Reducing wound bioburden and biofilm formation using a nanoscale wound surface en

使用纳米级伤口表面减少伤口生物负荷和生物膜形成

基本信息

批准号：
8518098
负责人：
CHARLES Joseph CZUPRYNSKI
金额：
$ 21.29万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8518098
关键词：
Address Adsorption Adverse effects Age Amino Acids Anti-Bacterial Agents Bacillus subtilis Back Bacteria Beds Caring Chronic Data Debridement Defense Mechanisms Effectiveness Elderly Engineering Film Goals Healed Health Health Care Costs Healthcare Host Defense Human Immobilization Impaired wound healing In Vitro Incidence Infection Intervention Investigation Leucine Mediating Medical Methionine Methods Microbial Antibiotic Resistance Microbial Biofilms Modeling Organism Population Prevention Procedures Productivity Pseudomonas aeruginosa Quality of life Reporting Research Personnel Research Project Grants Research Support Resistance Sepsis Silver Skin Solutions Staphylococcus aureus Structure Surface Testing Therapeutic Thick Tryptophan Tyrosine United States United States National Institutes of Health Wound Infection antimicrobial antimicrobial drug arm base cost cytotoxicity enantiomer healing imprint improved in vivo innovation killings microbial microbial colonization nano nanoparticle nanoparticulate nanoscale nanostructured novel novel strategies open wound prevent socioeconomics wound

项目摘要

DESCRIPTION (provided by applicant): Management of chronic wounds represent a major healthcare challenge responsible for over $15 billion in expenses annually. Wound surface sepsis, in particular biofilm formation, is a significant factor in nonhealing wounds. In chronic wounds, >60% have been observed to have clear evidence of a biofilm. Further, NIH has estimated that 65-80% of microbial infections in humans are biofilm-mediated. Biofilms are characterized by resistance to host defenses and to therapeutics that would otherwise have efficacy against the organisms planktonic state. Thus, biofilms present two distinct challenges: 1) the biofilm must be removed or dispersed to reduce bacterial defense mechanisms; and 2) effective antimicrobial agents applied to suppress the resident bacteria. In this application, we seek to address this problem by investigating a novel intervention with potential to prevent chronic colonization of wounds and disperse pre-existing biofilms. The innovation underlying our approach revolves around engineering the surfaces of wound beds to both promote the dissolution of biofilm bacteria back to a planktonic state, where they are more susceptible to antimicrobial agents, and immobilize antimicrobial agents at the wound surface where biofilm formation occurs. Our approach involves incorporation of absorbable nanobeads loaded with antibiofilm agents in a nanoscopic thin film, manufactured of polyelectrolyte multilayers containing silver nanoparticles, that is used to re-engineer the wound surface to increase its resistance to microbial colonization and biofilm formation. This structured engineered approach allows effective antimicrobial action with very low non-toxic concentrations of active agents. The innovative combination of these approaches in a single nanostructured film has the potential to markedly increase anti-biofilm and antimicrobial efficacy in vivo. In particular, use of nano-beads permits precise control over concentrations and release rates of the antibiofilm agent. They also penetrate and create microdomains within the biofilm, increasing surface contact by >80%, to increase adsorption of antibiofilm and antimicrobial agents concurrently and generating progressive dispersion-kill zones emanating from the beads at a nanoscale level. The central hypothesis of this study, supported by exciting preliminary data, is that incorporating select D- and L- amino acids into the wound bed will reduce bacterial biofilm formation and increase biofilm dissolution. A secondary hypothesis is that this approach will enhance the antimicrobial activity of silver nanoparticles immobilized at the wound surface. To address these goals we propose 3 Aims. In Aim 1, we will evaluate the ability of select D- and L- amino acids immobilized in polyelectrolyte thin films and loaded into absorbable PLGA beads to prevent a biofilm from forming and to stimulate dissolution of existing biofilms of Pseudomonas aeruginosa and Staphylococcus aureus in vitro . In Aim 2, we will optimize the integration of select amino acids and nano-beads onto model wound surfaces (full and partial thickness skin wounds), using polyelectrolyte thin film immobilization methods, and evaluate their efficacy in preventing biofilm formation and biofilm dissolution in vivo; and in Aim 3, we will test the hypothesis that combined application of silver nanoparticles and select amino acids further reduces biofilm formation and minimizes microbial bioburden in wounds in vivo. At the conclusion of this study, we expect to provide proof of concept that a two-armed approach to wound biofilms contained in an integrated nanoscale wound bed engineering platform will have increased efficacy against biofilms with reduced cytotoxicity in the wound bed. This approach is labile and generalizable to immobilization of other antibiofilm and antimicrobial agents. Thus, upon successful completion of this R21 application, we will seek support for research (via the R01 mechanism) that will broaden the scope of these investigations in optimizing these strategies and in evaluating the efficacy of an array of antimicrobial and antibiofilm agents with the goal of maximizing the ability to suppress wound bed sepsis and improve healing of chronic open wounds.

描述（由申请人提供）：慢性伤口的管理代表了一项重大的医疗挑战，每年负责超过150亿美元的费用。伤口表面脓毒症，尤其是生物膜形成，是非污染伤口的重要因素。在慢性伤口中，已经观察到> 60％的生物膜有明确的证据。此外，NIH估计人类中有65-80％的微生物感染是生物膜介导的。生物膜的特征是对宿主防御和疗法的抗性，否则对生物体的浮游状态具有疗效。因此，生物膜提出了两个不同的挑战：1）必须去除或分散生物膜以减少细菌防御机制； 2）用于抑制居民细菌的有效抗菌剂。在此应用中，我们试图通过调查一种新的干预措施来解决此问题，该干预措施有可能防止伤口的长期定植并分散现有的生物膜。我们方法的基础创新围绕工程围绕伤口床的表面旋转，以促进生物膜细菌的溶解回到浮游状态，在那里它们更容易受到抗菌剂的影响，并固定在生物膜形成的伤口表面抗菌药物。我们的方法涉及在纳米薄膜中掺入载有抗生素剂的可吸收纳米光，该薄膜由含有银纳米颗粒的聚电解质多层生产，用于重新工程，以增加伤口表面，以增加其对微生物结肠化和生物膜形成的耐药性。这种结构化工程方法允许有效的抗菌作用，具有非常低的活性剂浓度。这些方法在单个纳米结构膜中的创新组合具有显着提高体内抗生物膜和抗菌功效的潜力。特别是使用纳米珠允许精确控制抗胶质膜剂的浓度和释放速率。它们还穿透并在生物膜内产生微域，使表面接触> 80％增加，以增加抗生素和抗菌剂的吸附，并同时同时产生从纳米级水平的珠子中产生的渐进分散性杀伤区。这项研究的中心假设得到了令人兴奋的初步数据的支持，是将精选的D-氨基酸和氨基酸纳入伤口床将减少细菌生物膜的形成并增加生物膜溶解。次要假设是，这种方法将增强固定在伤口表面的银纳米颗粒的抗菌活性。为了解决这些目标，我们提出了3个目标。在AIM 1中，我们将评估在聚电解质薄膜中固定的选择D-和L-氨基酸的能力，并将其装入可吸收的PLGA珠中，以防止生物膜形成并刺激铜绿假单胞菌和葡萄球菌的假单胞菌的现有生物膜的溶解。在AIM 2中，使用聚电解质薄膜固定方法，我们将优化精选的氨基酸和纳米珠在模型伤口表面（全厚性皮肤伤口）上的整合，并评估其在体内防止生物膜形成和生物膜溶解的功效；在AIM 3中，我们将检验以下假设，即银纳米颗粒的应用和选择氨基酸进一步降低了生物膜的形成，并最大程度地减少了体内伤口中的微生物生物毛。在这项研究的结论中，我们期望提供概念证明，即在纳米级伤口床工程平台中包含的两臂生物膜的两臂方法将提高对生物膜的疗效，并在伤口床中降低了细胞毒性。这种方法不稳定，可以推广到其他抗体胶质膜和抗菌剂的固定。因此，在成功完成此R21应用程序后，我们将寻求对研究（通过R01机制）的支持，这些研究将扩大这些研究的范围，以优化这些策略，并评估抗菌和抗生素剂阵列的功效，以最大程度地抑制伤口床Sepsis和Chrecic of Specs hoperic hears的能力。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Reduction in wound bioburden using a silver-loaded dissolvable microfilm construct.

DOI：
10.1002/adhm.201300537
发表时间：
2014-06
期刊：
ADVANCED HEALTHCARE MATERIALS
影响因子：
10
作者：
Herron, Maggie;Agarwal, Ankit;Kierski, Patricia R.;Calderon, Diego F.;Teixeira, Leandro B. C.;Schurr, Michael J.;Murphy, Christopher J.;Czuprynski, Charles J.;McAnulty, Jonathan F.;Abbott, Nicholas L.
通讯作者：
Abbott, Nicholas L.