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: 10653967
• 负责人: Jingwei Xie
• 金额: $ 31.69万
• 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/10653967
• 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; Engraftment; Foundations; Funding; Gases; Genes; Goals; Grant; Health Care Costs; Human; Immune; Immune response; Immune system; Immunity; Infection; Infection prevention; Inflammation; Inflammatory; Infrastructure; Inpatients; Intervention; Investments; Knowledge; Life; Mass Spectrum Analysis; Measures; Mechanics; Membrane; Mesenchymal; Methods; MicroRNAs; Modeling; Morphology; Multi-Drug Resistance; Mus; Nanofiber Scaffold; Natural Immunity; Operating Rooms; Operative Surgical Procedures; Paper; Patients; Peptides; Play; Postoperative Period; Primates; Productivity; Property; Proteins; Proteomics; Publishing; Resistance development; Skin; Speed; Staphylococcus aureus; Sterile coverings; Sterility; Structure; Surgical Wound Infection; Surgical incisions; Techniques; Testing; Therapeutic; Topical application; Transfection; Transgenic Mice; United States; Virulence; Vitamin D; Work; Wound Infection; Wound models; antimicrobial; biomaterial compatibility; cathelicidin antimicrobial peptide; combat injury; conventional therapy; cost; cytokine; cytotoxicity; effective therapy; exosome; healing; healthcare-associated infections; immune cell infiltrate; immunoregulation; improved; innovation; keratinocyte; miRNA expression profiling; 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.

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