School of Pharmaceutical Sciences, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325000, PR China.
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, Zhejiang 325035, PR China.
J Control Release. 2024 Dec;376:701-716. doi: 10.1016/j.jconrel.2024.10.046. Epub 2024 Oct 30.
Basic fibroblast growth factor (bFGF) has proved to be effective for wound healing, yet its effectiveness is extremely retarded in diabetic wounds due to the severe oxidative stress in wound beds. To solve this issue, herein a novel combination therapy of bFGF and N-acetylcysteine (NAC, antioxidant) was devised for improved diabetic wound repair. To avoid rapid loss of both drugs in the wound beds, a bioresponsive hydrogel (bFGF-HSPP-NAC) was engineered by incorporating bFGF and NAC into polymer-drug conjugates (HSPP) via thiol-disulfide exchange reactions. In response to oxidative stress (e.g., reactive oxygen species), the disulfide bonds (SS) within the hydrogel are broken into thiol groups (-S-H), thereby promoting hydrogel degradation and enabling controlled drug release. Initially, NAC is released to scavenge free radicals and ameliorate oxidative damage. Subsequently, bFGF is released to expedite tissue regeneration. This combinatorial strategy is tailored to the specific characteristics of the wound microenvironment at various stages of diabetic wound healing, thereby achieving therapeutic efficacy. The results indicate that the bFGF-HSPP-NAC hydrogel markedly enhances re-epithelialization, collagen deposition, hair follicle regeneration, and neovascularization. In conclusion, the bioresponsive bFGF-HSPP-NAC hydrogel demonstrates significant potential for application in combinatorial therapeutic approaches for diabetic wound healing.
碱性成纤维细胞生长因子（bFGF）已被证明对伤口愈合有效，但由于伤口床中严重的氧化应激，其在糖尿病伤口中的效果极其缓慢。为了解决这个问题，本文设计了一种碱性成纤维细胞生长因子（bFGF）和 N-乙酰半胱氨酸（NAC，抗氧化剂）的新型联合治疗方法，以改善糖尿病伤口修复。为了避免两种药物在伤口床中迅速流失，通过巯基-二硫交换反应将 bFGF 和 NAC 掺入聚合物-药物缀合物（HSPP）中，设计了一种响应性水凝胶（bFGF-HSPP-NAC）。响应氧化应激（例如，活性氧物种），水凝胶中的二硫键（SS）断裂成巯基（-S-H），从而促进水凝胶降解并实现药物控制释放。最初，NAC 被释放以清除自由基并改善氧化损伤。随后，bFGF 被释放以加速组织再生。这种组合策略针对糖尿病伤口愈合各个阶段的伤口微环境的特定特征进行了定制，从而实现了治疗效果。结果表明，bFGF-HSPP-NAC 水凝胶显著增强了再上皮化、胶原沉积、毛囊再生和新血管生成。总之，响应性 bFGF-HSPP-NAC 水凝胶在糖尿病伤口愈合的联合治疗方法中具有显著的应用潜力。
