加载aFGF的泊洛沙姆-肝素共聚物温敏凝胶的研制及其促进糖尿病溃疡修复作用研究

The microenvironment of diabetic ulcer would cause lack of growth factor and their receptor in the damage tissue which is an important reason for the delay of the wound.Obviously, aFGF’s effect on acute wound healing is widely acknowledged. However, on chronic ulcer where there are covered with inflammation factors, aFGF is quite easy to be decomposed by extracellular protease and thereby losing its pharmacological action. Therefore, the effect of directly using aFGF on diabetic ulcer would not give us a very pleasant outcome. Engineering skin which is created by Poloxamer hydrogel has not only can provide the matrix components but also can accelerate the rate of tissue repair. It is also can reverse poor repair condition by maintaining aFGF’s effective concentration on ulcer area via slowly releasing aFGF. Heparin-Poloxamer (HP) which was prepared by the project team during earlier period has already been applied on revision of anastomosis of blood vessel. In this experiment, we used heparin-Poloxamer (HP) to create a thermosensitive hydrogels which carries aFGF. Also we applied modern pharmacology method to study the effect of aFGF-HP on chronic wound and the improvement on ulcer microenvironment.

糖尿病溃疡创面微环境改变,导致组织生长因子及其受体表达下调,是糖尿病溃疡难愈合的重要原因之一。aFGF在创面愈合中的作用已得到广泛认可,但是在炎症因子介导的慢性溃疡创面，aFGF很容易被细胞外蛋白酶降解而丧失药理作用，因此，aFGF应用在糖尿病等慢性溃疡创面其效果受到极大影响。以泊洛沙姆水凝胶材料负载生长因子制备的组织工程皮肤，不仅可以提供创面愈合所需的基质成份，而且有利于aFGF在创面局部缓慢、持续释放，保持aFGF在用药局部的有效浓度，达到加速组织修复和改善创面微环境的作用。项目组制备的可控相变温度的肝素-泊洛沙姆（HP）新材料已经应用于血管吻合术创口愈合中。本项目采用可控相变温度的肝素-泊洛沙姆（HP）新材料，制备包载aFGF的原位温敏型水凝胶，运用现代药理学和药效学方法，评价包载aFGF的温敏型水凝胶对慢性溃疡创面的修复及改善溃疡微环境的作用。

糖尿病溃疡创面微环境改变,导致组织生长因子及其受体表达下调,是糖尿病溃疡难愈合的重要原因之一。aFGF在创面愈合中的作用已得到广泛认可,但是在炎症因子介导的慢性溃疡创面，aFGF很容易被细胞外蛋白酶降解而丧失药理作用，因此，aFGF应用在糖尿病等慢性溃疡创面其效果受到极大影响。以泊洛沙姆水凝胶材料负载生长因子制备的组织工程皮肤，不仅可以提供创面愈合所需的基质成份，而且有利于aFGF在创面局部缓慢、持续释放，保持aFGF在用药局部的有效浓度，达到加速组织修复和改善创面微环境的作用。在此理论基础上，本项目采用可控相变温度的肝素-泊洛沙姆（HP）新材料，制备包载aFGF的原位温敏型水凝胶，运用现代药理学和药效学方法，评价包载aFGF的温敏型水凝胶对慢性溃疡创面的修复及改善溃疡微环境的作用。.本项目自立项以来围绕课题设定的研究路线开展了 [aFGF-肝素-泊洛沙姆]递送系统制备、质量评价、体外及体内药效学评价等研究。水凝胶制备工艺优化中我们最终选择比较适合体表胶凝的18.0%-20.0% HP水凝胶为最终浓度，确定19.0%HP和1.0%甘油的配方在外观、均匀性和耐寒性方面具有较好的性能且在12h内可实现aFGF的缓释，同时保湿效果也比较好；该凝胶应用于实际组织表面受组织渗液影响胶凝温度将升高4℃；流变学性质显示19% HP水凝胶的相转变温度低于皮肤温度；HP-aFGF温敏水凝胶体外研究显示可促进细胞增殖迁移且不促进细胞的凋亡。体外药效学试验结果显示HP-aFGF温敏水凝胶可明显促进糖尿病大鼠创面的愈合，通过调控炎症因子IL-6、IL-10、TGF-β的表达改善创面的微环境。.以上研究显示创新制备的[aFGF-肝素-泊洛沙姆]递送系统各项性能有利于提高aFGF 的物理稳定性，促进糖尿病慢性溃疡愈合，同时揭示了aFGF炎症调节的新机制，为其进一步开发为促愈合及抗炎药物奠定了基础。