ELASTOMERIC POLYMERS & TUNABLE BIOLOGICAL FUNCTIONS FOR VOCAL FOLD TISSUE ENG

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 大自然设计的最引人注目的机械装置之一是由两个小折叠组成的 一种叫做声带的组织，它负责发出各种各样的声音 被气管气流震动。在正常情况下，声带可以承受30%的压力 频率为100至1000赫兹。然而，过度的机械应力和有害的病理 这种情况会对这一脆弱的系统造成损害，导致一系列声带疾病。至 迄今为止，声带疾病的最佳治疗尚未实现，组织工程学方法 为功能性声带的再生带来希望。然而，独特的生化成分， 声带的结构组织和粘弹性特性具有明显复杂的组织结构 利用传统聚合物生物材料的工程努力。 在这项新的合作努力中，整合了初级和职业早期教师的独特专业知识，我们 将产生新型生物活性弹性体，可用作声带组织的良好支架 工程学。这些生物材料将捕捉到分子的结构和力学特性 天然弹性蛋白(弹性蛋白和Resilin)；考虑到这两者的不同物理化学性质 蛋白质，使用两者将提供一种综合的方法来调整形态，机械和 新材料中的生物学特性。弹性蛋白模拟杂化聚合物(EMHP)将包括 多嵌段结构，具有交替的疏水、弹性合成结构域和亲水性、基于多肽的结构 交联域。合成块预计将表现出橡胶般的弹性，将在功能上 模拟弹性蛋白弹性域的性质，而多肽域将服务于结构上的 和生物功能。此外，基于resilin的模块化多肽(RBMP)将与 多个重复的独特功能模块，包括基于resilin的多肽结构域、肝素结合 多肽、细胞粘附肽和基质金属蛋白酶敏感结构域，以产生呈现 有用的生物线索，同时在高频下表现出高弹性。我们的综合战略将利用 已建立的合成聚合物化学和固态多肽合成的多功能性，以及新的 在这个科布雷提案中发展的正交有机化学。化学方法使用天然的 并将非天然氨基酸用于EMHP和RBMP的交联，以系统匹配机械 天然声带固有层的特性。在克里斯蒂安娜的临床合作者的帮助下 CARE和A.I.杜邦儿童医院将评估生物活性弹性体的能力 促进声带细胞增殖、血管生成和细胞外基质的产生。这些新材料和 方法提供了有希望的途径，最终工程功能性声带固有层通过 活细胞、弹性支架、生物因素和机械刺激的组合。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. One of the most remarkable mechanical devices that Nature has engineered consists of two small folds of tissue called vocal folds, which are responsible for the production of a great variety of sounds when vibrated by the tracheal air-stream. Under normal conditions, vocal folds can sustain up to 30% strain at frequencies of 100 to 1000 Hz. However, excessive mechanical stresses and deleterious pathological conditions can cause damage to this delicate system, resulting in a wide spectrum of vocal fold disorders. To date, optimal treatment for vocal fold disorders has not yet been realized, and tissue engineering methods hold promise for the regeneration of functional vocal folds. However, the unique biochemical composition, structural organization, and viscoelastic properties of vocal folds have significantly complicated tissue engineering efforts that utilize traditional polymeric biomaterials. In this new collaborative effort that integrates the unique expertise of junior and early-career faculty, we will produce novel bioactive elastomers that can be used as conducive scaffolds for vocal fold tissue engineering. These biomaterials will capture the molecular architecture and mechanical characteristics of natural elastic proteins (elastin and resilin); given the different physicochemical properties of these two proteins, employing both will offer a comprehensive approach for tuning morphological, mechanical and biological properties in the new materials. The elastin mimetic hybrid polymers (EMHP) will comprise a multiblock structure with alternating hydrophobic, elastic synthetic domains and hydrophilic, peptide-based cross-linking domains. The synthetic blocks are expected to show rubber-like elasticity that will functionally mimic the properties of the elastic domains of elastin, while the peptide domains will serve both structural and biological function. In addition, resilin-based modular polypeptides (RBMP) will be produced with multiple repeats of unique functional modules including resilin-based peptide domains, heparin-binding peptides, cell-adhesive peptides, and MMP-sensitive domains in order to produce materials that present useful biological cues while exhibiting high resilience at high frequencies. Our synthetic strategies will exploit the established versatility of synthetic polymer chemistry and solid state peptide synthesis, as well as new orthogonal organic chemistry developed in this COBRE proposal. Chemical methods employing both natural and non-natural amino acids will be used to crosslink EMHP and RBMP to systematically match mechanical properties to those of the natural vocal fold lamina propria. With the aid of clinical collaborators at Christiana Care and the A.I. duPont Hospital for Children, the bioactive elastomers will be evaluated for their ability to promote vocal fold cell proliferation, angiogenesis, and ECM production. These new materials and approaches offer promising routes to ultimately engineering functional vocal fold lamina propria via a combination of viable cells, elastic scaffolds, biological factors and mechanical stimulation.