Tissue Engineering Analysis of PG-Dependent Biomechanics

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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.