Silver Carboxylate-Eluting Titanium Dioxide/Polydimethyl Siloxane Antibiotic-Independent Antimicrobial Coating as a Safe and Efficacious Alternative for Antibiotic Resistance

项目摘要 引言：抗生素耐药性迫使临床医生和研究人员竞相寻找抗菌药物 改善患者预后的替代策略。手术部位感染（SSI）特别困难， 治疗和预防由于暴露于非无菌外部环境。为了解决当前的抗菌 需要，我们建议评估一种新的和药理学可预测的抗菌技术， 二氧化钛（TiO 2）和聚二甲基硅氧烷（PDMS）的羧酸银洗脱基质。这 抗微生物制剂利用银的多模态抗微生物特性来处理细菌 感染，而不管抗生素耐药性，没有以前的制剂的毒性。我们 假设羧酸银对耐药病原体有效， 对参与伤口愈合的原代细胞类型的毒性。 意义：植入式器械的广泛使用突出了对新技术的需求， 假体周围感染花费了数十亿美元的医疗保健和严重的患者残疾。上涨 抗生素耐药性和缺乏新型抗生素造成了严重的世界性问题。相对于 银具有单一的抗菌作用机制，而银具有多种抗菌机制， 从而限制了耐药性的可能性，并为耐药性菌株提供了一种可行的替代品。 创新：所提出的化学物质显示出对细菌细胞壁的渗透性提高， 通过可定制的TiO 2/PDMS基质控制释放速率和生物利用度。我们假设这个新的 化学将减少与不可预测的浓度和长期存在的毒性 临床上使用的广谱和“最后手段”抗生素。以前对这项技术的研究主要集中在 防止细菌粘附在脊柱植入物、假体内衬和缝线上。十几种细菌 和真菌病原体已经被测试在24至72小时内具有相当水平的抗微生物活性。 研究计划：我们提出了2个具体目标：1）提供银羧酸盐低的证据 使用细胞代谢活性测定MTT， LDH，坏死和凋亡。2)量化羧酸银对常见药物的效力 通过剂量-反应曲线和Kirby Bauer试验确定抗生素耐药病原体。拟议目标将 提供关于化学品对细菌有效性的额外数据，无论革兰氏阴性菌名称如何，或 抗微生物抗性，同时显示出对参与伤口愈合的细胞的低毒性。这些数据将 用于追求R 01补助金，这将集中在确定银羧酸盐的作用机制， 对生物膜的渗透率，以及对生物膜持续细胞的活性。

Project Summary Introduction: Antibiotic resistance has forced clinicians and researchers into a race to find antimicrobial alternative strategies to improve patient outcomes. Surgical site infections (SSIs) are particularly difficult due to treat and prevent due to the exposure to the non-sterile external environment. To address current antimicrobial needs, we propose to evaluate a novel and pharmacologically-predictable antimicrobial technology composed of a silver carboxylate eluting matrix of titanium dioxide (TiO2) and polydimethyl siloxane (PDMS). This antimicrobial formulation utilizes the multi-modal antimicrobial properties of silver to treat bacterial infections regardless of antibiotic resistance, without the toxicity of previous formulations. We hypothesize silver carboxylate will be efficacious against drug-resistant pathogens with no local toxicity to primary cell types involved in wound healing. Significance: The extensive use of implantable devices has accentuated the need for new technologies as periprosthetic infections cost billions of dollars to healthcare and significant patient disability. The rise in antibiotic resistance and lack of novel antibiotics create a significant worldwide problem. In contrast to the single mechanism of antibiotic action, silver has multiple antimicrobial mechanisms that are difficult for bacteria to counteract, thus limiting potential for resistance and providing a viable alternative to resistant strains. Innovation: The proposed chemistry shows improved penetration into the cell wall of bacteria, while controlling rate of release and bioavailability via the customizable TiO2/PDMS matrix. We hypothesize this new chemistry will decrease toxicity associated with unpredictable concentrations and prolonged presence of clinically used broad spectrum and “last resort” antibiotics. Previous research on this technology has focused on prevention of bacterial adherence on spinal implants, prosthetic liners, and sutures. Over a dozen bacterial and fungal pathogens have been tested with considerable levels of antimicrobial activities from 24 to 72 hours. Research Plan: We propose 2 specific aims which will: 1) Provide Evidence of Silver Carboxylate’s Low Cytotoxicity in Primary Cell Lines Involved in Wound Healing using the cell metabolic activity assay MTT, LDH, Necrosis and Apoptosis. 2) Quantify Silver Carboxylate’s Potency against Commonly-Encountered Antibiotic-Resistant Pathogen via dose-response curves and Kirby Bauer Assays. Proposed aims will provide additional data on the efficacy of the chemistry against bacteria regardless of gram designation or antimicrobial resistance while showing low toxicity against cells involved in wound healing. This data will be utilized to pursue an R01 grant which will focus on determining the mechanism of action of silver carboxylate, penetrance into biofilms, as well as activity against biofilm persister cells.