Tissue Engineering Analysis of PG-Dependent Biomechanics

描述（由申请人提供）：蛋白聚糖（pg）和糖胺聚糖（GAGs）是组织组织、行为和命运的建筑师。这种不同种类的细胞外基质分子动态地连接和分离纤维蛋白、胶原蛋白和弹性蛋白，从而控制活组织的生物力学。pg和GAGs还具有广泛研究的实质性生物学功能，但已证明难以测量其力学贡献。因此，组织力学分析经常忽略pg和gag，即使它们表现出广泛不同的、显著的生物力学影响。例如，小的富含亮氨酸的PGs (slrp) decorin和biglycan控制胶原纤维的直径和堆积，从而控制组织强度。这些功能对正常和病变组织力学，以及替代组织的设计有着巨大的影响。我们的假设是，decorin和biglycan对胶原组织的拉伸变形有不同的生物力学影响。提出了一种新的生物工程和组织工程方法-将来自decorin缺乏，biglycan缺乏或野生型小鼠的成纤维细胞植入纤维蛋白凝胶支架中-通过以下目的研究它们对胶原纤维形成，组织结构和组织力学的影响：(1)量化decorin和biglycan如何影响工程组织替代品的收缩和生化组成；(2)量化不同工程组织替代物中胶原原纤维、pg和硫酸盐/未硫酸盐化gag的纳米级结构；(3)通过评估工程组织替代物在单轴拉伸下的弹性模量、拉伸率、破坏强度，推断出decorin和biglycan的材料贡献（弹性模量、拉伸率、破坏强度）。这项研究的结果将促进我们对slrp的生物力学理解，slrp影响组织组装、更新和疾病，从而影响功能。我们的方法将为其他pg的研究铺平道路，允许更精确的本构模型，更精确的力学模拟，并促进组织工程在其他实验应用中的应用。与公共健康相关：我们建议培育“设计”结缔组织，这将使我们发现特殊的非膳食复合碳水化合物如何帮助组织变得更强壮。这项基础研究将提高我们对替代组织的生物力学、发育和生长的理解。

DESCRIPTION (provided by applicant): Proteoglycans (PGs) and glycosaminoglycans (GAGs) are the architects of tissue organization, behavior, and fate. This diverse class of extracellular matrix molecules dynamically connects and separates the fibrous proteins collagen and elastin and thereby controls the biomechanics of living tissues. PGs and GAGs also have substantial biological functions that are widely studied, but it has proven difficult to measure their mechanical contributions. As a result, analyses of tissue mechanics frequently ignore PGs and GAGs, even through they demonstrate widely varying, significant biomechanical influences. For example, the small leucine-rich PGs (SLRPs) decorin and biglycan control collagen fibril diameter and packing and thus tissue strength. These functions have enormous implications for normal and diseased tissue mechanics, as well as the design of replacement tissues. Our hypothesis is that decorin and biglycan have distinct biomechanical influences over tensile deformations of collagenous tissues. A novel bioengineering and tissue engineering approach - seeding fibroblasts from decorin-deficient, biglycan-deficient, or wild type mice within fibrin gel scaffolds - is proposed to investigate their effects on collagen fibril formation, tissue architecture, and tissue mechanics, via the following aims: (1) Quantify how decorin and biglycan affect the contraction and biochemical makeup of engineered tissue surrogates; (2) Quantify the nanoscale architecture of the collagen fibrils, PGs, and sulfated/ unsulfated GAGs within different engineered tissue surrogates; (3) Deduce the material contributions (elastic modulus, extensibility, failure strength) of decorin and biglycan by evaluating the engineered tissue surrogates in uniaxial tension. The results of this study will advance our biomechanical understanding of SLRPs, which affect tissue assembly, turnover, and disease, and hence function. Our approach will pave the way for investigations of other PGs, permit more precise constitutive models, more accurate mechanical simulations, and promote the use of tissue engineering for other experimental applications. RELEVANCE TO PUBLIC HEALTH: We propose to grow "designer" connective tissues that will allow us find out how special non-dietary complex carbohydrates help make tissues stronger. This basic research will improve our understanding of biomechanics, development, and the growth of replacement tissues.