Novel Growth Factor Combination for Improving Rotator Cuff Repair: A Rat In Vivo Study

Abstract

Background: The lack of healing at the repaired tendon-bone interface is an important cause of failure after rotator cuff repair. While augmentation with growth factors (GFs) has demonstrated promise, the ideal combination must target all 3 tissue types at the tendon-bone interface. Hypothesis: The GF combination of transforming growth factor beta 1, Insulin-like growth factor 1, and parathyroid hormone will promote tenocyte proliferation and differentiation and improve the biomechanical and histological quality of the repaired tendon-bone interface. Study Design: Controlled laboratory study. Methods: In vitro, human tenocytes were cultured in the presence of the GF combination for 72 hours, and cell growth assays and the expression of genes specific to tendon, cartilage, and bone were analyzed. In vivo, adult rats (N = 46) underwent detachment and repair of the left supraspinatus tendon. A PVA-tyramine gel was used to deliver the GF combination to the tendon-bone interface. Histological, biomechanical, and RNA microarray analysis was performed at 6 and 12 weeks after surgery. Immunohistochemistry for type II and X collagen was performed at 12 weeks. Results: When treated with the GF combination in vitro, human tenocytes proliferated 1.5 times more than control ( P = .04). The expression of scleraxis increased 65-fold ( P = .013). The expression of Sox-9 ( P = .011), type I collagen ( P = .021), fibromodulin ( P = .0075), and biglycan ( P = .010) was also significantly increased, while the expression of PPARγ was decreased ( P = .007). At 6 and 12 weeks postoperatively, the quality of healing on histology was significantly higher in the GF group, with the formation of a more mature tendon-bone interface, as confirmed by immunohistochemistry for type II and X collagen. The GF group achieved a load at failure and Young modulus >1.5 times higher at both time points. Microarrays at 6 weeks demonstrated upregulation of genes involved in leukocyte aggregation ( S100A8, S100A9) and tissue mineralization ( Bglap, serglycin, Fam20c). Conclusion: The GF combination promoted protendon and cartilage responses in human tenocytes in vitro; it also improved the histological appearance and mechanical properties of the repair in vivo. Microarrays of the tendon-bone interface identified inflammatory and mineralization pathways affected by the GF combination, providing novel therapeutic targets for further research. Clinical Relevance: The use of this GF combination is translatable to patients and may improve healing after rotator cuff repair.