Qiu Xingan, Xiang Feng, Bu Pengzhen, Lv Qiqi, Liu Xuezhe, Zhou Bikun, Tan Meijun, Jiang Xiao, Cheng Xuan, Serda Maciej, Xiong Xiaojiang, Feng Qian, Cai Kaiyong
Department of Orthopedics, Chongqing University Three Gorges Hospital, Chongqing 404010, PR China; School of Medicine, Chongqing University, Chongqing 404010, PR China; Key laboratory of Biorheological Science and Technology, Ministry of Educations, Collage of Bioengineering, Chongqing University, Chongqing 400044, PR China.
Key laboratory of Biorheological Science and Technology, Ministry of Educations, Collage of Bioengineering, Chongqing University, Chongqing 400044, PR China.
Acta Biomater. 2025 Jun 15;200:340-357. doi: 10.1016/j.actbio.2025.05.044. Epub 2025 May 21.
Chronic diabetic wounds affect a significant number of individuals and present considerable challenges in clinical treatment. Ideal diabetic wound dressings should possess antibacterial properties, the ability to regulate redox balance, and the capacity to promote tissue regeneration. Herein, we developed an injectable mixed-valence copper nanocluster-crosslinked hydrogel (HS-Cu) through reductive metal-ligand coordination assembly of Cu and thiourea-grafted hyaluronic acid (HA-NCSN) to achieve the above-mentioned requirements in one-step. Density functional theory (DFT) calculations indicated that the bioactive mixed-valence copper nanoclusters exhibited enhanced photothermal properties and conductivity, enabling HS-Cu hydrogel to effectively combat bacteria and accelerate tissue regeneration through combined with photothermal therapy (PTT) and electrical stimulation (ES). Notably, the abundant thiourea groups inside the hydrogel acted as reactive oxygen species (ROS) scavengers to regulate the redox balance at the wound site. Additionally, in vivo experiments indicated that HS-Cu hydrogel promoted hemostasis in wounds. Overall, the HS-Cu hydrogel accelerated the three phases of diabetic wound healing: hemostasis, inflammation, and proliferation, with specific mechanisms including rapid hemostasis, bacterial eradication by PTT, scavenging of ROS, and wound healing acceleration through ES. All the results indicated that mixed-valence copper nanocluster-crosslinked hydrogel demonstrated great potential in the treatment of diabetic wounds. STATEMENT OF SIGNIFICANCE: This study developed an injectable hydrogel through metal-ligand coordination assembly, which showed great potential for accelerating diabetic wound repair in clinic. The hydrogel demonstrated superior antioxidant capacity, photothermal properties, and conductivity due to the internal bioactive mixed-valence copper nanoclusters formed through the reductive coordination between Cu ions and thiourea groups. By combining photothermal therapy (PTT) and electrical stimulation (ES), this hydrogel effectively addressed critical challenges in diabetic wound healing, including bacterial infection inhibition, oxidative stress reduction, and tissue regeneration acceleration, thereby significantly enhancing wound healing. The study also provides perspectives for the design and clinical application of ion chelation based functional biomaterials.
慢性糖尿病伤口影响着大量个体，给临床治疗带来了巨大挑战。理想的糖尿病伤口敷料应具有抗菌性能、调节氧化还原平衡的能力以及促进组织再生的能力。在此，我们通过铜与硫脲接枝透明质酸（HA-NCSN）的还原金属-配体配位组装，一步法制备了一种可注射的混合价态铜纳米簇交联水凝胶（HS-Cu），以满足上述要求。密度泛函理论（DFT）计算表明，生物活性混合价态铜纳米簇具有增强的光热性能和导电性，使HS-Cu水凝胶能够通过结合光热疗法（PTT）和电刺激（ES）有效对抗细菌并加速组织再生。值得注意的是，水凝胶内部丰富的硫脲基团作为活性氧（ROS）清除剂，调节伤口部位的氧化还原平衡。此外，体内实验表明HS-Cu水凝胶可促进伤口止血。总体而言，HS-Cu水凝胶加速了糖尿病伤口愈合的三个阶段：止血、炎症和增殖，具体机制包括快速止血、PTT清除细菌、ROS清除以及通过ES加速伤口愈合。所有结果表明，混合价态铜纳米簇交联水凝胶在糖尿病伤口治疗中显示出巨大潜力。重要性声明：本研究通过金属-配体配位组装开发了一种可注射水凝胶，在临床上加速糖尿病伤口修复方面显示出巨大潜力。由于铜离子与硫脲基团之间的还原配位形成了内部生物活性混合价态铜纳米簇，该水凝胶具有优异的抗氧化能力、光热性能和导电性。通过结合光热疗法（PTT）和电刺激（ES），这种水凝胶有效解决了糖尿病伤口愈合中的关键挑战，包括抑制细菌感染、降低氧化应激和加速组织再生，从而显著促进伤口愈合。该研究还为基于离子螯合的功能性生物材料的设计和临床应用提供了思路。
