Engineered biomimetic materials for intestinal mucosal healing

用于肠粘膜愈合的工程仿生材料

• 批准号: 10719681
• 负责人: Sufeng Zhang
• 金额: $ 36.93万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-17 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719681
• 关键词: Address; Bacteria; Bacterial Translocation; Biocompatible Materials; Biomimetic Materials; Biomimetics; Biopsy; Categories; Cells; Charge; Chemicals; Chronic; Clinical Trials; Colitis; Colon; Complex; Development; Disease; Disease remission; Drug Combinations; Drug Delivery Systems; Engineering; Epidermal Growth Factor; Epithelial Cells; Epithelium; Gastrointestinal tract structure; Gel; Gene Expression Profiling; Goals; Histology; Hydrogels; Immune response; Immune system; In Situ; Inflammation; Inflammation Process; Inflammatory Bowel Diseases; Interleukin-10; Intestinal Mucosa; Intestinal permeability; Invaded; Lamina Propria; Measures; Mediating; Mediator; Mucins; Mucositis; Mucous Membrane; Mucous body substance; Mus; Normal tissue morphology; Outcome; Pathogenicity; Patients; Permeability; Pharmaceutical Preparations; Polymers; Pre-Clinical Model; Process; Proteins; Regulatory T-Lymphocyte; Research; Ribosomal RNA; Rodent Model; Severities; Signal Transduction; Site; System; Therapeutic; Tissues; Treatment Efficacy; Ulcer; Vancomycin; chemically induced colitis; combinatorial; drug efficacy; epithelial repair; epithelium regeneration; evidence base; gut inflammation; healing; immunoregulation; improved; in vivo; innovation; intestinal epithelium; intestinal homeostasis; microbiota; mucosal site; murine colitis; nanoparticle; nanoparticle drug; novel strategies; premature; prevent; primary endpoint; protein expression; repaired; restoration; success; targeted treatment; tool

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.

项目摘要/摘要 尽管炎症性肠病（IBD）的治疗不断改善，但达到了粘膜 对于许多IBD患者来说，康复仍然很困难。 IBD的关键标志是受损的粘膜屏障 导致上皮的侵蚀和溃疡，从而增加上皮渗透性和 不受控制的免疫反应会影响和维持肠道炎症。治愈且完整的粘膜是 防止管腔中的细菌易位并调节免疫反应以恢复至关重要 肠内稳态。但是，对于完全粘膜愈合取得了有限的成功，可能是由于 为了过早的药物效率损失和正常组织中的脱靶效应。而且，仍然缺乏 对发炎粘膜的复杂愈合过程的清晰了解。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，在很大程度上是 未知。因此，对于可以针对发炎的粘膜来识别关键的策略的迫切需要 上皮修复中的介体和促进愈合。没有这样的策略，粘膜愈合将继续 “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生物剂 可以选择性地靶向发炎的粘膜并局部释放治疗的系统 上皮受损。该系统包括基于聚合物的水凝胶和载有药物的纳米颗粒 （NP） - 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 NP将在本地释放药物，以抑制细菌，解决注射并修复上皮。我们的 先前的研究表明，带负电的水凝胶优先粘附于发炎的基于粘膜的粘膜 在结肠炎和IBD患者活检的鼠模型中，电荷介导的相互作用。这项拟议的研究 将使用功能化的热响应性将基于电荷的相互作用与Sol-Gel转变相结合 聚合物增强选择性靶向。 NP提供了一个平台，用于加载不同的药物或药物 在炎症部位解决复杂的愈​​合过程的组合。总体目标 项目是通过模仿天然粘膜的药物来最大化发炎的粘膜的愈合 障碍和揭示调节上皮修复的关键介质。理由是确定 在IBD的临床前模型中，我们的仿生药物输送系统的治疗效率将提供强大的 可以开发出最大化粘膜愈合的新方法的科学框架。在这个项目中， 我们将追求三个具体目标：1）将表征基于聚合物的合成mutus层，并 优化，2）组合NP药物输送将用于检测调节上皮修复的关键介质， 3）将确定药物负载的仿生系统的治疗效率和粘膜愈合。 这些结果将对修复在腔内上皮界面处的粘膜屏障有重大影响 IBD，这也可能为治疗许多其他粘膜屏障疾病的新视野开放。