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通常涉及可降解聚合物的使用。在过去的50年里，全球范围内已经建立了大量关于可降解材料的物理特性，加工和安全数据。医疗器械、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，其中已知的材料库将不起作用。无法设计聚合物装置和药物递送的降解仍然是该领域工业创新的最重要障碍之一。由于这一障碍，临床前测试和开发工作仍然是经验性的（试错法），这是缓慢的，昂贵的，并经常迫使公司使用已在其他已获得监管批准的设备中使用的材料来降低风险。这个为期一年的FDA学者驻留项目的目标是启动一个框架，用于将体外与体内相关联，即，在实验室到体内，降解行为的基础上研究了一系列完全可吸收可降解的高分子材料。一个基准和验证的框架，将创建一个体外体内相关性（IVIVC）在新的和新兴的材料库将是一个宝贵的工具，所有利益相关者在学术界，行业和监管机构寻求加快生产开发时间表，提高安全性和降低监管风险。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，后者将利用在FDA获得的经验指导高中生、本科生和研究生。该项目的重点是开发基于氨基酸的聚酯脲的水传输、降解性能和机械性能随时间变化的相关性。聚合物的许多性质影响其降解的速度。开发IVIV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速率。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可水解降解聚合物。设计用于产生一系列水传输和机械性能的材料将在体外接受加速和生理降解条件，并将随时间跟踪分子量、分子量分布、机械和物理性能，并以动物模型中的体内皮下植入物为基准。拟议的研究将通过帮助建立用于构建IVIVC的框架来影响生物材料界，以用于降解和基于氨基酸的聚酯脲的机械性能的相关变化。这项工作将与CDRH/FDA的工作人员合作完成，他们在聚合物基医疗器械和组合产品的化学和加工方面具有丰富的监管科学经验。所产生的数据将帮助FDA产生基础和监管科学知识，用于评估使用新的可降解聚合物和加工技术制造的医疗产品。该奖项反映了NSF的法定使命，并被认为值得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来支持。

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.