Novel Methacrylate-Thiol-Ene Composites for Dental Restorative Materials

用于牙科修复材料的新型甲基丙烯酸酯-硫醇-烯复合材料

• 批准号: 8780413
• 负责人: NEIL B CRAMER
• 金额: $ 15万
• 依托单位: COLORADO PHOTOPOLYMER SOLUTIONS, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8780413
• 关键词: Acrylates; Adhesions; Adhesives; Area; Biocompatible Materials; Clinical; Collaborations; Colorado; Composite Resins; Conversion disorder; Coupled; Coupling; Dental; Dental Materials; Development; Drug Formulations; Elements; Failure; Fatigue; Filler; Funding; Glass; Goals; Grant; Growth; Health; Individual; Knowledge; Lead; Legal patent; Licensing; Life; Longevity; Mechanical Stress; Mechanics; Methacrylates; Methodology; Nature; Optics; Orthodontic; Oxygen; Peer Review; Performance; Phase; Plant Resins; Polymers; Positioning Attribute; Prevalence; Procedures; Property; Publications; Qualifying; Reaction; Refractive Indices; Reliance; Resistance; Safety; Sampling; Services; Small Business Innovation Research Grant; Smiling; Solutions; Speed; Stress; Sulfhydryl Compounds; System; Technology; Testing; Time; Tooth structure; Toxic effect; United States National Institutes of Health; Universities; Urethane; Water; Work; base; biomaterial compatibility; bisphenol A; commercialization; composite restoration; design; experience; forging; improved; innovation; mechanical behavior; medical specialties; monomer; novel; polymerization; premature; restoration; restorative dentistry; restorative material; restorative resins; triethylene glycol dimethacrylate; uptake

DESCRIPTION (provided by applicant): Novel Methacrylate-Thiol-Ene Composites for Dental Restorative Materials. As the demand for aesthetically pleasing restorative materials has increased, so has the desire and demand for improved performance. Despite their increasing prevalence, the resin phase of these materials has remained largely unaltered since Bowen first proposed the materials nearly 50 years ago. Presently, composites suffer from shrinkage and stress that arise during polymerization, a subsequent lack of appropriate mechanical properties of the resin material, and low depth of cure for polymerization. The composites also contain in their core monomer the substitutent bisphenol-A, which is associated with ever increasingly significant regulatory and health concerns. Following polymerization, the composites also contain significant fractions of unreacted monomer that results in the critical presence of extractables that coupled with moisture uptake by the sample can lead to degradation. The result is often secondary cavities and premature failure where composites average lifetime is less than 8 years. Classically, the limitations of these materials have involved a trade-off between the mechanical behavior, the stress and the extent of reaction/conversion of the material that limits extractables and water sorption. The BisGMA/TEGDMA system has proven to be a local optimum within this overall flawed compromise. Here, we propose a novel methodology that changes the reaction paradigm and allows for improvement in each of these critical areas - lower shrinkage and stress, improved mechanics, higher extent of reaction, improved depth of cure along with the elimination of bisphenol-A, and reduced extractables and degradation. An approach using thiol-ene click reactions and monomers is combined with an improved methacrylate approach to yield dramatic improvements in each of these critical areas. Within the two aims of this work, two distinct elements of the formulation are targeted - development and optimization of the resin phase, and development and optimization of the filler/filler coupling agent combination. While both of these aims can proceed independently and will yield valuable results in and of themselves. The synergistic combination of these approaches will forge an entirely new composite dental restorative with expected improvements in conversion, reduced degradation and improved biocompatibility and public safety, mechanics and service life. Specifically, in the first aim, we seek to incorporate urethane-based methacrylates in place of bisphenol-A based monomers. The increased refractive index of the thiol-ene components enables the use of non-bisphenol-A-based monomers - with corresponding benefits of enhanced material properties. Thus, the increased urethane content will result in both improved material properties and reduced shrinkage stress as compared to utilizing BisGMA or BisEMA as the methacrylate in methacrylate-thiol-ene formulations. Second, we propose to focus on the comprehensive development of an integrated filler system that is improved overall and designed specifically for integration with the methacrylate-thiol- ene resins. Our preliminary results have demonstrated a much greater mechanical property enhancement in composite methacrylate-thiol-ene systems than in the control composite BisGMA/TEGDMA systems. These results indicate that the increased conversion of methacrylate-thiol-ene systems will not only dramatically reduce the amount of extractable monomer but also enhance the interaction between the resin phase and the fillers, leading to enhanced mechanical properties. This same benefit is expected to lead to improved adhesion with the native tooth structure. The proposed aims are predicated on the hypothesis that appropriate materials synthesis and subsequent incorporation of urethane-methacrylate base components, optimization of the formulation composition and polymerization mechanism, and optimally designed and modified fillers will improve dental composites through dramatic reductions in shrinkage stress, improvement in composite mechanical properties, moisture uptake and reduced extractables along with improved toxicity and implementation of BPA-free formulations. Results to date demonstrate improved polymerization rates, volume shrinkage induced stress, mechanical properties, depth of cure, oxygen inhibition, toxicity and final conversion. These results will for dental composite systems with enhanced longevity and improved clinical scope. The methacrylate-thiol-ene technology was developed at the University of Colorado by Drs. Cramer and Bowman with funding from an NIH R01 grant (DE018233 - Development of Novel Thiol-Ene-Methacrylate Composites for Dental Restorative Materials). In total, the prior work supported in this area by the R01 grant, of which the PI for this proposal was a co-PI, resulted in 17 peer reviewed publications and two US patents that have been optioned by Colorado Photopolymer Solutions (CPS). Drs Cramer and Bowman have previous experience developing and commercializing dental restorative materials through their collaboration with Septodont Confi-Dental products. During this collaboration, a novel methacrylate formulation from University of Colorado was licensed by Septodont Confi-Dental Products Division and is available commercially as N'Durance (http://www.septodontusa.com/products/n-durance). This provides us with first-hand knowledge for the testing and procedures necessary to commercialize a dental restorative material as well as a potential partner for Phase III. CPS has significant experience in both dental materials and (meth)acrylate and thiol-ene materials. CPS has recently developed and licensed two orthodontic adhesives (Perfect-A-Smile and Bond Aligner) that are currently commercially available through Reliance Orthodontic Products (www.relianceorthodontics.com). CPS also develops and manufactures a range of (meth)acrylate and thiol-ene based formulations for adhesives, optical materials, and other specialty applications.

描述（由申请人提供）：用于牙科修复材料的新型甲基丙烯酸酯-硫醇-烯复合材料。随着对美观的修复材料的需求增加，对改进性能的渴望和需求也在增加。尽管它们越来越流行，但自从 Bowen 近 50 年前首次提出这些材料以来，这些材料的树脂相基本上没有改变。目前，复合材料遭受聚合过程中产生的收缩和应力、随后树脂材料缺乏适当的机械性能以及聚合固化深度低的问题。该复合材料的核心单体中还含有取代基双酚-A，这与日益重要的监管和健康问题相关。聚合后，复合材料还含有大量未反应的单体，导致可萃取物的严重存在，再加上样品吸收水分，可能导致降解。结果往往是产生二次空洞和过早失效，复合材料的平均寿命低于 8 年。传统上，这些材料的局限性涉及材料的机械行为、应力和反应/转化程度之间的权衡，从而限制了可萃取物和水吸附。 BisGMA/TEGDMA 系统已被证明是这个总体有缺陷的折衷方案中的局部最优方案。在这里，我们提出了一种新颖的方法，它改变了反应范式，并允许在每个关键领域进行改进 - 降低收缩和应力，改进机械性能，提高反应程度，提高固化深度并消除双酚-A，并减少可萃取物和降解。使用硫醇-烯点击反应和单体的方法与改进的甲基丙烯酸酯方法相结合，在每个关键领域都取得了显着的改进。在这项工作的两个目标中，有两个不同的配方要素：树脂相的开发和优化，以及填料/填料偶联剂组合的开发和优化。虽然这两个目标都可以独立进行，并且本身就会产生有价值的成果。这些方法的协同组合将打造出一种全新的复合牙科修复材料，有望改善转化、减少降解并提高生物相容性和公共安全、机械性能和使用寿命。具体来说，在第一个目标中，我们寻求采用聚氨酯基甲基丙烯酸酯来代替双酚A基单体。硫醇烯组分折射率的提高使得能够使用非双酚 A 基单体 - 从而具有增强材料性能的相应优点。因此，与使用BisGMA或BisEMA作为甲基丙烯酸酯-硫醇-烯配方中的甲基丙烯酸酯相比，增加的氨基甲酸酯含量将导致改善的材料性能和降低的收缩应力。其次，我们建议重点关注综合填料系统的全面开发，该系统经过整体改进，专门为与甲基丙烯酸酯-硫醇烯树脂的集成而设计。 我们的初步结果表明，与对照复合 BisGMA/TEGDMA 系统相比，复合甲基丙烯酸酯-硫醇-烯系统的机械性能得到了更大的提高。这些结果表明，甲基丙烯酸酯-硫醇-烯体系转化率的提高不仅会显着减少可萃取单体的量，而且会增强树脂相和填料之间的相互作用，从而提高机械性能。预计同样的好处会改善与天然牙齿结构的粘附力。所提出的目标基于这样的假设：适当的材料合成和随后的聚氨酯-甲基丙烯酸酯基础组分的掺入、配方组成和聚合机制的优化以及优化设计和改性的填料将通过显着降低收缩应力、改善复合材料机械性能、吸湿性和减少可萃取物以及改善毒性和实施来改善牙科复合材料。 不含 BPA 的配方。迄今为止的结果表明，聚合速率、体积收缩引起的应力、机械性能、固化深度、氧抑制、毒性和最终转化率均得到改善。这些结果将提高牙科复合材料系统的使用寿命并改善临床范围。甲基丙烯酸酯-硫醇-烯技术是由科罗拉多大学的 Drs. 开发的。 Cramer 和 Bowman 获得了 NIH R01 资助（DE018233 - 用于牙科修复材料的新型硫醇-烯-甲基丙烯酸酯复合材料的开发）。总的来说，R01 拨款支持的该领域的先前工作（其中该提案的 PI 是共同 PI）导致了 科罗拉多光聚合物解决方案 (CPS) 已选择了 17 篇同行评审出版物和两项美国专利。 Cramer 和 Bowman 博士之前通过与 Septodont Confi-Dental 产品合作开发和商业化牙科修复材料，拥有丰富的经验。在此次合作期间，科罗拉多大学的一种新型甲基丙烯酸酯配方获得了 Septodont Confi-Dental Products Division 的许可，并以 N'Durance 商品名上市 (http://www.septodontusa.com/products/n-durance)。这为我们提供了牙科修复材料商业化所需的测试和程序的第一手知识，以及第三阶段的潜在合作伙伴。 CPS 在牙科材料以及（甲基）丙烯酸酯和硫醇烯材料方面拥有丰富的经验。 CPS 最近开发并授权了两种正畸粘合剂（Perfect-A-Smile 和 Bond Aligner），目前可通过 Reliance Orthodontic Products (www.relianceorthodontics.com) 进行商业化购买。 CPS 还开发和生产一系列基于（甲基）丙烯酸酯和硫醇烯的配方，用于粘合剂、光学材料和其他特种应用。