Nanodefensin-encased hydrogel with dual bactericidal and pro-regenerative functions for advanced wound therapy.
Nanodefensin-encased hydrogel with dual bactericidal and pro-regenerative functions for advanced wound therapy.
复制标题
纳米防御素包裹的水凝胶具有双重杀菌和促再生功能，适用于高级伤口治疗。
作者：
Luo G;Sun Y;Zhang J;Xu Z;Lu W;Wang H;Zhang Y;Li H;Mao Z;Ye S;Cheng B;Fang X
背景资料：宿主防御肽（HDPs）已成为伤口管理的新型治疗范例;然而，由于其不良的药理学性质和缺乏合适的药物制剂，其临床应用仍然是一个挑战。纳米防御素（ND）是一种纳米工程化的人α-防御素5（HD 5），相对于母体化合物，已显示出改善的药理学特性。在这项研究中，我们设计了一种纳米防御素包裹的水凝胶（NDEFgel），研究了NDEFgel对伤口愈合的影响，并阐明了潜在的机制。方法：化学合成ND，并通过体外抗菌试验、划痕试验和免疫印迹试验进行功能测试。通过体外降解、药物释放和抗菌活性等实验对不同的NDEF凝胶进行了评价。在全层切除的小鼠模型中，将最佳NDEF凝胶直接应用于伤口部位，并评估疗效。此外，NDEF凝胶开发的促再生作用的潜在机制也进行了探讨。结果：ND除具有杀菌作用外，还通过促进成纤维细胞迁移和分化来调节成纤维细胞的行为。在测试的水凝胶中，Pluronic F127（Plu）水凝胶由于其有利的控制释放和与ND的相容性而代表了用于ND递送的最理想的载体。NDEF凝胶局部处理创面床导致加速伤口再生和减弱细菌负荷。我们进一步证明，NDEF凝胶治疗显著上调与胶原沉积和成纤维细胞相关的基因，并增加肌成纤维细胞和Rac 1的表达。因此，我们发现，Rac 1是一个关键因素，在ND诱导的调制成纤维细胞的行为在体外通过Rac 1依赖的细胞骨架重排。结论：我们的研究结果表明，NDEF凝胶可能是一个有前途的双重作用的治疗选择，先进的伤口管理在未来。
Background: Host defense peptides (HDPs) have emerged as a novel therapeutic paradigm for wound management; however, their clinical applications remain a challenge owing to their poor pharmacological properties and lack of suitable pharmaceutical formulations. Nanodefensin (ND), a nanoengineered human α-defensin 5 (HD5), has shown improved pharmacological properties relative to the parent compound. In this study, we engineered a nanodefensin-encased hydrogel (NDEFgel), investigated the effects of NDEFgel on wound healing, and elucidated underlying mechanisms. Method: ND was chemically synthesized and tested functions by in vitro antimicrobial and scratch assays and western blotting. Different NDEFgels were evaluated by in vitro characterizations including degradation, drug release and antimicrobial activity. In full-thickness excisional murine models, the optimal NDEFgel was directly applied onto wound sites, and the efficacy was assessed. Moreover, the underlying mechanisms of pro-regenerative effect developed by NDEFgel were also explored. Results: Apart from bactericidal effects, ND modulated fibroblast behaviors by promoting migration and differentiation. Among the tested hydrogels, the Pluronic F127 (Plu) hydrogel represented the most desirable carrier for ND delivery owing to its favorable controlled release and compatibility with ND. Local treatment of NDEFgel on the wound bed resulted in accelerated wound regeneration and attenuated bacterial burden. We further demonstrated that NDEFgel therapy significantly upregulated genes related to collagen deposition and fibroblasts, and increased the expression of myofibroblasts and Rac1. We therefore found that Rac1 is a critical factor in the ND-induced modulation of fibroblast behaviors in vitro through a Rac1-dependent cytoskeletal rearrangement. Conclusion: Our results indicate that NDEFgel may be a promising dual-action therapeutic option for advanced wound management in the future.