ELASTOMERIC POLYMERS & TUNABLE BIOLOGICAL FUNCTIONS FOR VOCAL FOLD TISSUE ENG

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 大自然设计的最引人注目的机械装置之一由两个小褶皱组成 一种叫做声带的组织，它负责产生各种各样的声音， 通过气管气流振动。在正常情况下，声带可以承受高达30%的应变， 频率为100至1000 Hz。然而，过度的机械应力和有害的病理性 条件可能会导致损害这一微妙的系统，导致广泛的声带疾病。到 迄今为止，声带疾病的最佳治疗尚未实现，组织工程方法 对功能性声带的再生有希望。然而，独特的生化成分， 结构组织和粘弹性特性的声带有显着复杂的组织 利用传统聚合物生物材料的工程努力。 在这种新的合作努力，整合了初级和早期职业教师的独特专业知识，我们 将产生新的生物活性弹性体，可用作声带组织的有益支架， 工程.这些生物材料将捕捉分子结构和机械特性， 天然弹性蛋白质（弹性蛋白和弹性蛋白）;鉴于这两种蛋白质的不同物理化学性质， 蛋白质，采用两者将提供一个全面的方法，调整形态，机械和 新材料的生物学特性。弹性蛋白模拟杂化聚合物（EMHP）将包含弹性蛋白模拟杂化聚合物。 具有交替的疏水性、弹性合成域和亲水性、肽基 交联结构域。预计合成块将显示出类似橡胶的弹性， 模拟弹性蛋白的弹性结构域的性质，而肽结构域将同时起结构上的作用。 和生物功能。此外，将用以下方法产生基于节枝弹性蛋白的模块化多肽（RBMP）： 独特功能模块的多个重复，包括基于节枝弹性蛋白的肽结构域、肝素结合 肽、细胞粘附肽和MMP-敏感结构域，以产生呈现 有用的生物线索，同时在高频率下表现出高弹性。我们的合成策略将利用 合成聚合物化学和固态肽合成的既定通用性，以及新的 正交有机化学在这个COBRE提案中发展。化学方法采用天然 和非天然氨基酸将用于交联EMHP和RBMP，以系统地匹配机械性能。 天然声带固有层的特性。在Christiana的临床合作者的帮助下， 护理和人工智能杜邦儿童医院，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ECM产生。这些新材料和 方法提供了有前途的途径，最终工程功能声带固有层通过 活细胞、弹性支架、生物因子和机械刺激的组合。

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.