Engineered biomimetic materials for intestinal mucosal healing

项目摘要/摘要 尽管炎症性肠病(IBD)的治疗不断改进，但实现了 对于许多IBD患者来说，治愈仍然很困难。IBD的一个重要特征是黏膜屏障受损。 导致上皮的侵蚀和溃疡，从而导致上皮通透性增加和 引起和维持肠道炎症的不受控制的免疫反应。愈合和完整的粘膜是 对防止细菌移位和调节免疫反应以恢复体液至关重要 肠道内环境平衡。然而，在粘膜完全愈合方面取得的成功有限，这可能是由于 在正常组织中过早丧失药效和偏离靶点的影响。此外，仍然缺乏 对炎症黏膜复杂的愈合过程有清晰的认识。在慢性炎症下，如何 免疫系统和微生物群可能会干扰上皮修复，从而阻碍愈合，在很大程度上 未知。因此，迫切需要能够针对炎症粘膜的策略来识别关键 促进上皮修复和愈合的中介物。如果没有这样的策略，粘膜愈合将继续 一个“治疗天花板”。为了应对这一挑战，我们建议设计一种基于生物材料的仿生体 该系统可以选择性地靶向发炎的粘膜，并将治疗药物局部释放到 受损的上皮细胞。该系统由聚合物水凝胶和载药纳米粒组成。 (NPS)-水凝胶将在发炎的粘膜上创建一个界面，充当合成粘液层，并且 NPS将在局部释放药物来抑制细菌，消解炎症，修复上皮。我们的 先前的研究表明，带负电荷的水凝胶优先附着在炎症的粘膜上。 小鼠结肠炎模型和IBD患者活检组织中电荷介导的相互作用。这项拟议的研究 将基于电荷的相互作用与使用功能化热响应的溶胶到凝胶的转变相结合 增强选择性靶向的聚合物。NPs为装载不同的药物或药物提供了一个平台 用于处理炎症部位复杂的愈合过程的组合。这样做的总体目标是 该项目是通过模仿天然粘膜的药物输送，最大限度地愈合发炎的粘膜 屏障和揭示调节上皮修复的关键介体。其基本原理是确定 我们的仿生给药系统在IBD临床前模型中的治疗效果将提供强大的 科学框架，从而可以开发最大限度地促进粘膜愈合的新方法。在这个项目中， 我们将追求三个具体目标：1)基于聚合物的合成粘液层将被表征和 优化，2)组合NP给药将用于检测调节上皮修复的关键介质， 3)载药仿生系统的治疗效果和粘膜愈合情况将被确定。 这些结果将对修复腔-上皮界面处的粘膜屏障产生重大影响。 IBD，这也可能为治疗许多其他粘膜屏障疾病开辟新的天地。

PROJECT SUMMARY/ABSTRACT Despite continual improvement in the treatment of inflammatory bowel disease (IBD), achieving mucosal healing remains difficult for many patients with IBD. A key hallmark of IBD is a compromised mucosal barrier leading to erosions and ulcerations of the epithelium, which result in increased epithelial permeability and uncontrolled immune response that induce and maintain intestinal inflammation. A healed and intact mucosa is essential for preventing bacterial translocation from the lumen and modulating immune response to regain intestinal homeostasis. However, limited success has been achieved for complete mucosal healing, likely due to premature loss of drug efficacy and the off-target effect in normal tissue. Moreover, there remains a lack of clear understanding on the complex healing process of the inflamed mucosa. Under chronic inflammation, how the immune system and the microbiota may interfere with epithelial repair, thereby hindering healing, is largely unknown. Therefore, there is a critical need for strategies that can target the inflamed mucosa to identify key mediators in epithelial repair and promote healing. Without such strategies, mucosal healing will continue to be a “therapeutic ceiling”. To address this challenge, we propose to engineer a biomaterial-based biomimetic system that can selectively target the inflamed mucosa and locally release therapeutics to the damaged epithelium. This system comprises a polymer-based hydrogel and drug-loaded nanoparticles (NPs)—a hydrogel will create an interface at the inflamed mucosa, acting as a synthetic mucus layer, and the NPs will release drugs locally to suppress bacteria, resolve inflammation, and repair the epithelium. Our previous study showed that negatively charged hydrogels preferentially adhered to the inflamed mucosa based on charge-mediated interaction in murine models of colitis and IBD patient biopsies. This proposed research will combine the charge-based interaction with sol-to-gel transition using functionalized thermo-responsive polymers to enhance the selective targeting. The NPs provide a platform for loading different drugs or drug combinations to tackle the complex healing process at the site of inflammation. The overall objective of this project is to maximize healing of the inflamed mucosa, enabled by drug delivery mimicking the natural mucosal barrier and uncovering key mediators that regulate epithelial repair. The rationale is that determining therapeutic efficacy of our biomimetic drug delivery system in preclinical models of IBD will provide a strong scientific framework whereby new approaches to maximize mucosal healing can be developed. In this project, we will pursue three specific aims: 1) a polymer-based synthetic mucus layer will be characterized and optimized, 2) combinatorial NP drug delivery will be used to detect key mediators regulating epithelial repair, and 3) therapeutic efficacy and mucosal healing by the drug-loaded biomimetic system will be determined. These results will have a significant impact on repairing the mucosal barrier at the luminal-epithelial interface in IBD, which may also open new horizons for treatment of many other mucosal barrier disorders.