Tendon Tissue Regeneration With Cell Orientation Using an Injectable Alginate-Cell Cross-linked Gel

Background: Tendons have a limited blood supply and form inferior scar tissue during repair, which increases the risk of reruptures, causes complications, and limits regenerative capacity. Current methods to repair injured tendon tissue use solid scaffolds, which carry the risk of contamination (infections) and require open surgery for transplantation. Hypothesis: Alginate-cell cross-linked gels, which can be applied by a percutaneous injection and transmit mechanical stress to cells via direct cell interaction, could induce tendon tissue regeneration. Study Design: Controlled laboratory study. Methods: A cross-linked gel was prepared to suspend azide-modified mesenchymal stromal cells (MSCs) in a dibenzocyclooctyne-modified branched alginic acid solution. The cross-linked gel was cultured in a bioreactor. In vivo, the Achilles tendon defects of 104 Lewis rats were injected with saline (control group), alginate gel alone (alginate group), alginate gel with MSCs (MSC group), and cross-linked gel (cross-link group). At 2 and 4 weeks postoperatively, histological and biochemical evaluations were performed. The biomechanical properties of repaired tissue were assessed at 4 weeks. Results: In the bioreactor culture, the cell orientation in the cross-linked gel was parallel to the direction of tension. Histological analysis of the cross-link group showed significantly more repaired tendon tissue and improved collagen fiber orientation compared with the alginate group or MSC group. The biomechanical properties of the cross-link group included higher stiffness. Conclusion: The cross-linked gel was injectable at the injury site and was able to induce tissue regeneration with cell-oriented adaptability to the mechanical environment of tissue defects. Clinical Relevance: Intercellular cross-linking technology holds the potential for clinical application as a minimally invasive therapeutic approach that can contribute to the qualitative improvement of tendon tissue regeneration.