Enhanced Rotator Cuff Tendon-Bone Interface Regeneration with Injectable Manganese-Based Mesoporous Silica Nanoparticle-Loaded Dual Crosslinked Hydrogels

Chen Zihang^1,2*Youjie Liu²Tianxiang Liang²Zhaoyuan Du²Liming Deng²Zhiwen Wu²Ye LI³Haobo Zhong⁴JinJin Ma⁴Riwang Li⁵Huajun Wang²Qiu Dong²Tao Yu²Xiaofei Zheng²

• ¹The University of Hong Kong, Pokfulam, Hong Kong, SAR China
• ²Jinan University, Guangzhou, China
• ³The Hong Kong Polytechnic University, Hong Kong, Hong Kong, SAR China
• ⁴Guangdong Medical University, Zhanjiang, China
• ⁵Foshan University, Foshan, China

During the healing process, the functional gradient attachment of the rotator cuff (RC) tendon-bone interface fails to regenerate, severely impairing load transfer and stress dissipation, thereby increasing the risk of retears. Consequently, the management of rotator cuff tears remains a significant clinical challenge. In this study, a dualcrosslinked hyaluronic acid/polyethylene glycol (HA/PEG) hydrogel scaffold was synthesized using hyaluronic acid and polyethylene glycol as base materials.Manganese-doped silica nanoparticles (Mn-MSN) were incorporated into the hydrogel system to fabricate a manganese-based mesoporous silica nanoparticle-loaded dualcrosslinked hydrogel (Mn-MSN@gel). Characterization revealed that Mn-MSN@gel possesses a porous three-dimensional matrix with uniform distributions of Si, O, and Mn elements, enabling sustained slow release of Si⁴⁺ and Mn⁴⁺ ions. Additionally, the composite exhibits excellent mechanical properties, biodegradability, and biocompatibility, avoiding immune rejection while promoting cell migration/proliferation and accelerating regeneration of the tendon-bone interface. Its rheological properties and self-healing capability ensure smooth injection and longterm stability in vivo. This material achieves precise repair through minimally invasive injection, combining mechanical support and bioactivity to significantly enhance the quality of tendon-bone healing post-RC injury, offering an integrated therapeutic strategy for RC repair and improving functional recovery and long-term prognosis. Mn-MSN@gel enhanced the expression of osteogenic differentiation genes (Runx2, Alp, Sox9) in rat-BMSCs, upregulating tenogenic differentiation markers (Scx, Tnmd, Col3a1) and downregulating Mmp3 expression in rat-TDSCs. Additionally, Mn-MSN@Gel modulated oxidative stress-related genes (Nrf2, Gpx4, Sod2) and inflammatory cytokine genes (IL-6, IL-10, Tnf-α), exhibiting anti-inflammatory effects and mitigating oxidative stress damage. In a rat rotator cuff repair model, Mn-MSN@Gel injection significantly improved postoperative biomechanical properties and promoted tissue regeneration at the tendon-bone interface (TBI). These findings collectively highlight Mn-MSN@Gel as a foundational biomaterial with promising therapeutic potential for structural TBI repair in rotator cuff injuries.