仿生构建具有“自适应”抗菌功能的胶原表面及其工作机制研究

How to circumvent the cytotoxicity of incorporated antibacterial agents is of great importance, and remains difficult for fully utilizing the inherent biocompatibility of collagen-based biomedical materials. Herein, the applicant, inspired by the hiding mechanism of nematocysts in sea anemones, intends to prepare bionic “tentacles” copolymerized by N-isopropylacrylamide and safrole, a hydrophobic model antibacterial agent, and design methods to immobilize them onto naturally occurring collagen surface. It is envisioned that when the modified collagen is transferred into living tissues from low-temperature storage liquid, the safrole monomeric units may be automatically hided with shielded cytotoxicity due to the coil-to-globule transition of the poly(N-isopropylacrylamide) “tentacles”, which is known as an entropically-driven hydrophobic association process. To verify this idea, this project plans to manipulate the content and distribution of safrole monomeric units on the poly(N-isopropylacrylamide) “tentacles” by using micellar copolymerization method, which enables systematic investigation of the molecular basis for proper working of these “tentacles”. Meanwhile, molecular dynamics simulation coupled with experimental assays will be conducted to establish a kinetic model that describes the working procedure of the “tentacles”, with corresponding thermodynamic theory elucidated. With the design principle, target-specific preparation method, and collagen-compatible immobilization strategy of the bionic “tentacles” obtained, a novel collagen surface with self-adaptive antibacterial function can be established, which addresses the cytotoxicity problem of physically-incorporated antibacterial agents. According to these anticipated results, we aim at opening up a new avenue for scientific utilization of traditional antibacterial agents. Also, these results are expected to provide new insight into solving the long-standing dilemma between the necessity of antibacterial treatment of collagen and the maintenance of its inherent biocompatibility, laying foundation for expanded high-valued utilization of collagen-based biomedical materials.

如何规避所含抗菌剂的毒副作用，是胶原基医用材料固有生物相容性得以充分利用的关键和难点。鉴于此，申请人受海葵刺细胞隐藏机制启发，拟以疏水黄樟素为模型抗菌剂，设计含抗菌黄樟素结构单元的聚（N-异丙基丙烯酰胺）仿生“触手”，研究其在胶原表面的安装方法，设想可利用该“触手”热致构象转变及熵驱动原理，实现胶原所含抗菌剂在活组织中的自动隐藏与毒性屏蔽。为此，本课题拟利用胶束共聚，控制黄樟素在“触手”主链上的含量与分布，研究该“触手”工作的结构基础，同时将实验与分子模拟相结合，建立其工作动力学模型并阐明热力学原理，获得具有指导意义的黄樟素抗菌活性调用“触手”设计理论、定向制备方法及与天然胶原结构相适应的安装方法，在胶原表面构建以“自适应”为特色的全新抗菌模式，为传统抗菌剂开辟科学利用新途径，为解决胶原抗菌防腐必要性与维持生物相容性完整间由来已久的矛盾提供新思路，为突破胶原基医用材料的应用限制奠定基础。

胶原结构独特、功能多样，在当代医美、组织工程领域占有重要地位。然而，天然胶原极易受微生物侵蚀。因此，抗菌防腐是其作为医用材料高值利用的必要前提。长期以来，通过外添加抗菌剂以提高胶原的抗菌防腐性被证明是一种行之有效的方法。然而，常用抗菌剂大多具有生理毒性；临床应用时，胶原器件中的抗菌剂可引发过敏、炎症、神经紊乱、甚至肾脏损伤等不良反应。因此，如何规避所含抗菌剂的毒副作用，是胶原基医用材料固有生物相容性得以充分利用的关键和难点。鉴于此，本课题受海葵触手上刺细胞隐藏机制启发，以疏水乙烯基环丙沙星为模型抗菌剂，设计其与N-异丙基丙烯酰胺共聚反应路线，控制两种结构单元在共聚物主链上的排列方式，研究共聚物热致构象转变过程中环丙沙星侧基仿生隐藏、抗菌活性屏蔽的分子结构基础，考察共聚物作为功能“触手”在胶原表面安装并“自适应”规避抗菌侧基毒副作用的可行性，取得成果如下：（1）探明了乙烯基环丙沙星结构单元含量、分布对其热致隐藏度、抗菌活性屏蔽度的影响规律，建立了仿生“触手”热致构象演化动力学模型并阐明了其热力学原理，揭示了环丙沙星侧基热致隐藏与活性屏蔽机制，获得了可按需调用其抗菌活性的仿生“触手”分子设计与制备方法；（2）在此基础上，以无损胶原独特的三股螺旋结构为原则，系统研究了上述仿生“触手”在胶原表面的安装方法，证实了利用该“触手”温敏特性及与临床相关的自然温差，“自适应”控制胶原抗菌功能的可行性，实现了胶原所含抗菌剂在活组织中的自动隐藏与毒性适时屏蔽。上述“自适应”抗菌模式的构建，为众多传统抗菌剂开辟了科学利用新途径，为解决天然胶原抗菌防腐必要性与维持生物相容性完整间由来已久的矛盾提供了新思路，为突破胶原基医用材料的应用限制奠定了基础，同时为其他生物质材料的抗菌策略优化提供了借鉴。