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.

absrtact 尽管为保持手术室无菌而做出了重大努力，但手术现场感染（SSIS）仍然是严重而又存活的 天生的问题，在美国每年最多杀死8200名患者，我们的长期目标是开发新的疗法 有效地降低SSIS的风险并促进伤口愈合。在以前的此奖项的资金周期中， 我们已经证明，我）成功封装和持续释放维生素D和其他免疫 调节化合物诱导较高的cathelicidin抗菌肽（CAMP）基因和蛋白质（HCAP18/LL-- 37）免疫细胞和角质形成细胞的水平，人类cAMP转基因小鼠伤口模型和 人类皮肤外植体； ii）局部维生素D增加了皮肤伤口感染中金黄色葡萄球菌的杀死 使用我们的人类cAMP转基因小鼠建模；和iii）从处理的免疫细胞分泌的外泌体 维生素D含有更高水平的HCAP18/LL-37。此外，我们开发了一种新型的气动燃料扩展 制造改进的3D纳米纤维支架的技术，洗脱了促进免疫细胞浸润的维生素D 诱导HCAP18/LL-37，炎症减少，并促进了新血管形成和胶原蛋白沉积 人免疫系统促进小鼠。在这些发现以及我们的初步数据的基础上，我们的目标 提案着重于开发基于纳米纤维的敷料，以增强先天免疫力。我们的 拱形假设是与从外泌体分泌的外泌体共同封闭免疫调节化合物 在3D纳米纤维支架中处理的免疫细胞将协同增强对SSIS的保护并促进 伤口愈合比单独的任何一个组件都更好。为此，有三个具体的目的：1）恶魔 - 从我们改进的3D纳米纤维中的免疫调节化合物的策略有效封装和洗脱 脚手架； 2）确定源自启动或人的外泌体的抗菌和伤口愈合功效 cAMP转染免疫细胞； 3）证明了免疫调节化合物和exo-的功效 躯体 - 合并的3D纳米纤维支架，以促进愈合并防止我们人性化的跨性别 基因小鼠模型和外体皮肤外植体。基于我们先前的赠款的工作，我们希望成功 续约目标的完成将为发展下一代小说奠定坚实的基础 治疗性的抗感染伤口敷料，可以极大地加速愈合，降低SSIS的速度并最小化 抗生素耐药性的发展。我们还希望这些敷料可以作为有效的治疗方法 创伤和战斗有关的伤害。