Zhang Zhengchuan, Shen Jiaqi, Xu Ruogu, Yang Yang, Yu Xiaolin, Yu Dongsheng, Deng Feilong
Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, PR China.
Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, PR China.
Mater Today Bio. 2025 May 20;32:101892. doi: 10.1016/j.mtbio.2025.101892. eCollection 2025 Jun.
Critical bone defect with soft tissue fenestration poses a significant therapeutic challenge without the premise of barrier periosteum in situ for the relatively independent repair spaces of soft tissue and bone. Inspired by the regenerative functions of mesenchymal stem cells (MSCs)-derived small extracellular vesicles (sEVs) and the guided properties of in situ-generated periosteum, here we report the therapeutic benefits of dual-functional biomimetic periosteum (DBP) incorporating engineered sEVs for treating critical bone defect with soft tissue fenestration. We started our experiment with the construction of engineered sEVs via porous titanium-preconditioned MSCs-derived sEVs (Ti-sEVs). COL1A1 and MMP1 were enriched in Ti-sEVs with enhanced uptake efficiency of fibroblasts and bone marrow-derived MSCs for scarless soft tissue and bone repair abilities via TGF-beta1/SMAD pathway in vitro. DPB was constructed via the chemically crosslinking and lyophilized treatment of a xenogenic acellular dermal matrix. Incorporation and in vivo delivery of Ti-sEVs were successfully achieved via the controlled-release DPB with the characteristics of a loose surface facing the bone defect and a dense surface facing the soft tissue fenestration. DBP incorporating Ti-sEVs promoted the repair of the surrounding native periosteum in situ via the critical skull defect with skin fenestration models in rats. Bone repair with scarless soft tissue was achieved by enhanced angiogenesis and limited osteoclastic activity. Collectively, this dual-functional system could synergistically achieve critical bone defect regeneration with scarless soft tissue repair via TGF-beta1/SMAD pathway with the sustained release of Ti-sEVs, providing a promising strategy of engineered sEVs for preferable tissue regeneration.
伴有软组织开窗的严重骨缺损在没有原位屏障骨膜为软组织和骨提供相对独立修复空间的前提下，构成了重大的治疗挑战。受间充质干细胞（MSCs）衍生的小细胞外囊泡（sEVs）的再生功能和原位生成骨膜的引导特性的启发，在此我们报告了包含工程化sEVs的双功能仿生骨膜（DBP）在治疗伴有软组织开窗的严重骨缺损方面的治疗益处。我们通过多孔钛预处理的MSCs衍生的sEVs（Ti-sEVs）构建工程化sEVs来开始我们的实验。COL1A1和MMP1在Ti-sEVs中富集，通过体外TGF-β1/SMAD途径，成纤维细胞和骨髓来源的MSCs对其摄取效率提高，具有无瘢痕软组织和骨修复能力。DBP通过对异种脱细胞真皮基质进行化学交联和冻干处理构建而成。通过具有面向骨缺损的疏松表面和面向软组织开窗的致密表面特征的控释DBP，成功实现了Ti-sEVs的包封和体内递送。在大鼠颅骨临界缺损伴皮肤开窗模型中，包含Ti-sEVs的DBP促进了周围原位天然骨膜的修复。通过增强血管生成和限制破骨细胞活性，实现了无瘢痕软组织的骨修复。总的来说，这个双功能系统可以通过TGF-β1/SMAD途径和Ti-sEVs的持续释放，协同实现严重骨缺损再生和无瘢痕软组织修复，为更好的组织再生提供了一种有前景的工程化sEVs策略。
