CAREER: Mechanically dynamic and viscoelastic hydrogels as tools for studying fibroblast epigenetic memory

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Non-technical Summary:This project will develop three-dimensional biomaterial models of tissue to better understand how tissue mechanics control persistent scarring, or fibrosis. This is an important societal challenge since fibrosis is a significant contributing factor to nearly half of the overall deaths in the developed world. Biomaterials called hydrogels, or water-swollen polymer networks like contact lenses, will be used to create models matching normal and scarred tissue mechanics. Fibroblasts, the primary cells that drive fibrosis, will be encapsulated in hydrogels that can change their mechanics upon controlled exposure to light. This platform will be used to make tissue models with patterned and reversible mechanical properties mimicking the irregular progression of fibrosis. Careful control of the mechanical signals presented to cells will enable improved fundamental understanding of how these signals are interpreted and “remembered” during fibrosis. This project will also include educational and outreach objectives where the overarching goal is to recruit, mentor, and empower students at all levels from underrepresented backgrounds on the design of biomaterial-based cell culture models.Technical Summary:Tissues undergo dynamic mechanical changes during diverse biological processes including development, disease progression, and remodeling. There is tremendous interest in understanding how these dynamic mechanical cues are sensed and integrated to direct cell behaviors in vivo. Unfortunately, mechanistic studies are complicated by the myriad cells, extracellular matrix (ECM) constituents, and signaling moieties at play. Therefore, there is a significant and unmet need for in vitro biomaterial models that deconstruct this complexity and enable systematic investigation of environmental regulators of cell fate. This proposal will address this critical challenge through the development of a 3D viscoelastic hyaluronic acid (HA) hydrogel platform that permits both dynamic stiffening and softening in the presence of encapsulated cells through the use of orthogonal photochemical reactions. The proposed hydrogel system will be used to study how fibroblasts form mechanical memories during activation into myofibroblasts that drive the pathological scarring process known as fibrosis. While the signaling mechanisms underlying mechanical memory are poorly understood, there is growing evidence that epigenetics (changes in gene function that do not involve alteration in DNA sequence like histone modification and DNA methylation) are prominently involved. The research objectives of this proposal are to develop 3D viscoelastic hydrogels with either 1) uniform stiffening, 2) patterned stiffening, or 3) patterned, reversible stiffening as tools to study the epigenetic regulation of fibroblast mechanical memory. Notable milestones will include photochemical cycling of mechanics from normal to fibrotic levels (stiffening) and back to normal (softening) and spatiotemporal control of hydrogel mechanics using photopatterning to mimic the heterogeneous development of fibrosis. This proposal integrates the PI’s research activities in biomaterials engineering with educational and outreach initiatives focused on mentoring and empowering underrepresented groups in STEM. Together, these efforts will enable the establishment of a laboratory program that designs biomaterial cellular microenvironments to investigate a range of fundamental bioengineering challenges while inspiring future generations of creative, rigorous, and ethical scientists.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.