Failure mechanisms in collagen of heart valves and tissue engineered replacements

心脏瓣膜和组织工程替代品胶原蛋白的失效机制

• 批准号: 191922-2010
• 负责人: Lee, Michael
• 金额: $ 1.68万
• 依托单位: Dalhousie University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2011
• 资助国家: 加拿大
• 起止时间: 2011-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=476558
• 关键词: Failure; mechanisms; collagen; heart; valves

Tissue engineering seeks to replace damaged or diseased tissues with fully natural, regenerated structures. Many of the targets for this enterprise are mechanically critical structures (e.g. heart valves, artery replacements, heart wall) where failure can mean severe illness or death for the patient. Since the heart beats 35 million times a year, there is a strong need to understand the mechanisms by which both native tissues and engineered replacements respond to the mechanical fatigue associated with repeated loading. Moreover, tissue-engineered replacements are often juvenile in structure and function and face real challenges in immediately taking over the duties of mature, adult tissues. In this research program, we are seeking to understand the fundamental structural roots of biomechanical failure, and its prevention, in natural heart valves and tissue engineered replacements. Thereby, we hope to decrease the likelihood of failure of a replacement valve in a patient and bioengineer valves that have a defined safety in their design. Project one will use synchrotron x-ray diffraction and small angle scattering to study the packing of collagen molecules (i) in intact tissues and tissues overloaded to failure, and (ii) in tissues of varying age, from neonatal life to old age. By this means we hope to understand how this molecule-level characteristic of tissue architecture defines the stability of collagen and thereby its resistance to uncoiling and degradation. Project two will use two new confocal laser microscopy techniques (2nd harmonic generation and CNA35 binding) to examine changes in collagen fibre and bundle structure during uniaxial and biaxial loading to failure. This approach will allow direct visualization of the mechanisms by which the collagen architecture is disrupted, and the influence that age, crosslinking, and mechanical fatigue has on those mechanisms. Finally, in Project three, we will use host inflammatory cells (macrophages) to look at how changes in collagen (fatigue damage, enzyme breakdown, and crosslinking) influence the host reaction to implanted tissue devices.

组织工程试图用完全自然的，再生的结构代替受损或患病的组织。该企业的许多目标是机械关键的结构（例如心脏瓣膜，动脉置换，心墙），失败可能意味着患者的严重疾病或死亡。由于心脏每年击败3500万次，因此非常需要了解天然组织和工程替换的机制对与重复负载相关的机械疲劳作出反应。此外，组织工程的替换通常在结构和功能上是少年，并且在接管成熟成人组织的职责时面临着真正的挑战。在该研究计划中，我们试图了解生物力学衰竭的基本结构根及其预防，在自然心脏瓣膜和组织工程替代物中。因此，我们希望减少患者和生物工具阀中替换阀失败的可能性，这些阀的设计具有确定的安全性。项目One将使用同步加速器X射线衍射和小角度散射来研究完整的组织中胶原蛋白分子（i）的堆积，并且在变化的年龄，从新生儿寿命到老年，在变化的组织中过载了。通过这种方式，我们希望了解该分子级结构的特征如何定义胶原蛋白的稳定性，从而对其对脱落和降解的抗性。项目二将使用两种新的共聚焦激光显微镜技术（第二次谐波生成和CNA35结合）来检查单轴和双轴负载在失败期间胶原蛋白纤维和束结构的变化。这种方法将直接可视化胶原蛋白结构被破坏的机制，以及年龄，交联和机械疲劳对这些机制的影响。最后，在项目第三项目中，我们将使用宿主炎症细胞（巨噬细胞）来研究胶原蛋白（疲劳损伤，酶分解和交联）如何影响宿主对植入组织装置的反应。