This Faculty Early Career Development (CAREER) award will examine how the mechanical forces of development guide cells to produce collagen fibers. Specifically, this work will study how fibers are made to have the same organization and strength as native collagen fibers. Collagen fibers are the primary source of strength in tissues throughout the body, particularly in tendons, ligaments, and menisci. However these fibers are not recreated after injury. Engineered tissue replacements do not include these fibers, which makes repair options inadequate. Native collagen fibers are primarily formed postnatally when mechanical cues guide cells to assemble small fibrils into larger fibers and fascicles. These mechanical cues are critical to fiber formation, however their individual contributions are unknown. This work will explore how developmental slow stretch and muscle-inspired cyclic loading drive cells to produce hierarchically organized collagen fibers. Additionally, this research will shed light on the mechanics that govern fiber formation. A multi-level educational program based in orthopaedics and tissue engineering will be developed as well, aimed at recruiting and retaining underrepresented minorities and women in STEM. Specifically, undergraduates will participate in research opportunities and interdisciplinary courses, middle and high school students will be engaged through hands-on research and National Biomechanics Day programming, and local middle and high school teachers will be trained in inquiry-based curriculum techniques to promote enhanced retention of STEM throughout the central Virginia area.
The specific goal of this research is to explore how developmentally-inspired mechanical loads drive ligament fibroblasts to produce engineered ligament with native organization and strength. The central hypothesize is that tensile strains, which mirror developmental slow elongation and rapid cyclic muscle activity, will individually and synergistically drive native-like hierarchical collagen organization and matrix maturation, in a magnitude- and duration-dependent fashion, resulting in significantly stronger, functional replacements. Using a novel culture system, which supports cellular development of the largest, most organized hierarchical fibers to date, this research will investigate how 1) slow strains (0.1-1 mm/day) that mimic postnatal growth rates, and 2) rapid intermittent cyclic tensile strains (1-2 mm/sec) that mimic muscular activity, individually and 3) in combination drive hierarchical collagen fiber maturation. Specifically, collagen organization at the fibril, fiber, and fascicle level, matrix composition, and tissue mechanical properties will be evaluated with each type of strain. Slow growth elongation and rapid cyclic muscle activity occur at strain rates orders of magnitude apart, most likely producing very different effects on cells. Understanding the different effects of these loads will not only help to engineer functional replacements, but will be integral in developing rehabilitation protocols to restore function after injury. Future work can use these results to drive regeneration of collagen fibers after injury.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
