Understanding and Manipulating Mechanics-Based Collagen Synthesis to Advance Functional Biomaterials

Montana State University, Bozeman MT

Investigators

Abstract

This award will study the mechanics of collagen. Collagen is a key structural protein in living organisms. It is essential to the function of soft tissues and load-bearing organs. Collagen is sensitive to mechanical loads. Even microscopic damage can significantly undermine health or lead to disease. For example, the commercial collagen market will soon exceed $6B annually as people seek supplements and treatments for anti-aging and health of joints, skin, bone, and muscle. The ability to reconstruct native collagen or to engineer collagen with functional specifications would fulfill unmet needs across a range of applications. Demand is enormous, but the knowledge required to meet it remains limited. Our objective is to determine, for the first time, how mechanical loading prompts cells to produce the building blocks of collagen (precursors) as well as to produce collagen itself. The project will provide fundamental new insight into how cells convert mechanical stimuli into biological responses. This new knowledge will advance production of collagen and transform tissue engineering, providing practical design principles for using mechanical loading (e.g. compression) to drive the production of collagen in a laboratory setting. This work will enable novel therapies for collagen-related morbidities and advance clinical treatment for patients with soft-tissue injuries, disease, and deformities, thus advancing the national health. A comprehensive outreach plan will disseminate results to both scientists and to the general public. The objectives of this project are to (1) establish the roles of mechanical strains and stresses in driving metabolic production of the amino acid precursors that precede production of collagen and (2) establish and validate design principles for load-induced production of collagen to unlock fundamental understanding and functional tissue engineering. The application of precise, cyclic mechanical loadings to cell-seeded agarose specimens will achieve homogeneous stimulation from distinct principal strains, and separately, stresses. Combining these experiments with metabolomic flux and statistical analyses will establish relationships between principal strains and production of precursors. Computational modeling will establish relationships between principal stresses and metabolomic responses. This work will measure production of type VI collagen under different applied strains/stresses to quantify and validate design principles that enable the in vitro synthesis of collagen with specified mechanical properties. The significance of this knowledge is twofold: it will (1) contribute original, foundational knowledge on the relationships between mechanical stimuli and collagen production; and (2) provide tools for tissue engineers to produce advanced cell-based materials for functional replication of soft tissues. By establishing how specific stresses and strains drive mechanotransduction, this work will transform a range of fields and translational applications. 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.