Noninvasive Monitoring of Tissue-engineered Constructs by US Elasticity Imaging

描述(申请人提供)：非侵入性监测组织支架降解、细胞生长和组织发育的程度将极大地帮助组织工程师在体内非破坏性地评估候选支架的性能。可生物降解的聚合物支架用于支持细胞和生长组织，直到它们被人体自身的细胞外基质(ECM)取代。创建理想的可生物降解聚合物支架的两个主要挑战是：(1)支架必须具有明确的形状和多孔的内部结构，适合直接组织植入，但具有适当的机械和降解性能；(2)支架必须具有合适的表面属性，为细胞附着、分化和铺设细胞外基质提供有利条件。为了设计随着时间的推移将其机械负荷适当地传递到正在生长的组织的支架，需要时间数据来验证重建结构的机械可行性。目前的分析方法是破坏性的，需要动物安乐死，并解释组织学和直接机械特征的构建。此外，不同的样品在不同的时间制备和测量，但样品之间的高生长偏差给分析带来了困难。理想情况下，组织工程师需要一种系统，可以非侵入性地监测同一标本随时间的生长情况。其他成像方法，如磁共振成像(MRI)和计算机断层扫描(CT)，提供内部支架结构信息，但它们仅限于提供形态信息。基于相敏散斑跟踪的超声易感性成像(UEI)能够以很高的分辨率和灵敏度表征植入的工程组织的力学、结构和功能的变化。当地的UEI提供了从根本上改进生物材料支架设计和工程化组织生长技术的潜力。这项研究计划的长期目标是在组织工程和再生医学领域开发一种新的非侵入性功能成像方式。本项目的目的是评估UEI作为非侵入性成像工具来评估支架降解和组织植入的机械、结构和功能特征。具体目的是：(1)建立非侵入性UEI与生物材料支架降解的力学和结构特征之间的体外关系。(2)建立无创性UEI与组织生长和支架降解同时发生的力学、结构和功能特征之间的体内关系。这些特定的目标将使用具有三种不同降解率的新型聚氨酯软组织支架进行评估。使用大鼠腹部修复模型也将证明体内的可行性。如果成功，集成到商业超声扫描仪中的UEI也可以迅速转化为临床实践，因为它基于对可以方便和非侵入性地从人类受试者获得的超声数据的新处理 与公共卫生相关：组织工程学是一个新兴的跨学科领域，对那些需要器官和组织替换和修复的人来说充满希望。然而，由于实验室反馈能力的限制，特别是动物实验中种植体的非侵入性评估工具的限制，一些主要的开发和翻译方面的限制仍然没有解决。组织工程治疗的临床应用还需要非侵入性监测功能组织再生的能力。建议的超声弹性成像技术将对工程组织在生长到天然组织中时的机械强度进行定量评估和监测。这项技术可以很容易地集成到商业超声扫描仪中，用于实时体内动物研究，显著减少研究所需的动物数量，并最终作为监测组织工程治疗的临床工具。

DESCRIPTION (provided by applicant): Non-invasively monitoring the extent of tissue scaffold degradation, cellular growth, and tissue development will greatly help tissue engineers to non-destructively evaluate candidate scaffold performance in vivo. Biodegradable polymer scaffolds are used to support cells and growing tissues until they are replaced by the body's own extracellular matrix (ECM). Two main challenges in creating the ideal biodegradable polymer scaffold are: (1) the scaffold must have a defined shape and porous internal architecture suitable for direct tissue ingrowths but with appropriate mechanical and degradation properties and (2) the scaffold must have the right surface properties to provide favorable conditions for cells to attach differentiate and lay down ECM. To design scaffolds which appropriately transfer their mechanical load over time to the in growing tissue, temporal data are required that verify the mechanical viability of the remodeling construct. Current analysis methods are destructive, requiring animal euthanasia and explanting the construct for histological and direct mechanical characterization. In addition, different samples are prepared and measured at varying times, but high growth deviation between specimens makes analysis difficult. Ideally, tissue engineers need a system that can non-invasively monitor growth in the same specimen over time. Other imaging methods, such as magnetic resonance imaging (MRI) and computed tomography (CT), provide internal scaffold structural information, but they are limited to providing only morphological information. Ultrasound easticity imaging (UEI) based on phase-sensitive speckle tracking can characterize the mechanical, structural, and functional change of the implanted engineered tissues at very high resolution and sensitivity. Local UEI offers the potential to radically improve the biomaterial scaffold design and engineered tissue growth techniques. The long term goal of this research program is to develop a novel noninvasive functional imaging modality in the field of tissue engineering and regenerative medicine. The objective of the current project is to evaluate UEI as noninvasive imaging tool to assess mechanical, structural, and functional characteristics of the scaffold degradation and tissue ingrowth. The specific aims are: (1) Establish the in vitro relationship between noninvasive UEI and the mechanical and structural characteristics of the biomaterial scaffold degradation. (2) Establish the in vivo relationship between noninvasive UEI and the mechanical, structural, and functional characteristics of simultaneous tissue growing and scaffold degradation. These specific aims will be evaluated using novel polyurethane-based soft tissue scaffolds with three different degradation rates. In-vivo feasibility will also be demonstrated using the rat abdominal repair model. If successful, UEI integrated into a commercial ultrasound scanner can also be rapidly translated into clinical practice since it is based upon novel processing of ultrasound data that can be obtained conveniently and non-invasively from human subjects PUBLIC HEALTH RELEVANCE: Tissue Engineering is an emerging, interdisciplinary field which is full of promise for those in need of organ and tissue replacement and repair. However, some major limitations with the development and translation remained unsolved mainly due to the limitations of laboratory feedback capabilities, especially non-invasive assessment tool for the implants in animal study. Clinical application of tissue engineering treatments will also require the ability to non-invasively monitor functional tissue regeneration. The proposed ultrasound elasticity imaging technique will provide quantitative assessment and monitoring of the mechanical strength of the engineered tissue as it grows into the native tissue. This technique can be easily integrated into a commercial ultrasound scanner for real-time in-vivo animal study, significantly reducing the number of animals required in the study, and eventually as a clinical tool to monitor the tissue engineering treatments.