Noninvasive Monitoring of Tissue-engineered Constructs by US Elasticity Imaging

描述（由申请人提供）：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评价候选支架性能。生物可降解聚合物支架用于支持细胞和生长组织，直到它们被身体自身的细胞外基质（ECM）取代。产生理想的可生物降解的聚合物支架的两个主要挑战是：（1）支架必须具有适合于直接组织向内生长的限定形状和多孔内部结构，但具有适当的机械和降解性质，以及（2）支架必须具有正确的表面性质，以提供细胞附着、分化和沉积ECM的有利条件。为了设计支架，其适当地将其机械负荷随时间转移到生长中的组织，需要时间数据来验证重塑结构的机械可行性。目前的分析方法是破坏性的，需要对动物实施安乐死，并对结构进行组织学和直接机械表征。此外，在不同的时间制备和测量不同的样品，但是样品之间的高生长偏差使得分析困难。理想情况下，组织工程师需要一个系统，可以非侵入性地监测随着时间的推移在同一标本的生长。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学信息。基于相敏散斑跟踪的超声弹性成像（UEI）技术能够以极高的分辨率和灵敏度表征植入组织的力学、结构和功能变化。局部UEI提供了从根本上改善生物材料支架设计和工程组织生长技术的潜力。该研究项目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模式。本项目的目的是评价UEI作为非侵入性成像工具，以评估支架降解和组织长入的机械、结构和功能特征。具体目标是：（1）建立无创性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)建立非侵入性UEI与同时组织生长和支架降解的机械、结构和功能特征之间的体内关系。这些具体的目标将使用具有三种不同降解速率的新型聚乙烯基软组织支架进行评估。还将使用大鼠腹部修复模型证明体内可行性。如果成功的话，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地和非侵入性地从人类受试者获得的超声数据的新颖处理 公共卫生相关性：组织工程是一个新兴的跨学科领域，对于那些需要器官和组织替换和修复的人来说充满了希望。然而，由于实验室反馈能力的限制，特别是动物研究中植入物的非侵入性评估工具的限制，开发和翻译的一些主要限制仍未解决。组织工程治疗的临床应用还需要非侵入性监测功能性组织再生的能力。所提出的超声弹性成像技术将提供定量评估和监测的机械强度的工程组织，因为它生长到天然组织。该技术可以很容易地集成到商业超声扫描仪中进行实时体内动物研究，显著减少研究所需的动物数量，并最终作为临床工具来监测组织工程治疗。

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.