INTELLECTUAL MERIT: Understanding the complex interplay between cells and their microenvironment, the extracellular matrix (ECM), is essential in designing new therapeutic approaches to mitigate disease progression or direct tissue regeneration. Biomimetic materials have emerged as tools to probe the role of microenvironment signals in cell behavior; however, creating materials that fully recapture dynamic biological processes remains difficult. This proposal addresses a critical challenge in designing and applying materials that adequately mimic the spatiotemporal and multisize scale complexity of the native ECM to determine the key signals that regulate tissue homeostasis, disease, and repair. For example, in response to tissue injury or chronic insults, fibroblasts activate into myofibroblasts, a wound healing phenotype responsible for tissue repair and ECM remodeling. Misregulation and persistence of myofibroblasts, through mechanisms that are not fully understood, leads to deposition and accumulation of excess collagen, tissue stiffening, and ultimately fibrosis. Innovative tools are needed to recreate microenvironment changes that occur during fibrosis to identify the pivotal signals in myofibroblast activation and persistence. To address this, the PI proposes to establish a dynamic, structurally complex hydrogel using a combination of light-mediated, multisize-scale biomimetic, and tunable responsive chemistries to mimic temporally evolving collagenous tissue repair and disease progression. The goal is to design a unique three-dimensional (3D) hydrogel culture system that captures critical components of the native ECM, including nano- to submicron-scale fibrils, nano-scale integrin binding sequences, and spatiotemporally evolving biophysical and biochemical properties, to understand myofibroblastic activation and fibrosis. To achieve this, she proposes to: (1) create hydrogels with controlled biophysical and biochemical properties that mimic soft tissues over multiple size-scales, from nano-, submicron-, to macro-scale; (2) demonstrate increasing hydrogel modulus and incorporating integrin-binding peptides in a spatiotemporal fashion to mimic fibrosis progression; and (3) determine magnitudes and rates of increasing modulus that promote fibroblast activation in both 2D and 3D culture within this model system.
BROADER IMPACTS: Biomaterials and bioengineering have the potential to revolutionize our understanding and control of biological systems through the development and application of novel tools to complex health-related problems. However, students often have limited knowledge of these fields, owing to insufficient exposure to related engineering concepts and educational and career opportunities throughout secondary schools and college. The educational goal of this proposal is to create a comprehensive program for increasing the supply of students, especially underrepresented groups, participating and trained in biomaterials and bioengineering through new educational efforts at the secondary, college, and graduate levels. To address these needs the PI will: (1) develop and implement a biomaterials and bioengineering museum kiosk and a 5-7th grade student Family Friday and Mini-camp; (2) mentor high school students in biomaterials and bioengineering through research internships; and (3) develop new Biomaterials & Integrative Biology coursework within the engineering curriculum. The kiosk will allow our team to reach a large and diverse audience (> 100,000 students over 5 years), while the targeted educational programs will enable more in-depth training of students from 5th grade to graduate school and continuing education. Integrating the proposed research within these educational programs aimed at secondary and college curricula will enable innovation at the interface of materials, engineering, and biology through the increased participation, training, and diversity of workers in the field.
