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

项目概要 简介：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 改善患者治疗效果的替代策略。手术部位感染（SSI）特别困难，因为 由于暴露于非无菌外部环境而导致的治疗和预防。为了解决当前的抗菌 需要，我们建议评估一种新颖且药理学可预测的抗菌技术，其组成 羧酸银洗脱二氧化钛 (TiO2) 和聚二甲基硅氧烷 (PDMS) 基质的结果。这个 抗菌配方利用银的多模式抗菌特性来治疗细菌 无论抗生素耐药性如何，都能抑制感染，并且没有以前配方的毒性。我们 假设羧酸银对局部无耐药性的病原体有效 对参与伤口愈合的原代细胞类型的毒性。 意义：植入式设备的广泛使用凸显了对新技术的需求 假体周围感染给医疗保健造成数十亿美元的损失，并导致患者严重残疾。的上升 抗生素耐药性和新型抗生素的缺乏造成了一个重大的世界性问题。相比之下 抗菌作用机制单一，银具有多种抗菌机制，对细菌来说是困难的 来抵消，从而限制耐药性的可能性，并为耐药菌株提供可行的替代品。 创新：所提出的化学方法显示出对细菌细胞壁的渗透力有所提高，同时 通过可定制的 TiO2/PDMS 基质控制释放速率和生物利用度。我们假设这个新的 化学将降低与不可预测的浓度和长期存在相关的毒性 临床上使用广谱和“最后手段”抗生素。此前对该技术的研究主要集中在 防止细菌粘附在脊柱植入物、假体衬垫和缝合线上。十多种细菌 经测试，真菌病原体在 24 至 72 小时内具有相当高水平的抗菌活性。 研究计划：我们提出 2 个具体目标，其中：1) 提供羧酸银低浓度的证据 使用细胞代谢活性测定 MTT 观察参与伤口愈合的原代细胞系的细胞毒性， LDH、坏死和细胞凋亡。 2) 量化羧酸银对抗常见疾病的功效 通过剂量反应曲线和柯比鲍尔测定法确定抗生素耐药病原体。拟议的目标将 提供有关化学对抗细菌功效的附加数据，无论克名称或 抗菌药物耐药性，同时对参与伤口愈合的细胞表现出低毒性。该数据将是 用于寻求 R01 资助，重点是确定羧酸银的作用机制， 对生物膜的渗透性，以及针对生物膜持久细胞的活性。

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.