Nanofiber-based Delivery of Combined Immune-modulating Compounds to Minimize Infection and Enhance Wound Healing

基于纳米纤维的组合免疫调节化合物的递送以最大程度地减少感染并促进伤口愈合

• 批准号: 10299094
• 负责人: Jingwei Xie
• 金额: $ 34.08万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10299094
• 关键词: 3-Dimensional; Address; Anti-Infective Agents; Antibiotic Resistance; Antibiotics; Award; Bacteria; Cell Culture Techniques; Cell Proliferation; Cells; Cessation of life; Clinical; Collagen; Data; Deposition; Development; ESKAPE pathogens; Encapsulated; Foundations; Funding; Gases; Gene Proteins; Genes; Goals; Grant; Health Care Costs; Hospital Costs; Human; Immune; Immune response; Immune system; Immunity; Infection; Infection prevention; Infiltration; Inflammation; Inflammatory; Infrastructure; Inpatients; Intervention; Investments; Knowledge; Life; Mass Spectrum Analysis; Measures; Mechanics; Membrane; Mesenchymal; Methods; MicroRNAs; Modeling; Morphology; Multi-Drug Resistance; Mus; Natural Immunity; Operating Rooms; Operative Surgical Procedures; Paper; Patients; Peptides; Play; Postoperative Period; Primates; Productivity; Property; Proteins; Proteomics; Publishing; Skin; Speed; Staphylococcus aureus; Sterile coverings; Sterility; Structure; Surgical Wound Infection; Surgical incisions; Techniques; Testing; Therapeutic; Topical application; Transgenic Mice; United States; Virulence; Vitamin D; Work; Wound Infection; Wound models; antimicrobial; base; biomaterial compatibility; cathelicidin antimicrobial peptide; combat injury; conventional therapy; cytokine; cytotoxicity; effective therapy; exosome; healing; healthcare-associated infections; improved; innovation; keratinocyte; migration; mouse model; nanofiber; nanomaterials; neovascularization; next generation; novel; novel strategies; novel therapeutics; overexpression; pathogen; preclinical study; prevent; readmission rates; response; risk minimization; scaffold; skin wound; two-dimensional; wound dressing; wound healing

ABSRTACT Despite major efforts to keep operating rooms sterile, surgical site infections (SSIs) remain a serious and stub- born problem, killing up to 8,200 patients a year in the U.S. Our long-term goal is to develop novel therapies that effectively minimize risk of SSIs and promote wound healing. During the previous funding cycles of this award, we have demonstrated that i) successful encapsulation and sustained release of vitamin D and other immuno- modulating compounds induced higher cathelicidin antimicrobial peptide (CAMP) gene and protein (hCAP18/LL- 37) levels in immune cells and keratinocytes in cell culture, a human CAMP transgenic mouse wound model and human skin explants; ii) topical vitamin D increased killing of Staphylococcus aureus in a skin wound-infection model using our human CAMP transgenic mouse; and iii) exosomes secreted from immune cells treated with vitamin D contained higher levels of hCAP18/LL-37. Furthermore, we developed a novel gas-foaming expansion technique to fabricate improved 3D nanofiber scaffolds eluting vitamin D that promoted immune cell infiltration, induced hCAP18/LL-37, decreased inflammation, and promoted neovascularization and collagen deposition in human immune system-engrafted mice. Building on these findings, and our preliminary data, the goal of our proposal focuses on the development of nanofiber-based dressings for enhancing innate immunity. Our over- arching hypothesis is that co-encapsulating immunomodulating compounds with exosomes secreted from treated immune cells in 3D nanofiber scaffolds will synergistically enhance protection against SSIs and promote wound healing better than either component alone. To accomplish this, there are three specific aims: 1) Demon- strate efficient encapsulation and elution of immunomodulating compounds from our improved 3D nanofiber scaffolds; 2) Determine the antimicrobial and wound-healing efficacy of exosomes derived from primed or human CAMP transfected immune cells; and 3) Demonstrate the efficacy of immunomodulating compounds and exo- somes - co-incorporated 3D nanofiber scaffolds to promote healing and prevent infection in our humanized trans- genic mouse model and ex vivo human skin explants. Building on work from our prior grant, we expect successful completion of the aims in this renewal will lay a strong foundation for developing the next generation of novel therapeutic anti-infective wound dressings that could greatly speed healing, reduce rates of SSIs and minimize development of antibiotic resistance. We also expect these dressings could serve as effective treatments for traumatic and combat-related injuries.

摘要 尽管付出了巨大努力来保持手术室无菌，但手术部位感染（SSI）仍然是一个严重且顽固的问题。 与生俱来的问题，在美国每年导致多达 8,200 名患者死亡。我们的长期目标是开发新疗法 有效降低 SSI 风险并促进伤口愈合。在该奖项之前的资助周期中， 我们已经证明 i) 成功封装并持续释放维生素 D 和其他免疫- 调节化合物诱导较高的抗菌肽 (CAMP) 基因和蛋白 (hCAP18/LL- 37) 细胞培养物、人 CAMP 转基因小鼠伤口模型中免疫细胞和角质形成细胞的水平，以及 人类皮肤外植体； ii) 外用维生素 D 可增加对皮肤伤口感染中金黄色葡萄球菌的杀灭作用 使用我们的人类 CAMP 转基因小鼠建立模型； iii) 经处理的免疫细胞分泌的外泌体 维生素 D 含有较高水平的 hCAP18/LL-37。此外，我们还开发了一种新型气体发泡膨胀剂 制造改进的 3D 纳米纤维支架的技术，可洗脱维生素 D，促进免疫细胞浸润， 诱导 hCAP18/LL-37，减少炎症，促进新血管形成和胶原蛋白沉积 植入人类免疫系统的小鼠。基于这些发现和我们的初步数据，我们的目标 该提案的重点是开发基于纳米纤维的敷料，以增强先天免疫力。我们的超 拱形假设是，将免疫调节化合物与分泌的外泌体共同封装 3D 纳米纤维支架中经过处理的免疫细胞将协同增强对 SSI 的保护并促进 伤口愈合比单独使用任何一种成分都要好。为了实现这一目标，有三个具体目标：1）恶魔- 从我们改进的 3D 纳米纤维中有效封装和洗脱免疫调节化合物 脚手架； 2) 确定源自引发剂或人类的外泌体的抗菌和伤口愈合功效 CAMP转染免疫细胞； 3) 证明免疫调节化合物和外切酶的功效 somes - 在我们的人性化转基因中共同加入 3D 纳米纤维支架，以促进愈合并预防感染 基因小鼠模型和离体人类皮肤外植体。在我们之前资助的工作的基础上，我们期望成功 本次更新目标的完成，将为下一代小说的开发打下坚实的基础。 治疗性抗感染伤口敷料可以大大加速愈合、降低 SSI 发生率并最大限度地减少 抗生素耐药性的发展。我们还期望这些敷料可以作为有效的治疗方法 外伤和战斗相关伤害。