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.

项目总结/摘要 尽管炎症性肠病（IBD）的治疗不断改进，但实现粘膜免疫仍是一个难题。 对于许多患有IBD的患者来说，愈合仍然是困难的。IBD的一个关键标志是粘膜屏障受损 导致上皮糜烂和溃疡，这导致上皮通透性增加， 不受控制的免疫反应，诱导和维持肠道炎症。愈合和完整的粘膜是 对于防止细菌从管腔移位和调节免疫应答以重新获得 肠内稳态然而，在完全粘膜愈合方面取得的成功有限，可能是由于 药物功效的过早丧失和正常组织中的脱靶效应。此外，仍然缺乏 对发炎粘膜的复杂愈合过程有清晰的认识。在慢性炎症下， 免疫系统和微生物群可能干扰上皮修复，从而阻碍愈合， 未知因此，迫切需要能够靶向发炎粘膜的策略，以确定炎症的关键因素。 介质在上皮修复和促进愈合。如果没有这样的策略，粘膜愈合将继续 “治疗上限”。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 该系统可以选择性地靶向发炎的粘膜并局部释放治疗剂至粘膜， 上皮受损该系统包括基于聚合物的水凝胶和载药纳米颗粒 （NP）-水凝胶将在发炎的粘膜处产生界面，充当合成粘液层，并且水凝胶将在发炎的粘膜处产生界面。 纳米颗粒将在局部释放药物以抑制细菌，解决炎症和修复上皮。我们 先前的研究表明，带负电荷的水凝胶优先粘附于发炎的粘膜， 在结肠炎和IBD患者活检的鼠模型中的电荷介导的相互作用。这项拟议的研究 将联合收割机与使用功能化的热响应的溶胶-凝胶转变相结合 聚合物以增强选择性靶向。纳米颗粒提供了用于装载不同药物或药物载体的平台。 联合治疗以解决炎症部位复杂的愈合过程。本报告的总体目标 该项目是最大限度地愈合发炎的粘膜，使药物输送模仿自然粘膜 屏障和发现调节上皮修复的关键介质。理由是， 我们的仿生药物递送系统在IBD的临床前模型中的治疗功效将提供强有力的 科学框架，从而可以开发新的方法，以最大限度地提高粘膜愈合。在本项目中， 我们将追求三个具体目标：1）将表征基于聚合物的合成粘液层， 优化，2）组合NP药物递送将用于检测调节上皮修复的关键介质， 和3）测定载药仿生系统的治疗功效和粘膜愈合。 这些结果将对修复管腔-上皮界面的粘膜屏障产生重大影响， IBD，这也可能为许多其他粘膜屏障疾病的治疗开辟新的视野。