Condensed tannin polymers as a new functional biomaterials

医学植入物会引起生物反应，如细菌感染和炎症。在正常的愈合过程中，身体的免疫系统会帮助抵抗感染并清除受损组织。炎症应该是暂时的，应该随着新的健康组织的形成而消退，但长期的炎症会延迟或阻止愈合。长期的炎症不仅会破坏周围组织，还会通过一种叫做氧化的化学过程破坏植入材料。在严重的情况下，未解决的炎症或感染必须移除或更换种植体。虽然我们对外来物质如何导致炎症了解甚多，但对它们如何促进炎症的消退和随后的组织愈合知之甚少。这些问题可以通过开发促进炎症消退的新材料来解决。这项工作提出了一个受生物学启发的解决方案。植物产生一种叫做“浓缩单宁”的物质，它可以保护植物组织免受细菌和真菌病原体的侵害以及氧化的有害影响。这项工作将基于这些浓缩单宁开发新的植入材料。浓缩单宁将被修饰，这样它们就可以引导炎症反应，从而促进愈合，同时也赋予种植体表面抗氧化和抗菌活性。这项工作还将发现这些新材料如何调节与骨愈合相关的其他结果，例如干细胞生长和矿化，以便将这项工作转化为骨科植入物。这些基于浓缩单宁的新型生物材料将从丰富的可再生资源中开发出来，它们将为改善种植体周围的愈合提供新的策略。这项工作将为功能性生物材料的设计提供新的见解，这些材料可以促进愈合，减少氧化相关的损伤，并抵抗感染。国际合作者将为全球工程和创业研究生课程做出贡献。向公众宣传如何从丰富的可再生资源中获取可持续材料来解决医学中的重要挑战。技术摘要“生物惰性”生物材料的理想尚未实现。与生物环境接触的材料会吸附蛋白质，从而引起炎症反应。长时间的炎症会引起组织和材料的氧化损伤，抑制伤口愈合，导致种植体失败。缩合单宁是一类植物衍生的多酚类物质，具有优良的加工特性和宝贵的生物学特性。细胞对含有商业上可用的两性胺化缩合单宁（tanfloc）的物质的反应有报道。这项工作假设，缩合单宁的化学可以被修改，以调节重要的生物反应缩合单宁为基础的材料。这项工作的目的是：(1)化学修饰tanfloc以改变其酸度、碱度和抗氧化活性；（ii）利用化学修饰来调节蛋白质结合，从而调节巨噬细胞的极化、细胞炎症和抗菌活性；(3)利用化学修饰调节与骨愈合相关的间充质干细胞分化和矿化。含有新缩合单宁衍生物的表面结果将与用聚多巴胺（一种具有与tanfloc相似的儿茶酚胺化学性质的生物聚合物）修饰的表面、低聚乙二醇表面（呈现氢键受体，但没有酸性或碱性基团）以及骨组织工程中常用的其他材料进行比较。这项工作将产生三种新的缩合单宁衍生物，含有增加的（酚类）酸度，增加的（季胺）碱度，或增加的醚（邻甲基醚）官能团，具有良好表征的多电解质行为，抗氧化活性和降解动力学。这项工作将阐明结构-性质关系，证明缩合单宁化学如何改变以调节蛋白质结合、巨噬细胞极化、吞噬、异物巨细胞形成和抗菌活性。这项工作还将证明浓缩单宁的化学作用可以调节干细胞的分化和表面矿化。这项工作将扩大本科生和硕士生对研究计划的参与。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。

Non-technical abstractMedical implants can cause biological responses such as bacterial infection and inflammation. In normal healing, body’s immune system helps to fight infection and remove damaged tissue. Inflammation should be temporary, and should wane as new healthy tissue is formed, but prolonged inflammation can delay or prevent healing. Prolonged inflammation can damage not only the surrounding tissue but also the implant material through a chemical process called oxidation. In severe cases of unresolved inflammation or infection implants must be removed or replaced. While much is known about how foreign materials lead to inflammation, very little is known about how they can promote the resolution of inflammation and subsequent tissue healing. These problems could be addressed by development of new materials that promote the resolution of inflammation. This work proposes a solution inspired by biology. Plants produce materials called “condensed tannins” that protect plant tissues from bacterial and fungal pathogens and from the harmful effects of oxidation. This work will develop new materials for implants based on these condensed tannins. Condensed tannins will be modified so that they can guide inflammatory responses, and thereby promote healing, while also imparting antioxidant and antibacterial activity to implant surfaces. This work will also discover how these new materials modulate other outcomes related particularly to bone healing, such as stem cell growth and mineralization, so that the work can be translated to orthopedic implants. These new biomaterials based on condensed tannins will be developed from an abundant renewable resource, and they will provide new strategies for improving healing around implants. This work will yield new insights into the design of functional biomaterials that promote healing, reduce oxidation related damage, and fight infections. An international collaborator will contribute to a graduate course in global engineering and entrepreneurship. Outreach to the public will communicate how sustainable materials from abundant renewable resources can solve important challenges in medicine.Technical abstractThe ideal of a “bioinert” biomaterial has not been realized. Materials in contact with biological environments adsorb proteins, which can induce inflammatory responses. Prolonged inflammation can cause oxidative damage to tissues and materials, and inhibit wound healing, leading to implant failure. Condensed tannins are a class of plant-derived polyphenols, with excellent processing characteristics and valuable biological properties. Cellular responses to materials containing a commercially available, amphoteric aminated condensed tannin called tanfloc have been reported. This work hypothesizes that the chemistry of condensed tannins can be modified to modulate important biological responses to condensed tannin-based materials. This work aims to (i) chemically modify tanfloc to alter its acidity, basicity, and antioxidant activity; (ii) use the chemical modification to modulate protein binding, thereby modulating the polarization of macrophages, cellular inflammation, and antibacterial activity; and (iii) use the chemical modification to modulate mesenchymal stem cell differentiation and mineralization that are related to bone healing. Outcomes on surfaces containing the new condensed tannin derivatives will be compared to surfaces modified with polydopamine (a biopolymer with similar catecholamine chemistry to tanfloc), to oligoethylene glycol surfaces (presenting hydrogen bond acceptors but no acidic or basic groups), and to other materials commonly used in bone tissue engineering. This proposed work will produce three new condensed tannin derivatives, containing either increased (phenolic) acidity, increased (quaternary amine) basicity, or increased ether (o-methyl ether) functional groups, with well-characterized polyelectrolyte behavior, antioxidant activity, and degradation kinetics. This work will elucidate structure-property relationships that demonstrate how condensed tannin chemistry can be altered to modulate protein binding, macrophage polarization, phagocytosis, foreign body giant cell formation, and antibacterial activity. This work will also demonstrate that the chemistry of condensed tannins can modulate stem cell differentiation and mineralization on surfaces. The work will broaden participation of undergraduate and masters students in the research program.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.