NSF/FDA SIR: Designing for Degradation: A framework for Predicting in vivo Degradation and Mechanical Property Changes in Degradable Polymers

新药和医疗器械的商业化常常涉及到可降解聚合物的使用。在过去的50年里，在全球范围内建立了大量关于可降解材料的物理特性、处理和安全数据，这些数据都是关于一个很小的可降解材料库的。医疗设备、生物医学植入物和药物输送等整个行业都是在这些数据集的基础上建立和维持的。然而，有一些新兴的应用和研究路线，在这些应用和研究路线中，已知的资料库将不起作用。无法设计聚合物设备和药物递送的降解仍然是该领域工业创新的最大障碍之一。由于这一障碍，临床前测试和开发工作仍然是经验性的（试错），这是缓慢、昂贵的，并且经常迫使公司使用已经在其他设备中使用的材料，这些材料已经获得监管部门的批准，以降低风险。这个为期一年的FDA驻团学者项目的目标是建立一个框架，将体外和体内，即实验室和体内，基于一系列完全可吸收可降解聚合物材料的降解行为进行研究。对于学术界、工业界和监管机构寻求加速生产开发时间表、提高安全性和降低监管风险的所有利益相关者来说，一个基准和经过验证的框架将在新兴的材料库中创建体外体内相关性（IVIVC），这将是一个宝贵的工具。该项目还将在FDA和研究者实验室之间建立强有力的合作，并为研究生提供独特的培训经验，研究生将利用在FDA获得的经验指导高中生、本科生和研究生。本项目的重点是发展氨基酸基聚脲的水运输、降解性能和力学性能随时间变化的相关性。聚合物的许多特性影响其降解的速度。开发体外受精相关性的挑战在于，旨在开发半经验模型的体外试验不能准确预测体内发生的降解率。这主要是由于复杂的动态过程无法在静态模型中轻松捕获。本提案中收集的体外和体内数据将提供建立该框架所需的初始数据集，并帮助FDA推进监管科学，以确保在未来几代植入物中安全使用水解可降解聚合物。设计用于创造一系列水运输和机械性能的材料将在体外加速和生理降解条件下进行，分子质量，分子质量分布，机械和物理性能将随着时间的推移而被跟踪，并与动物模型中的体内皮下植入物进行基准测试。该建议的研究将通过帮助建立用于降解和氨基酸基聚脲力学性能相关变化的IVIVC的框架来影响生物材料界。这项工作将与CDRH/FDA的工作人员合作完成，他们在聚合物医疗器械和组合产品的化学和加工方面拥有丰富的监管科学经验。所产生的数据将帮助FDA为评估使用新的可降解聚合物和加工技术制造的医疗产品提供基础和监管科学知识。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The commercialization of new medicines and medical devices often involves the use of degradable polymers. Over the last 50 years, a tremendous volume of physical property, processing and safety data has been built up globally about a very small library of degradable materials. Entire industries in medical devices, biomedical implants and drug delivery have been built and sustained on these data sets. However, there are emerging applications and routes of investigation in which the known library of materials will not work. The inability to design for degradation in polymeric devices and drug delivery remains one of the most significant barriers to industrial innovation in this area. As a result of this barrier, pre-clinical testing and development efforts remain empirical (trial and error) which is slow, expensive, and frequently pushes companies to utilize materials that have been used in other devices that have gained regulatory approval to lessen risk. The goal of this one-year FDA scholar in residence project is to initiate a framework for correlating in vitro to in vivo, i.e., in the lab to in the body, degradation behavior based on studies in a series of fully resorbable degradable polymer materials. A benchmarked and validated framework that would create an in vitro in vivo correlation (IVIVC) in new and emerging libraries of materials would be an invaluable tool to all stakeholders in academia, industry and regulatory agencies seeking to accelerate produced development timelines, increase safety and reduce regulatory risk. The project will also establish a robust collaboration between the FDA and the Investigator’s lab and provide a unique training experience for a graduate student who will in turn use experiences gained at the FDA to mentor high school, undergraduate and graduate students.This project is focused on developing correlations of water transport, degradation properties and time dependent changes in mechanical properties in amino acid-based poly(ester urea)s. Many properties of polymers affect how fast it degrades. The challenge for developing IVIV correlations is that in vitro tests, designed to develop semi-empirical models, do not accurately predict degradation rates that occur in vivo. This is primarily due to complicated dynamic processes that cannot be easily captured within static models. The in vitro and in vivo data collected in this proposal will provide the initial data sets needed to establish this framework and aid the FDA in advancing regulatory science that will be needed to ensure the safe use of hydrolytically degradable polymer in future generations of implants. Materials designed to create a range of water transport and mechanical properties will be subjected in vitro to accelerated and physiological degradation conditions and the molecular mass, molecular mass distribution, mechanical and physical properties will be tracked over time and benchmarked against in vivo subcutaneous implants in an animal model. The proposed research will impact the biomaterials community by helping to establish a framework for building IVIVC for degradation and the associated changes in the mechanical properties of amino acid-based poly(ester urea)s. This work will be done in collaboration with staff at CDRH/FDA, who have extensive regulatory science experience in chemistry and processing of polymer-based medical devices and combination products. The data generated will help the FDA generate fundamental and regulatory science knowledge for evaluating medical products fabricated using new degradable polymers and processing technologies.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.