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特性，这在很大程度上取决于其潜在的结构组织。然而，微观（胶原）性质和宏观（组织）行为之间的关系仍然不清楚。最近成功应用了将这两种尺度直接关联的多尺度建模方法来评价接种细胞的I型胶原凝胶（组织等效物或TE）的双轴拉伸试验。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，这些组织类似物还没有被用于充分评估更复杂的加载方案，例如体内许多组织所经历的那些，包括压缩力和剪切力。一个例子是肩袖的冈上肌腱（SST），其具有高退化率和损伤，这可能是由于肩部的复杂负载环境。作为评价SST（和其他在多轴载荷环境中发挥作用的软组织）的桥梁，使用TE将允许开发、测试和分析越来越复杂的系统。例如，最近一项在胶原凝胶形成过程中添加琼脂糖的研究报告了组织硬度的增加，而胶原纤维结构的变化最小。这对TE模型系统提出了有价值的修改，通过使我们能够研究非胶原细胞外基质（ECM）（例如，蛋白聚糖、糖胺聚糖等）到组织特性。因此，本研究的目的是通过实验分析和多尺度建模量化组织和成分变化的组织等效物（TE）的力学和结构特性来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（由琼脂糖表示）的相对刚度的差异将导致TE在复杂负载中的宏观尺度机械和局部结构响应的大变化（即，压痕和剪切）。提出了以下目标：具体目标#1：制造不同组织结构（胶原纤维排列）和组成（仅胶原或胶原-琼脂糖）的组织等同物（TE），并量化其在复杂载荷条件下的三维结构和机械性能（即，压痕和剪切）。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、成分和机械性能之间的关系。 这项研究将提供有价值的洞察的性质，和之间的关系，TE的机械，结构和组成特性，这将奠定必要的基础，为未来的实验和计算评估类似的属性在健康和受伤的天然组织。这些研究将提供数据，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。 公共卫生相关性：软组织的变性和损伤通常会导致疼痛和残疾，并且无法有效预防或治疗这些损伤可能是由于对多个长度尺度上的组织特性的不完全理解。本研究的目的是使用机械/结构分析和计算机建模来评估生物工程组织类似物的微观尺度和宏观尺度特性，这为天然组织提供了一个简化的模型系统。这项研究将提供有价值的洞察的性质，和之间的关系，机械，结构和组成特性的组织等效物，这将奠定必要的基础，为未来的评估类似的属性在健康和受伤的天然组织。这些研究将提供数据，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.