Macrophage And Fibroblast Modulation Toward Chronic Vocal Fold Scar Restoration

描述(申请人提供)：声带疤痕是一种虚弱的情况，已被证明难以用目前的外科技术或标准的注射填充物治疗。我们的龙 术语的目标是设计可注射的产品，促进伤口修复和诱导组织再生，以治疗慢性声带疤痕和固有层的其他细胞外基质(ECM)缺陷。这项建议旨在利用植入材料的能力来调节侵袭的巨噬细胞和声带成纤维细胞的表型，以实现改善慢性声带瘢痕的修复。我们将开发基于PEGDA的可注射水凝胶，它将与先前被认为具有抗纤维化和/或免疫调节作用的细胞因子偶联。我们的工作假设是，这些PEGDA细胞因子水凝胶将能够将慢性瘢痕中的肌成纤维细胞转变为与正常声带固有层结构和功能相关的正常声带成纤维细胞表型。我们进一步假设，在我们开发的水凝胶存在下，不适合慢性声带瘢痕修复的经典激活表型将被修改为抗炎表型。我们将采用系统的化学、体外细胞2D/3D单细胞/共培养研究、体内和体外研究的独特组合来解决细胞生物材料特性之间的复杂相互作用，以及对细胞行为、生物力学和手术条件的影响，以创造合适的临床结果。我们的发现将为处理慢性声带瘢痕表型作为促进声带功能快速、完全恢复的机制提供必要的基础工作。

DESCRIPTION (provided by applicant): Vocal fold scarring is a debilitation condition that has proven difficult to treat with current surgical techniques or standard injectable fillers. Our long term aim is to engineer injectable products that promote wound repair and induce tissue regeneration to treat chronic vocal fold scarring and other extracellular matrix (ECM) defects of the lamina propria. This proposal aims to harness the capacity of implanted materials to modulate the phenotype of invading macrophages and vocal fold fibroblasts toward achieving improved restoration of chronic vocal fold scar. We will develop PEGDA based injectable hydrogels that will be conjugated to cytokines previously identified as anti-fibrotic and/or immunomodulatory. Our working hypothesis is that these PEGDA cytokine hydrogels will be able to shift myofibroblasts found in chronic scar toward a normal vocal fold fibroblast phenotype associated with normal vocal fold lamina propria structure and function. We further hypothesize that the classically activated phenotype that is undesirable for chronic vocal fold scar restoration will be modified to an anti-inflammatory phenotype in the presence of our developed hydrogels. We will employ a unique combination of systematic chemical, in vitro cell 2D/3D mono/co culture studies, in vivo and ex vivo studies to resolve the complex interactions among cell biomaterial characteristics, and influences on cell behavior, biomechanics and the surgical requisites necessary to create a suitable clinical outcome. Our findings will provide the necessary ground work for manipulating chronic vocal fold scar phenotypes as a mechanism to promote rapid, complete restoration of vocal fold function.