Rechargeable Long-term Antifungal Denture Materials

可充电长期抗真菌义齿材料

• 批准号: 7576132
• 负责人: YUYU SUN
• 金额: $ 7.18万
• 依托单位: UNIVERSITY OF SOUTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7576132
• 关键词: Acids; Affect; Age; Animal Model; Anti-Bacterial Agents; Antibiotics; Antifungal Agents; Appearance; Back; Binding; Candida; Carbohydrates; Cells; Charge; Chronic; Clinical; Clinical Trials; Complex; Cyclodextrins; Dental; Dental Hygiene; Dental caries; Denture Bases; Denture Stomatitis; Denture Wear; Dentures; Development; Devices; Diabetes Mellitus; Diffuse; Disease; Disinfection; Drug Carriers; Effectiveness; Environment; Enzymes; FDA approved; General Practices; Glass Ionomer Cements; Goals; Growth; Habits; Health; Health Benefit; Healthcare; Immunocompromised Host; Immunosuppression; Incidence; Individual; Industrial fungicide; Infection; Inflammatory; Intake; Malnutrition; Measures; Mechanics; Medical Device; Methods; Microbial Biofilms; Natural regeneration; Nutritional status; Oral; Patients; Pattern; Periodontal Diseases; Pharmaceutical Preparations; Predisposition; Preventive; Property; Prosthesis; Quality of life; Radiation therapy; Reaction; Reporting; Research; Resistance; Risk; Root Caries; Rotation; Safety; Salivary; Speech; Structure; Study Section; Surface; System; Systemic disease; Technology; Testing; Time; Tissues; Toxin; acrylic acid; biomaterial compatibility; carboxyl radical; covalent bond; design; gastrointestinal; glass ionomer; high risk; improved; innovation; ionic bond; microbial; microorganism; microorganism antigen; novel strategies; polyacrylate; polymerization; prevent

DESCRIPTION (provided by applicant): Project Summary: Using antifungal dentures is an attractive approach to manage Candida-associated denture stomatitis (CADS), a common recurring disease among denture wearers, particularly in those who are immunocompromised or medically compromised. The effectiveness of this approach has been demonstrated in short-term studies. However, the current antifungal dentures are not effective for long-term use. After days to weeks, the antifungals released cannot reach the necessary concentrations, and inhibitory effects are lost. We propose to use rechargeable technology to create infection-responsive antifungal denture materials for long-term applications. Poly acrylic acid (PAA, a major component of glass-ionomer cements) and ¿-cyclodextrin (¿-CD, a widely used FDA approved drug carrier) will be covalently bound onto denture surfaces. The negatively charged PAA will bind and slowly release cationic antifungals through ionic complexes. The release rate is expected to be infection-responsive since the colonization of Candida species will decrease pH values, which will break the ionic complexes and thereby increase the rate of antifungal release. The hydrophobic cavities of ¿-CD will bind and release antifungals through inclusion complexes. This dual binding mechanism is anticipated to significantly increase the antifungal-binding capacity of the dentures. Moreover, various classes of antifungals can then be combined into one denture system through ionic and/or inclusion complexes, which is expected to markedly enhance inhibitory potency and reduce the risk of microbial resistance. After a certain period of time (e.g., weeks), the concentration of the antifungals released will decrease to suboptimal levels. However, when this happens, the dentures will be cleaned and recharged with antifungals again. Because the PAA and ¿-CD are permanently attached to the dentures through covalent bonds, they will not diffuse away from the dentures. Therefore, the "new" antifungals will be bound onto the denture surfaces by forming ionic and/or inclusion complexes. The recharged dentures will again provide infection-responsive release of a sufficient amount of antifungals to inhibit Candida colonization. Thus, the new dentures will act as a "rechargeable battery" of antifungals that can be repeatedly recharged to provide long- term protection. In recharging, the antifungals can be changed/rotated to further enhance inhibitory activity and minimize the risk of microbial resistance. If successful, this technology will provide an innovative approach to controlling CADS and other dental and medical device-related infections. The proposed research is designed to establish the feasibility, effectiveness, and safety of the new approach. The specific aims are to: (1) create rechargeable infection-responsive antifungal denture materials; and (2) characterize the mechanical properties, anti-colonization and anti-biofilm activity, durability, rechargeability, biocompatibility and safety of the denture materials developed. Project Narrative: The unique features of the new approach include the rechargeability of the released antifungals to achieve long-term protection, the infection-responsive release pattern to increase the quantity of antifungals released when the drugs are most needed, and the use and rotation of multiple antifungal agents in the initial binding and subsequent recharging treatments to improve inhibitory potency and minimize the risk of microbial resistance. These advantages make the rechargeable infection-responsive antifungal approach an attractive candidate for controlling Candida colonization/biofilm formation and reducing the incidence of CADS in long- term applications among high-risk patients. In addition, the rechargeable infection-responsive approach may stimulate the development of other long-term infection-resistant dental/medical devices that will make significant contributions to improving healthcare.

描述（由申请人提供）： 项目摘要：使用抗真菌假牙是治疗念珠菌相关假牙口腔炎 (CADS) 的一种有吸引力的方法，CADS 是假牙佩戴者中常见的复发性疾病，尤其是那些免疫功能低下或健康状况不佳的人。这种方法的有效性已在短期研究中得到证明。然而，目前的抗真菌假牙对于长期使用效果不佳。几天到几周后，释放的抗真菌药物无法达到必要的浓度，抑制作用就会消失。我们建议使用可充电技术来制造感染反应性抗真菌义齿材料，以供长期使用。聚丙烯酸（PAA，玻璃离子水门汀的主要成分）和 ¿-环糊精（¿-CD，FDA 批准的广泛使用的药物载体）将共价结合到义齿表面。带负电荷的 PAA 将通过离子复合物结合并缓慢释放阳离子抗真菌药物。由于念珠菌物种的定殖会降低 pH 值，从而破坏离子复合物，从而增加抗真菌药物的释放速率，因此释放速率预计是感染响应的。 ¿-CD 的疏水空腔将通过包合物结合并释放抗真菌药物。这种双重结合机制预计将显着提高假牙的抗真菌结合能力。此外，可以通过离子和/或包合络合物将各类抗真菌剂组合到一种义齿系统中，这有望显着增强抑制效力并降低微生物耐药性的风险。经过一段时间（例如几周）后，释放的抗真菌药物的浓度将降低至次优水平。然而，当发生这种情况时，假牙将被清洁并再次注入抗真菌药物。由于 PAA 和 ¿-CD 通过共价键永久附着在假牙上，因此它们不会从假牙上扩散开。因此，“新的”抗真菌剂将通过形成离子和/或包合络合物而结合到假牙表面上。重新充电的假牙将再次提供足量抗真菌药物的感染反应性释放，以抑制念珠菌定植。因此，新型假牙将充当抗真菌药物的“充电电池”，可以反复充电以提供长期保护。在充电时，可以更换/轮换抗真菌药物，以进一步增强抑制活性并最大限度地降低微生物耐药性的风险。如果成功，这项技术将为控制 CADS 以及其他牙科和医疗器械相关感染提供一种创新方法。拟议的研究旨在确定新方法的可行性、有效性和安全性。具体目标是：（1）制造可充电的感染反应性抗真菌义齿材料； (2) 表征所开发的义齿材料的机械性能、抗定殖和抗生物膜活性、耐久性、可充电性、生物相容性和安全性。 项目叙述：新方法的独特之处包括所释放的抗真菌药物的可充电性以实现长期保护，感染响应释放模式以在最需要药物时增加抗真菌药物的释放量，以及在初始结合和随后的再充电治疗中使用和轮换多种抗真菌药物以提高抑制效力并最大限度地降低微生物耐药性的风险。这些优点使得可充电感染反应性抗真菌方法成为控制念珠菌定植/生物膜形成并降低高危患者长期应用中 CADS 发生率的有吸引力的候选药物。此外，可充电感染响应方法可能会刺激其他长期抗感染牙科/医疗设备的发展，这将为改善医疗保健做出重大贡献。