Self-Locomotive Antimicrobial Micro-Robot (SLAM) Enhancing Biofilm-Infected Wound Healing

自移动抗菌微型机器人 (SLAM) 增强生物膜感染伤口愈合

• 批准号: 10612835
• 负责人: Hyunjoon Kong
• 金额: $ 42.52万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612835
• 关键词: 3-Dimensional; Aging; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Bacteria; Blood; CD34 gene; Cell Wall; Cell secretion; Cells; Cessation of life; Chronic; Clinical; Collaborations; Collagen; Complex; Cytoprotection; Debridement; Deposition; Dermatologist; Diatoms; Disease; Disinfectants; Disinfection; Edema; Enzymes; Excision; Exhibits; FGF2 gene; Female; Fibroblast Growth Factor; Fracture; Gelatinase B; Goals; Growth; Growth Factor; Hematopoietic Stem Cell Mobilization; Human body; Hydrogen Peroxide; Immune system; Impaired wound healing; Infection; Inflammation; Invaded; Irrigation; Liquid substance; Locomotion; MMP9 gene; Malignant - descriptor; Matrix Metalloproteinases; Metabolic; Metalloproteases; Methods; Microbial Biofilms; Microbubbles; Modeling; Monitor; Multi-modal optical imaging; Mus; Oxygen; PTPRC gene; Patients; Polymers; Porosity; Procedures; Pseudomonas aeruginosa; Recombinants; Recurrence; Regenerative Medicine; Residual state; Scheme; Self Efficacy; Services; Site; Skin; Structure; Surveys; Thick; Time; Tissues; Toxic effect; Translating; United States; United States National Institutes of Health; Vancomycin; Vascularization; Water; Wound Infection; antimicrobial; antimicrobial drug; bioimaging; cost; disability; efficacy evaluation; epithelial wound; extracellular; imaging system; improved; inhibitor; innovation; invention; keratinocyte growth factor; male; mechanical energy; methicillin resistant Staphylococcus aureus; microbial; microrobot; nanosheet; neovascularization; prevent; skin regeneration; stem; stem cells; success; traumatic event; treatment duration; wound; wound biofilm; wound healing; wound treatment

Project Summary Biofilm, a protective extracellular-polymeric substance that surrounds bacterial colonies, is associated with more than 80% of microbial infections. In the United States, the management cost for biofilm- associated infections reaches 94 billion US dollars and is responsible for 0.5 million deaths annually. In particular, millions of wound patients suffer from biofilm-associated infections that lead to persistent inflammation and edema, and ultimately hinder wound healing. Biofilm bacteria are 1,000 times more resistant to antibiotics than free-floating bacteria. In a clinical setting, it is common to remove biofilm from the wound with debridement or enzymes. However, these methods do not remove biofilm in space deep in the wounded tissue, thus allowing biofilm recurrence. To this end, we recently invented a self-locomotive, antimicrobial micro-robot (SLAM) that can invade and remove biofilm. The SLAM is prepared by activating diatom biosilica doped with MnO2 nanocatalysts (MnO2-diatom) to generate oxygen microbubbles using a 3 % hydrogen peroxide solution. The activated MnO2-diatoms propel themselves to enter the biofilm. Within the biofilm, the activated MnO2-diatoms continue to generate microbubbles that fuse and produce mechanical energy high enough to fracture biofilm. It takes 10 minutes for the activated MnO2-diatoms to remove more than 99.9 % of 0.8 mm-thick P. aeruginosa biofilm with similar depth to full-thickness skin. No adverse toxic effects are observed after cleaning. With this success, our overall goals are to improve biofilm removal from the infected wound using SLAM and, in turn, to promote skin regeneration in the wound. We hypothesize that the activated MnO2-diatoms would detach biofilm from wounds and, in turn, increase access of antibiotics to residual biofilm bacteria. The subsequently enhanced wound disinfection would serve to improve the efficacy of regenerative medicine to skin regeneration in wounds. We will examine this hypothesis by using the vancomycin and a pair of keratinocyte growth factor (KGF)-2 and fibroblast growth factor (FGF)-2 as a model antibiotic and regenerative medicine, respectively. Our specific aims are to: (1) evaluate the efficacy of activated MnO2-diatoms to remove biofilm in wounds, (2) examine if activated MnO2- diatoms improve the efficacy of vancomycin to prevent biofilm re-growth, and (3) investigate the extent that activated MnO2-diatoms increase the KGF2/FGF2 efficacy in stimulating skin regeneration. We will conduct each aim study using the P. aeruginosa or methicillin-resistant S. aureus biofilm-infected excisional wound of male and female CD1 mice. We will assess the biofilm removal and skin regeneration in wounds using a multimodal optical imaging system through collaboration with the Boppart group with expertise in bioimaging. We will also determine the matrix metalloproteinase-9 and tissue inhibitor to metalloproteinase levels in the wound fluid, CD34+/CD45- stem cell mobilization, pro-inflammation and edema, and minimal toxicity of SLAM under guidance by Dr. Neitzel, a dermatologist. Overall, this proposed study will significantly impact efforts to treat non-healing, biofilm-infected wounds using innovative SLAMs. In the end, this study will save wound patients from disability and death.

Project摘要生物膜是一种围绕细菌菌落的保护性细胞外聚合物物质，是 与超过80％的微生物感染相关。在美国，生物膜的管理成本 相关感染达到940亿美元，每年造成50万人死亡。尤其， 数以百万计的伤口患者患有生物膜相关感染，导致持续的炎症和 水肿，最终阻碍了伤口愈合。生物膜细菌对抗生素的耐药性比 自由浮动细菌。在临床环境中，通常是通过清创或 酶。但是，这些方法不会去除受伤组织深处的空间中的生物膜，从而允许 生物膜复发。为此，我们最近发明了一种自属性的抗菌微型机器人（SLAM） 可以入侵并去除生物膜。大满贯是通过激活MNO2掺杂的硅藻生物硅酸盐来制备的 纳米催化剂（MNO2-Diotom）使用3％过氧化氢溶液生成氧微泡。这 激活的MNO2-二鼠会推动自己进入生物膜。在生物膜内，激活的MNO2-DIATOM 继续生成融合并产生足够高以断裂生物膜的机械能的微泡。它 激活的MNO2-DIOTOM需要10分钟才能去除0.8毫米厚的铜绿P.铜绿的99.9％以上 具有相似深度与全厚度皮肤的生物膜。清洁后未观察到不良毒性作用。有了这个成功， 我们的总体目标是使用SLAM从受感染的伤口中清除生物膜，然后促进 伤口中的皮肤再生。我们假设活化的MNO2-Diatoms将从 伤口，进而增加抗生素对残留生物膜细菌的访问。随后增强了 伤口消毒将有助于提高再生医学对伤口中皮肤再生的功效。 我们将通过使用万古霉素和一对角质形成细胞生长因子（KGF）-2和成纤维细胞来检查这一假设 生长因子（FGF）-2作为模型抗生素和再生医学。我们的具体目的是：（1） 评估激活的MNO2-二元组在伤口中去除生物膜的功效，（2）检查是否活化的MNO2-- 硅藻提高了万古霉素预防生物膜重新生长的功效，（3）研究激活的程度 MNO2-Diatoms在刺激皮肤再生中提高了KGF2/FGF2的功效。我们将使用 铜绿假单胞菌或耐甲氧西林的金黄色葡萄球菌生物膜感染的雄性和雌性CD1的弹性伤口 老鼠。我们将使用多模式光学成像评估伤口中的生物膜去除和皮肤再生 通过与Boppart集团合作具有生物成像专业知识来系统。我们还将确定矩阵 金属蛋白酶-9和组织抑制剂在伤口液中的金属蛋白酶水平CD34+/CD45-干细胞中 皮肤科医生Neitzel博士在指导下，动员，促炎和水肿以及SLAM的最小毒性。 总体而言，这项拟议的研究将极大地影响使用使用生物膜感染的非治疗的努力 创新的大满贯。最后，这项研究将使伤口患者免于残疾和死亡。