Mei Rui, Sun Jinpeng, Cao Shuchang, Shi Mohan, Song Zeyuan, Hua Feng, Zhou Gaoxin, Zhang Mingshun, Liu Jun
Department of Orthopedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China.
School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing 211166, China.
Acta Biomater. 2024 Oct 15;188:420-431. doi: 10.1016/j.actbio.2024.09.006. Epub 2024 Sep 12.
Epidural fibrosis is a primary contributor to the failure of laminectomy surgeries, leading to the development of failed back surgery syndrome (FBSS). Post-laminectomy, neutrophils infiltrate the surgical site, generating neutrophil extracellular traps (NETs) that contribute to epidural fibrosis. Reactive oxygen species (ROS) play a pivotal role in mediating NETs formation. Molecular hydrogen, recognized for its selective antioxidant properties and biosafety, emerges as a potential therapeutic gas in suppressing epidural fibrosis. In this study, we developed an in-situ hydrogen release hydrogel that inhibits the formation of NETs and mitigates epidural scarring. Biodegradable magnesium (Mg) microspheres served as a hydrogen source, coated with PLGA to regulate hydrogen release. These microspheres (Mg@PLGA) were then incorporated into a PLGA-PEG-PLGA thermosensitive hydrogel (Mg@PLGA@Gel), providing a surgical implant for sustained, long-term hydrogen release. In vitro experiments confirmed the biocompatibility of the system, demonstrating that hydrogen produced by Mg@PLGA effectively neutralizes neutrophil intracellular ROS and inhibits NETs formation. Histological analyses, including H&E staining, MRI, Masson staining, and immunohistochemistry, collectively indicate that Mg@PLGA@Gel is biocompatible and effectively inhibits epidural fibrosis post-laminectomy. Furthermore, Mg@PLGA@Gel inhibits ROS accumulation and NETs formation at the surgical site. These findings suggest that Mg@PLGA@Gel ensures continuous, therapeutic hydrogen concentration, providing relief from epidural fibrosis in a laminectomy mouse model. STATEMENT OF SIGNIFICANCE.
硬膜外纤维化是椎板切除术失败的主要原因，会导致腰椎手术失败综合征（FBSS）的发生。椎板切除术后，中性粒细胞浸润手术部位，产生有助于硬膜外纤维化的中性粒细胞胞外陷阱（NETs）。活性氧（ROS）在介导NETs形成中起关键作用。分子氢因其选择性抗氧化特性和生物安全性而受到认可，成为抑制硬膜外纤维化的潜在治疗性气体。在本研究中，我们开发了一种原位释氢水凝胶，可抑制NETs形成并减轻硬膜外瘢痕形成。可生物降解的镁（Mg）微球作为氢源，表面包覆聚乳酸-羟基乙酸共聚物（PLGA）以调节氢释放。然后将这些微球（Mg@PLGA）掺入PLGA-聚乙二醇-PLGA热敏水凝胶（Mg@PLGA@Gel）中，提供一种用于持续、长期释氢的手术植入物。体外实验证实了该系统的生物相容性，表明Mg@PLGA产生的氢有效中和中性粒细胞内ROS并抑制NETs形成。包括苏木精-伊红染色、磁共振成像、马松染色和免疫组织化学在内的组织学分析共同表明，Mg@PLGA@Gel具有生物相容性，可有效抑制椎板切除术后的硬膜外纤维化。此外，Mg@PLGA@Gel抑制手术部位的ROS积累和NETs形成。这些发现表明，Mg@PLGA@Gel可确保持续的治疗性氢浓度，在椎板切除小鼠模型中缓解硬膜外纤维化。重要性声明。
