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

基本信息

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
项目类别：
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

项目摘要

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.

项目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， 80%以上的微生物感染与此有关。在美国，生物膜的管理成本相关感染每年达到 940 亿美元，导致 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，导致持续炎症和水肿，最终阻碍伤口愈合。生物膜细菌对抗生素的抵抗力比细菌高 1,000 倍自由漂浮的细菌。在临床环境中，通常通过清创或清除伤口上的生物膜酶。然而，这些方法并不能去除受伤组织深处的生物膜，因此允许生物膜复发。为此，我们最近发明了一种自移动抗菌微型机器人（SLAM）可以侵入并去除生物膜。 SLAM是通过活化掺杂MnO2的硅藻生物硅制备的纳米催化剂（MnO2-硅藻）使用 3% 的过氧化氢溶液产生氧气微泡。这活化的二氧化锰硅藻推动自身进入生物膜。在生物膜内，活化的 MnO2-硅藻继续产生微泡，微泡融合并产生足够高的机械能以破坏生物膜。它活化的 MnO2-硅藻需要 10 分钟即可去除 99.9% 以上的 0.8 毫米厚的铜绿假单胞菌生物膜的深度与全层皮肤相似。清洁后未观察到不良毒性作用。凭借这次成功，我们的总体目标是使用 SLAM 改善受感染伤口上生物膜的去除，进而促进伤口处的皮肤再生。我们假设活化的 MnO2-硅藻会使生物膜从伤口，进而增加抗生素接触残留生物膜细菌的机会。随后增强的伤口消毒将有助于提高再生医学对伤口皮肤再生的功效。我们将使用万古霉素和一对角质形成细胞生长因子 (KGF)-2 以及成纤维细胞来检验这一假设生长因子（FGF）-2分别作为模型抗生素和再生医学。我们的具体目标是：（1）评估活化 MnO2-硅藻去除伤口生物膜的功效，(2) 检查活化 MnO2- 是否硅藻提高万古霉素防止生物膜重新生长的功效，并且（3）研究激活的程度 MnO2-硅藻增加 KGF2/FGF2 刺激皮肤再生的功效。我们将使用以下方法进行每项目标研究男性和女性 CD1 的铜绿假单胞菌或耐甲氧西林金黄色葡萄球菌生物膜感染的切除伤口老鼠。我们将使用多模态光学成像评估伤口中生物膜的去除和皮肤再生通过与拥有生物成像专业知识的 Boppart 团队合作开发系统。我们还将确定矩阵伤口液中金属蛋白酶 9 和金属蛋白酶水平的组织抑制剂、CD34+/CD45- 干细胞在皮肤科医生 Neitzel 博士的指导下，SLAM 具有动员、促炎和水肿以及最小毒性等特点。总体而言，这项拟议的研究将显着影响使用药物治疗不愈合、生物膜感染伤口的努力创新的 SLAM。最终，这项研究将使伤口患者免于残疾和死亡。