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

• 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
• 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

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（由申请人提供）：可注射生物材料已用于治疗声带瘢痕、萎缩或声带沟，其中部分柔软柔韧的固有层消失或被坚硬的纤维组织取代。脂肪和胶原蛋白等生物植入物已被用于治疗这些疾病，但它们只允许非常有限的生物活性，因此只能提供短期的声音恢复解决方案。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，该材料具有生物活性，有助于细胞附着，迁移和增殖。 我们假设，这种凝胶基支架有能力促进声带组织的永久性自我再生，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成分。我们假设，发声类机械刺激所需的支架衍生组织的发展，成熟和功能正常。一 本论文采用工程学、物理学、生物学和计算科学相结合的多学科方法，研究了支架成分和机械刺激对HA-Ge支架工程组织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声音的机械刺激来监测HA-Ge支架内的局部机械应力、细胞活性、细胞外基质（ECM）组织和弹性。我们将改变支架成分和机械刺激。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置于仿生合成声带内的HA-Ge支架中，该仿生合成声带响应于气流以发声的典型频率振动。ECM将使用在线非线性激光扫描显微镜原位成像。测量人工声带上的局部机械应力分布。将对细胞和ECM比对进行成像和定量。将使用蛋白质测定来测量控制ECM产生和重塑的其他生物因子。我们将创建新的计算模型，定量地将机械和生物因素联系起来，并预测支架衍生ECM的组织弹性作为发声条件和支架成分的函数。这项研究扩展了我们以前的工作，工程师可注射支架，可以再生ECM具有类似于人类声带固有层组织的机械性能。我们将研究注射后发声如何影响组织工程的结果和支架成分的影响。这项工作的人口意义来自于与声带瘢痕、萎缩和声带沟（即，仅在美国每年就需要数十亿美元）以及目前可用的、不令人满意的治疗选择的不可预测的功能结果。