Downregulation of the PI3K/AKT/mTOR/MMP-13 pathway for promoting interface healing via lubricating microspheres

Interface friction impedes tissue healing and stimulates interface cells to produce matrix metalloproteinases (MMPs); however, the precise mechanisms underlying matrix degradation, and the formation of fibrous scars remain unclear. This research involved the development of interface lubricating microspheres that inhibit the PI3K/AKT/mTOR signaling pathway in tenocytes. This inhibition significantly decreased MMP-13 expression and increased COL-1 production, thereby facilitating interface repair and regeneration. In vitro experiments demonstrated that interface friction activates the PI3K/AKT/mTOR/MMP-13 signaling pathway, while the use of interface lubricating microspheres reduced friction by 78 %, resulting in a threefold decrease in MMP-13 expression through pathway inhibition. Animal studies showed that the application of interface lubricating microspheres reduced friction at the tendon-bone interface, mitigating MMP-13-mediated matrix degradation and effectively reducing fibrous scar formation (as evidenced by decreased α-SMA expression), thus promoting interface healing following ACLR surgery in rats. Consequently, this study suggests that interface friction can trigger the PI3K/AKT/mTOR signaling pathway in tenocytes, leading to increased MMP-13 expression, matrix degradation, and fibrous scar formation. The use of interface lubricating microspheres can enhance interface healing by inhibiting this pathway, offering strategies for improving interface healing and minimizing fibrous scar formation. STATEMENT OF SIGNIFICANCE: Interface healing plays a crucial role following tendon-bone surgeries, yet it is often hindered by challenges such as interface friction and scar formation. In this study, we propose a combined approach in which lubricating microspheres and an anti-matrix degradation drug are used to enhance interface healing. We fabricated novel lubricating microspheres that exhibit outstanding biocompatibility and degradability; these microspheres serve as lubricants for the tendon-bone interface and facilitate the delivery of doxycycline to reduce excessive matrix metalloproteinase (MMP) secretion. The experimental results demonstrated that this method could enhance tendon-bone interface healing in rats, resulting in increased bone formation and higher histological scores than those of the control group. This study represents a preliminary effort to integrate lubrication and anti-matrix degradation in interface healing, potentially offering new insights into the mechanism between interface friction and fibrous scar healing, while promoting interface healing by reducing interfacial friction.