Multiscale structural and mechanical analysis of soft tissue under complex loads

描述（由申请人提供）：软组织具有复杂的机械性能，主要取决于其潜在的结构组织。然而，微观尺度（胶原蛋白）特性与宏观尺度（组织）行为之间的关系尚不清楚。一种多尺度建模方法，将这两个尺度直接联系起来，最近成功地应用于评估细胞种子胶原I型凝胶（组织当量，或TEs）的双轴拉伸测试。te是特别有用的模型系统，其组成和组织属性可以很容易地修改。不幸的是，这些组织类似物尚未用于充分评估更复杂的加载方案，如许多组织在体内所经历的加载方案，包括压缩和剪切力。其中一个例子是肩袖的冈上肌腱（SST），由于肩部复杂的负荷环境，其退行性变和损伤的发生率很高。作为评估SST（以及其他在多轴载荷环境下发挥作用的软组织）的桥梁，TEs的使用将允许对越来越复杂的系统进行开发、测试和分析。例如，最近的一项研究表明，在胶原蛋白凝胶形成过程中加入琼脂糖会增加组织硬度，而胶原纤维结构的变化很小。这对TE模型系统提出了一个有价值的修改，使我们能够研究非胶原细胞外基质（ECM）（如蛋白聚糖、糖胺聚糖等）对组织特性的机械和结构贡献。因此，本研究的目的是通过实验分析和多尺度建模来量化组织和成分变化组织当量（TEs）的力学和结构特性，从而表征复杂载荷下软组织的三维行为。我们假设，微尺度胶原纤维组织和非胶原ECM组分（以琼脂糖为代表）的相对刚度的差异将导致TEs在复杂载荷（即压痕和剪切）下宏观力学和局部结构响应的巨大变化。具体目标#1：制造不同组织结构（胶原纤维排列）和成分（纯胶原或胶原-琼脂糖）的组织当量（te），并量化其在复杂加载条件（即压痕和剪切）下的三维结构和力学性能。具体目标2：利用三维TE行为的多尺度计算模型来表征结构、成分和力学性能之间的关系。该研究将为te的性质和力学、结构和组成特性之间的关系提供有价值的见解，这将为未来在健康和受伤的天然组织中进行类似特性的实验和计算评估奠定必要的基础。这些研究提供的数据将极大地帮助临床医生和科学家制定治疗、修复或替换软组织的策略。

DESCRIPTION (provided by applicant): Soft tissues have complex mechanical properties that depend largely on their underlying structural organization. However, the relationship between microscale (collagen) properties and macroscale (tissue) behavior remains unclear. A multiscale modeling approach, which relates these two scales directly, was recently applied successfully to evaluate biaxial tensile testing of cell-seeded collagen Type I gels (tissue- equivalents, or TEs). TEs are particularly useful model systems whose compositional and organizational properties can be easily modified. Unfortunately, these tissue analogs have not been used to fully evaluate more complex loading protocols such as those experienced by many tissues in vivo, including compression and shear forces. One example is the supraspinatus tendon (SST) of the rotator cuff, which has a high rate of degeneration and injury that may be due to the complex loading environment of the shoulder. As a bridge to evaluating the SST (and other soft tissues that function in multiaxial loading environments), the use of TEs will allow for the development, testing, and analysis of progressively more complex systems. For example, a recent study that added agarose during collagen gel formation reported an increase in tissue stiffness with minimal changes to collagen fiber architecture. This presents a valuable modification to the TE model system, by enabling us to investigate the mechanical and structural contribution of non-collagenous extracellular matrix (ECM) (e.g., proteoglycans, glycosaminoglycan, etc.) to tissue properties. Therefore, the objective of this study is to characterize the three-dimensional behavior of soft tissues under complex loads by quantifying the mechanical and structural properties of organizationally- and compositionally-varying tissue-equivalents (TEs) using experimental analysis and multiscale modeling. We hypothesize that differences in the microscale collagen fiber organization and the relative stiffness of the non-collagenous ECM components (represented by agarose) will result in large changes in the macroscale mechanical and localized structural response of TEs in complex loading (i.e., indentation and shear). The following aims are proposed: Specific Aim #1: Fabricate tissue-equivalents (TEs) of varying organizational structure (collagen fiber alignment) and composition (collagen-only or collagen-agarose), and quantify their three-dimensional structural and mechanical properties under complex loading conditions (i.e., indentation and shear). Specific Aim #2: Utilize multiscale computational models of three-dimensional TE behavior to characterize the relationships among structural, compositional and mechanical properties. This study will provide valuable insight into the nature of, and relationships between, the mechanical, structural and compositional properties of TEs, which will lay the necessary groundwork for future experimental and computational evaluations of similar properties in healthy and injured native tissues. Such studies will provide data that will greatly aid clinicians and scientists in strategies for treating, repairing, or replacing soft tissues. PUBLIC HEALTH RELEVANCE: Degeneration and injury of soft tissues commonly result in pain and disability, and the inability to effectively prevent or treat these injuries is likely due to an incomplete understanding of tissue properties on multiple length-scales. The purpose of this study is to use mechanical/structural analyses and computer modeling to evaluate the microscale and macroscale properties of bioengineered tissue analogs, which present a simplified model system for native tissues. This study will provide valuable insight into the nature of, and relationships between, the mechanical, structural and compositional properties of tissue-equivalents, which will lay the necessary groundwork for future evaluations of similar properties in healthy and injured native tissues. Such studies will provide data that will greatly aid clinicians and scientists in strategies for treating, repairing, or replacing soft tissues.