Abstract：
Avoiding ischemic necrosis after flap transplantation remains a significant clinical challenge. Developing an effective pretreatment method to promote flap survival postoperatively is crucial. Cobalt chloride (CoCl2) can increase cell tolerance to ischemia and hypoxia condition by stimulating hypoxia-inducible factor-1 (HIF-1) expression. However, the considerable toxic effects severely limit the clinical application of CoCl2. In this study, cobalt-based metal-organic frameworks (Co-MOF) encapsulated in a microneedle patch (Co-MOF@MN) was developed to facilitate the transdermal sustained release of Co2+ for rapid, minimally invasive rapid pretreatment of flap transplantation. The MN patch was composed of a fully methanol-based two-component cross-linked polymer formula, with a pyramid structure and high mechanical strength, which satisfied the purpose of penetrating the skin stratum corneum of rat back to achieve subcutaneous vascular area administration. Benefiting from the water-triggered disintegration of Co-MOF and the transdermal delivery via the MN patch, preoperative damage and side effects were effectively mitigated. Moreover, in both the oxygen-glucose deprivation/recovery (OGD/R) cell model and the rat dorsal perforator flap model, Co-MOF@MN activated the HIF-1α pathway and its associated downstream proteins, which reduced reperfusion oxidative damage, improved blood supply in choke areas, and increased flap survival rates post-transplantation. This preprotection strategy, combining MOF nanoparticles and the MN patch, meets the clinical demands for trauma minimization and uniform administration in flap transplantation. STATEMENT OF SIGNIFICANCE: Cobalt chloride (CoCl2) can stimulate the expression of hypoxia-inducible factor (HIF-1) and improve the tolerance of cells to ischemia and hypoxia conditions. However, the toxicity and narrow therapeutic window of CoCl2 severely limit its clinical application. Herein, we explored the role of Co-MOF as a biocompatible nanocage for sustained release of Co2+, showing the protective effect on vascular endothelial cells in the stress model of oxygen-glucose deprivation. To fit the clinical needs of minimal trauma in flap transplantation, a Co-MOF@MN system was developed to achieve local transdermal delivery at the choke area, significantly improving blood supply opening and flap survival rate. This strategy of two-step delivery of Co2+ realized the enhancement of biological functions while ensuring the biosafety.
摘要：
避免皮瓣移植后缺血性坏死仍然是一个重大的临床挑战。开发有效的预处理方法以促进皮瓣术后存活至关重要。氯化钴(CoCl2)可通过刺激缺氧诱导因子-1(HIF-1)的表达来提高细胞对缺血缺氧的耐受性。然而,严重的毒性作用严重限制了CoCl2的临床应用。在这项研究中,开发了封装在微针贴片（Co-MOF@MN）中的钴基金属有机骨架（Co-MOF@MN），以促进Co2+的透皮持续释放，皮瓣移植的微创快速预处理。MN贴片由完全基于甲醇的双组分交联聚合物配方组成，具有金字塔结构和高机械强度，达到穿透大鼠皮肤角质层的目的，达到皮下血管面积给药的目的。受益于Co-MOF的水触发崩解和通过MN贴剂的透皮递送，术前损伤和副作用得到有效缓解。此外，在氧糖剥夺/恢复（OGD/R）细胞模型和大鼠背侧穿支皮瓣模型中，Co-MOF@MN激活HIF-1α通路及其相关下游蛋白,减少再灌注氧化损伤，改善窒息区的血液供应，移植后皮瓣存活率提高。这种预保护策略，结合MOF纳米粒子和MN贴片，满足皮瓣移植中创伤最小化和统一给药的临床需求。意义:氯化钴(CoCl2)可刺激缺氧诱导因子(HIF-1)的表达,提高细胞对缺血缺氧的耐受性。然而,CoCl2的毒性和狭窄的治疗窗口严重限制了其临床应用。在这里，我们探索了Co-MOF作为生物相容性纳米笼持续释放Co2+的作用，在氧糖剥夺应激模型中显示了对血管内皮细胞的保护作用。为满足皮瓣移植中创伤小的临床需要,开发了一种Co-MOF@MN系统，以在扼流圈区域实现局部透皮递送，显著提高供血开放和皮瓣成活率。这种两步递送Co2+的策略在保证生物安全性的同时实现了生物功能的增强。
