构筑细菌微环境响应性自愈合水凝胶多重促进糖尿病足创面修复研究

Aiming at the low intelligence, short service life and insufficient antibacterial effect of the traditional dressings, according to the biological characteristics of wound micro-environment in diabetic foot and the reason why the wound is difficult to heal, this project intends to prepare bacteria-triggered self-healing hydrogels by means of molecular design, functional modification and dynamic covalent bond cross-linking techniques. In order to promote the wound repair of diabetic foot, the hydrogels are expected to respond to the bacterial micro-environment against infection, balance the internal micro-environment of the wound and provide a good environment for the wound through self-healing. By introducing active functional groups and specific molecules, the influence of material structure and composition to self-healing, bacteria-triggering, antibacterial activity and ability to balance the concentration gradient of chemokines will be studied systematically for exploring the basic rules of material design. We will also establish a model of chronic wound in diabetic rats to investigate the effect and interaction characteristics of material factors on chronic wound healing, and reveal the multi-promoting mechanism of hydrogels to wound repair from the molecule, cell and whole hierarchy levels. The successful implementation of the project will lay the foundation for the development and application of new multi-functional dressings, and it is also expected to provide a new strategy and theoretical basis for non-surgical treatment of chronic wounds in diabetic foot.

针对传统敷料缺乏智能性、使用寿命短、抗菌时效短等不足，依据糖尿病足伤口微环境的生物学特性和创面难愈合的原因，利用分子设计、功能改性和动态共价键交联技术等设计理念和方法，构建细菌微环境响应性自愈合水凝胶，以期水凝胶从响应伤口表面细菌微环境抗感染、平衡伤口内部微环境和自修复为伤口提供良好环境等方面促进糖尿病足创面修复。本项目拟通过引入活性功能基团和特异分子，系统研究材料结构与组成对水凝胶自愈合性、细菌微环境响应性、抗菌活性和平衡趋化因子浓度梯度的影响和规律，探寻材料设计的基本规律；建立糖尿病大鼠慢性创面模型，研究材料学因素对慢性伤口愈合的影响及其作用规律，从分子、细胞和整体层次上系统揭示水凝胶多重促进创面修复的机制。该项目的成功实施将为新型多功能敷料的开发与应用奠定基础，也有望为糖尿病足慢性创面的非手术治疗提供新策略与理论基础。

耐药性细菌生物膜的形成和伤口微环境的失调使糖尿病足（DF）等慢性伤口愈合困难。依据DF伤口微环境的生物学特性，利用动态共价键技术制备可响应伤口表面细菌微环境抗感染、调控伤口内部微环境和自修复为伤口提供闭合环境的多功能水凝胶促进DF创面修复是本项目的核心研究内容。围绕此核心，已成功制备一系列性能良好的多功能抗菌水凝胶，并探究了其促进全层皮肤损伤或糖尿病感染伤口的愈合机制。根据所制备的抗菌水凝胶，现对重要结果、关键数据、科学意义进行分类概述：.（1）A-HA/HA-ADH/AGs抗菌水凝胶：通过动态亚胺键和酰腙键交联成功制备具有止血性、抗氧化活性和自愈和能力A-HA/HA-ADH/AGs水凝胶，该水凝胶在酸性和HAase条件下可加速降解释放更多的氨基糖苷抗生素（AGs）按需和持续的抗感染，减少病原体的数量和伤口处的炎症反应，促进全层皮肤伤口的愈合。.（2）GQDs-ε-PL掺杂的抗菌水凝胶：通过动态亚胺键交联成功制备GQDs-ε-PL掺杂的抗菌水凝胶。GQDs-ε-PL纳米粒的掺杂，不仅改善了水凝胶的机械性能，还赋予了水凝胶光热/化学协同杀菌能力，使水凝胶可以通过止血、响应细菌感染微环境，光热/化学抗菌，自愈合等多种功能促进糖尿病大鼠感染伤口愈合。.（3）可调控伤口微环境的多功能水凝胶：通过动态硼酸酯键交联成功制备BP/Bi2O3/ε-PL@APBA-g-OCS/PVA水凝胶，该水凝胶可通过光热/化学联合治疗高效抗炎，还可清除ROS和调节细胞因子的表达改善伤口微环境，从而加速胶原蛋白的沉积，促进肉芽组织的形成和血管生成，实现糖尿病感染伤口快速愈合。.综上，上述多功能抗菌水凝胶的制备层层递进，研究层层深入，为新型多功能敷料的开发与应用奠定了基础，也为DF等慢性创面的非手术治疗提供了新策略与理论基础。本项目的研究成果已发表论文11篇，达到预期研究目标要求。