基于木葡聚糖基水凝胶的防术后粘连及相关分子机制研究

Post-operative intestinal adhesion is one of the common and serious complications in surgery. It can cause pain, infertility, and intestinal obstruction etc. The anti-adhesion approach could primarily be divided into two categories: pharmacological treatment and barrier-based devices. Among those methods, solid or liquid barriers are currently the most useful for reducing adhesion. The films are hard to cover over the tissues of complex geometry, and aggressively adhere to any moisture even on the surgeon’s gloves during placement.. Recently, much attention has been paid on injectable hydrogels in the fields of biomaterials and polymer science. A series of in situ formed chemically crosslinked injectable hydrogels have been successfully tried to prevent peritoneal adhesion. For a chemical hydrogel, the addition of chemical initiators or any other treatments for triggering chemical reactions in the body may bring with biocompatibility problems to a certain extent. Physically crosslinked hydrogels have got to be an alternative choice.. In this project, xyloglucan will be selected as the main chain because of its excellent biocompatibility and thermos-responsive sol-gel transition behavior. Polybetaine, a zwitterionic polymer, with non-fouling properties will grafted on xyloglucan through ATRP and obtain the copolymer of xyloglucan-g-polybetaine (XG-PB). XG-PB is expected to have the advantage of biodegradable with non-toxicity degradation product, being solution at the room temperature and gelation at body temperature and resistance to non-specific protein adsorption. The mechanism for its thermos-responsive performance and non-fouling behavior will be investigated in molecular level. The in vitro biocompatibility and anti-cell adhesion will be evaluated with L929, RAW264.7 and HUVEC as model cells. An animal model of sidewall defect-bowel abrasion will be employed to study the in vivo prevention efficacy to peritoneal adhesion. The successful of this project will pioneer a new way for the treatment of post-operative intestinal adhesion.

针对临床上普遍存在但难以克服的术后粘连问题，本项目以具有“室温溶解，体温凝胶”特征的木葡聚糖为基材，将具有优异抗蛋白质非特异性吸附的两性离子引入，制得木葡聚糖基两性离子聚合物(XG-PB)，赋予其良好的抗蛋白质非特异性吸附性能和适宜的热致凝胶行为。从分子和基团层次上揭示XG-PB的热致凝胶机理，探索其结构与抗蛋白吸附行为之间的内在关系。在此基础上，以L929、RAW264.7和HUVEC为模型细胞，SD大鼠和新西兰白兔为实验动物，研究XG-PB凝胶的抗细胞粘附及防术后粘连的相关分子机制。研究结果将在改善防术后粘连操作的便利性、提高防粘连效果的同时，对多糖基聚合物的热致响应行为及抗蛋白质吸附机理有更为深刻的认识，拓展其在生物医学领域的应用。

由于术后粘连的普遍性和粘连后果的严重性，对于术后粘连的预防成为临床上亟需解决的医学难题之一。可注射水凝胶由于兼具液态类材料的操作便利性和固态类材料的物理屏障性，并能结合微创疗法，在术后防粘连领域得到了广泛的关注。针对现有的可注射凝胶在预防术后粘连方面存在的生物安全性差及防粘连效果不佳等问题，本项目设计并构建了三类基于温敏和点击化学的可注射水凝胶，在对理化性能及体内外生物相容性和降解性研究的基础上，建立了不同的粘连模型并对所制备水凝胶的防粘连效果进行了评价。. （1） 利用绿色酶解反应制得了具有反向温敏行为的mXG多糖水凝胶，基于mXG的可注射性和良好的生物相容性及生物可降解性，首次将其应用于术后防粘连的研究中，不仅提高了手术操作的便利性，而且在SD大鼠腹壁-盲肠损伤模型、腹壁-盲肠粘连松解术后二次损伤模型和70%肝切除模型中均取得了良好的预防术后粘连的效果。研究结果不仅揭示了mXG的温敏凝胶机制，而且作为术后防粘连材料，具有明显地临床应用价值。. （2）首次将两种同时具有反向温度响应性的多糖基温敏凝胶进行共混，制备了可注射温敏mXG/HBC复合水凝胶，揭示了mXG/HBC复合体系的温敏机理。将mXG/HBC复合水凝胶用于术后防粘连的研究，证明其不仅能够有效地预防粘连松解术后再次粘连的发生，还能够促进创面愈合、减少瘢痕形成。研究成果补充了聚合物温敏行为机理，所开发的防粘连体系具有良好的应用前景。. （3）基于两性离子聚合物所特有的抗蛋白质非特异性黏附的特性，设计并制备了点击可注射Z凝胶及负载头孢西丁钠的Z/C凝胶，结果表明两种凝胶均可以预防术后粘连的发生，并且Z/C凝胶在防粘连的基础上能够有效的抑制腹腔内的细菌感染，减缓炎症反应，并促进创面组织的愈合。