Enhanced rotator cuff tendon-bone interface regeneration with injectable manganese-based mesoporous silica nanoparticle-loaded dual crosslinked hydrogels.

INTRODUCTION

During the healing process, the functional gradient attachment of the rotator cuff (RC) tendon-bone interface fails to regenerate, which severely impedes load transfer and stress dissipation, thereby increasing the risk of retears. As a result, the treatment of rotator cuff tears remains a significant clinical challenge.

METHODS

In this study, a dual-crosslinked hyaluronic acid/polyethylene glycol (HA/PEG) hydrogel scaffold was synthesized using hyaluronic acid and polyethylene glycol as base materials. Manganese-doped mesoporous silica nanoparticles (Mn-MSN) were incorporated into the hydrogel system to fabricate a manganese-based mesoporous silica nanoparticle-loaded dual-crosslinked hydrogel (Mn-MSN@Gel). The physicochemical properties of Mn-MSN@Gel, including porosity, elemental distribution, mechanical properties, biodegradability, and biocompatibility, were systematically characterized. The ion release profiles of Si and Mn were evaluated to assess sustained delivery. Rheological properties and self-healing capabilities were examined to determine injectability and in vivo stability. In vitro, the effects of Mn-MSN@Gel on cell migration, proliferation, and differentiation were assessed using rat bone marrow mesenchymal stem cells (rat-BMSCs) and tendon-derived stem cells (rat-TDSCs). The expression of osteogenic, tenogenic, oxidative stress-related, and inflammatory cytokine genes was analyzed. In vivo, a rat rotator cuff repair model was established to evaluate the biomechanical properties and tissue regeneration at the tendon-bone interface (TBI) following Mn-MSN@Gel injection.

RESULTS

Characterization demonstrated that Mn-MSN@Gel possesses a porous three-dimensional structure with uniform distribution of silicon, oxygen, and manganese elements, enabling sustained and slow release of Si and Mn ions. Additionally, the composite material exhibited excellent mechanical properties, biodegradability, and biocompatibility, while promoting cell migration/proliferation and accelerating regeneration of the tendon-bone interface. Mn-MSN@Gel enhanced the expression of osteogenic differentiation genes (Runx2, Alp, Sox9) in rat-BMSCs, upregulated tenogenic differentiation markers (Scx, Tnmd, Col3a1), and downregulated Mmp3 expression in rat-TDSCs. Furthermore, Mn-MSN@Gel modulated genes related to oxidative stress (Nrf2, Gpx4, Sod2) and inflammatory cytokines (IL-6, IL-10, Tnf-α), exhibiting anti-inflammatory effects and alleviating oxidative stress damage. In the rat rotator cuff repair model, Mn-MSN@Gel injection significantly improved postoperative biomechanical properties and promoted tissue regeneration at the TBI.

DISCUSSION

The self-healing and injectable properties of Mn-MSN@Gel ensure precise delivery and stable integration in vivo. By combining mechanical support with sustained release of bioactive ions, Mn-MSN@Gel provides a comprehensive therapeutic strategy for regenerative repair of the tendon-bone interface. Its biocompatibility and bioactivity facilitate cell recruitment, migration, and lineage-specific differentiation, which are crucial for reconstructing the functional gradient structure of the TBI. The anti-inflammatory and antioxidant effects further contribute to a favorable healing microenvironment. Overall, these findings indicate that Mn-MSN@Gel is a foundational biomaterial with significant therapeutic potential for enhancing structural regeneration and functional recovery of the TBI following rotator cuff injury.