Macrophage And Fibroblast Modulation Toward Chronic Vocal Fold Scar Restoration

描述（由申请人提供）：声带瘢痕是一种衰弱性疾病，已被证明难以用当前的手术技术或标准的可注射填充物治疗。我们漫长 长期目标是设计可注射产品，促进伤口修复和诱导组织再生，以治疗慢性声带瘢痕和固有层的其他细胞外基质（ECM）缺陷。该提议旨在利用植入材料调节侵入巨噬细胞和声带成纤维细胞表型的能力，以实现改善慢性声带瘢痕的恢复。我们将开发基于PEGDA的可注射水凝胶，其将与先前被鉴定为抗纤维化和/或免疫调节的细胞因子缀合。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发现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的存在下，对于慢性声带瘢痕修复不期望的经典活化表型将被修饰为抗炎表型。我们将采用系统化学、体外细胞2D/3D单一/共培养研究、体内和离体研究的独特组合，以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、生物力学和创造合适临床结果所需的手术操作的影响。我们的研究结果将为操纵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.