CAREER: Spatiotemporally addressable hydrogel biomaterials as tools for investigating fibroblast mechanobiology

University Of Colorado At Denver, Aurora CO

Investigators

Abstract

PART 1: NON-TECHNICAL SUMMARY Using principles of materials science, materials that closely match the properties of living tissue will be developed. The materials will enable studies of fibrosis, a condition resulting in scarring of the lung, heart, and other tissues, accounting for over one third of global deaths per year. Despite great efforts to study the cellular processes that cause fibrosis, the conditions which lead to fibrosis are still poorly understood. While most studies are typically performed in a Petri dish, recent discoveries show that these flat, stiff dishes cause unintended reactions that produce misleading results. To overcome this limitation, the project aims to create three-dimensional (3D) models of both healthy and scarred lung tissue, using new materials with mechanical properties that can be dynamically changed to match real pulmonary tissues. The materials will combine a synthetic soft plastic with proteins derived from lung tissue. The materials developed will be sensitive to light, changing their stiffness upon illumination, allowing spatial patterning of material stiffness. These improved 3D models will be used to study cell responses in a more natural environment. These models will be used to test how cells respond to changes in their environment, like stiffening from scarring in fibrotic lung disease, to better understand the cellular origins of these conditions. An educational curriculum to engage a range of students from middle to graduate school in the translational aspects of biotechnology and biomedical engineering is proposed to further complement these fundamental biomaterial-based studies. PART 2: TECHNICAL SUMMARY The overarching goal of this proposal is to design and synthesize hydrolytically stable, dynamically tunable hybrid hydrogel biomaterials. Using fundamental principles of materials science and engineering, photo-addressable hybrid biomaterial platforms that will mimic critical aspects of fibrotic disease progression in vitro will be developed. A new class of photo-addressable poly(ethylene glycol) (PEG)-based hybrid hydrogels will be synthesized. These innovative biomaterials will combine a phototunable PEG backbone with decellularized ECM (dECM) from healthy or diseased lung tissue, to decouple fibrotic tissue composition from subsequent changes in mechanical properties. The chemistries and multi-stage reaction schemes introduced will provide unprecedented reversible spatiotemporal control over microenvironmental mechanical properties with submicron resolution independent of composition. The materials developed will allow studying the influence of cell-matrix interactions on fibroblast mechanobiology in vitro. These materials will improve our understanding of the fundamental cellular and molecular processes underlying chronic diseases such as pulmonary fibrosis. Improved in vitro models that reproduce key aspects of human physiology, including the dimensionality, dynamic heterogeneity, and mechanical properties of the extracellular matrix (ECM) composition, will facilitate studies of critical cell-matrix interactions underlying fibrotic disease. These biomaterial systems will allow answers to fundamental questions related to fibroblast mechanobiology to be answered: 1) How do pathological changes in matrix composition and modulus influence the phenotype of encapsulated fibroblasts? 2) Which of these inputs is the more potent driver of fibrosis, i.e., the best target for therapeutics? and 3) Are these phenotypic changes reversible? An educational curriculum to engage a range of students from middle to graduate school in the translational aspects of biotechnology and biomedical engineering is proposed to further complement these fundamental biomaterial-based studies. These research and educational objectives will advance knowledge and train the next generation of engineers and scientists. Sharing the results of this project across multiple platforms within local public schools and bioengineering courses will inspire teachers and students to use STEM-principles to solve problems in life sciences and healthcare. 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.