Design, construction, and evaluation of implants for vocal fold alteration and re

声带改造和再造植入物的设计、构建和评估

基本信息

批准号：
8890823
负责人：
LUC MONGEAU
金额：
$ 50.87万
依托单位：
MCGILL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8890823
关键词：
Adhesions Affect Air Atomic Force Microscopy Atrophic Biochemical Biocompatible Materials Biological Biological Assay Biological Factors Biology Biomimetics Bioreactors Cell-Matrix Junction Cells Characteristics Cicatrix Clinic Visits Collagen Collagen Fiber Communication impairment Complement Computational Science Computer Simulation Crosslinker Custom Data Elasticity Elastin Elastin Fiber Engineering Environment Evaluation Evolution Extracellular Matrix Extracellular Matrix Proteins Fatty acid glycerol esters Fibroblasts Financial cost Frequencies Funding Gel Gelatin Goals Growth Health Human Hyaluronic Acid Image Imagery Imaging Techniques Immunohistochemistry Implant In Situ In Vitro Injectable Injection of therapeutic agent Laboratories Lamina Propria Laser Scanning Confocal Microscopy Laser Scanning Microscopy Lasers Life Link Longevity Measurement Measures Mechanical Stimulation Mechanical Stress Mechanics Modeling Monitor Natural regeneration Optics Organ Outcome Particle Size Patients Phonation Physics Pliability Population Process Production Property Proteins Regimen Relative (related person)Research Role Scanning Solid Solutions Spatial Distribution Stress Structure Surface Testing Therapeutic Time Tissue Engineering Tissues Variant Voice Weight Width Work base cell behavior cell motility design design and construction functional outcomes functional status improved migration mimetics novel particle repaired research study response restoration scaffold success tissue regeneration viscoelasticity vocal cord vocalis muscle

项目摘要

DESCRIPTION (provided by applicant): Injectable biomaterials have been used to treat vocal fold scarring, atrophy or sulcus vocalis, in which part of the soft and pliable lamina propria is lst or replaced by stiff fibrous tissue. Bioimplants such as fats and collagen have been used to treat these conditions, but they only allow very limited biological activity and thus merely offer a shor-term solution to voice restoration. Over the last two funding cycles, our laboratory has developed an injectable scaffold biomaterial composed of hyaluronic acid and gelatine particles (HA-Ge), which are biologically active and facilitate cell attachment, migration and proliferation. We hypothesize that this gel-based scaffold has the capacity to promote permanent self-regeneration of the vocal fold tissue without the need for periodic re-injection. But the functionality of the regenerated tissue is variable. We are currently unable to predict how phonation may influence the outcome of tissue engineering treatments, and it is not clear if such influence depends on scaffold composition. We hypothesize that phonation-like mechanical stimulation is required for the scaffold-derived tissue to develop, mature and function properly. A multi-disciplinary approach combining engineering, physics, biology, and computational sciences is proposed to study the influence of scaffold composition and mechanical stimulation on the regeneration process and functional outcomes of HA-Ge scaffold-engineered tissue. We will use an airflow-induced self-excited vocal fold bioreactor reproducing phonation-like mechanical stimulation to monitor local mechanical stress, cell activity, extracellular matrix (ECM) organization, and elasticity within the HA-Ge scaffold. We will vary scaffold composition and mechanical stimulation. The experiments will be performed over a time period suitable for neo-tissue growth and maturation. Vocal fold fibroblast cells will be placed into an HA-Ge scaffold within a biomimetic synthetic vocal fold vibrating in response to airflow at frequencies typical of phonation. The ECM will be imaged in-situ using online nonlinear laser scanning microscopy. Measurements of the local mechanical stress distribution on the synthetic vocal fold will be made. Cell and ECM alignments will be imaged and quantified. Additional biological factors controlling ECM production and remodeling will be measured using protein assays. We will create new computational models to link mechanical and biological factors quantitatively and to predict tissue elasticity of the scaffold-derived ECM as a function of phonation conditions and scaffold composition. This study expands our prior work to engineer an injectable scaffold that can regenerate ECM having mechanical properties similar to those of human vocal fold lamina propria tissue. We will investigate how post-injection phonation influences tissue-engineering outcomes and the effect of scaffold composition. The population significance of this work comes from the extensive personal and financial costs associated with vocal fold scarring, atrophy and sulcus vocalis (i.e., billions of dollars annually in the U.S. alone) and the unpredictable functioal outcomes of the currently available, unsatisfactory treatment options.

描述（申请人提供）：可注射生物材料已用于治疗声带疤痕、萎缩或声带沟，其中部分柔软而柔韧的固有层首先被坚硬的纤维组织取代或替代。脂肪和胶原蛋白等生物植入物已被用来治疗这些疾病，但它们只具有非常有限的生物活性，因此只能为声音恢复提供短期解决方案。在过去的两个资助周期中，我们的实验室开发了一种由透明质酸和明胶颗粒（HA-Ge）组成的可注射支架生物材料，其具有生物活性并促进细胞附着、迁移和增殖。我们假设这种基于凝胶的支架能够促进声带组织的永久自我再生，而不需要定期重新注射。但再生组织的功能是可变的。我们目前无法预测发声如何影响组织工程治疗的结果，也不清楚这种影响是否取决于支架组成。我们假设支架衍生组织的发育、成熟和正常功能需要类似发声的机械刺激。一个提出了结合工程学、物理学、生物学和计算科学的多学科方法来研究支架组成和机械刺激对 HA-Ge 支架工程组织的再生过程和功能结果的影响。我们将使用气流诱导的自激声带生物反应器再现类似发声的机械刺激，以监测局部机械应力、细胞活性、细胞外基质 (ECM) 组织和 HA-Ge 支架内的弹性。我们将改变支架组成和机械刺激。实验将在适合新组织生长和成熟的时间段内进行。声带成纤维细胞将被放置在仿生合成声带内的 HA-Ge 支架中，声带以典型的发声频率响应气流而振动。 ECM 将使用在线非线性激光扫描显微镜进行原位成像。将测量合成声带上的局部机械应力分布。细胞和 ECM 排列将被成像和量化。控制 ECM 产生和重塑的其他生物因素将使用蛋白质测定进行测量。我们将创建新的计算模型来定量连接机械和生物因素，并预测支架衍生的 ECM 的组织弹性作为发声条件和支架组成的函数。这项研究扩展了我们之前的工作，设计了一种可注射支架，该支架可以再生具有与人类声带固有层组织相似的机械特性的 ECM。我们将研究注射后发声如何影响组织工程结果和支架成分的影响。这项工作对人群的重要性来自于与声带疤痕、萎缩和声带沟相关的大量个人和财务成本（仅在美国每年就花费数十亿美元）以及当前可用的、不令人满意的治疗方案的不可预测的功能结果。