaffold with BMSCs may have a great potential for clinical application.