(753c) Designing Engineered Tissue Platforms for in Vitro Disease Modeling and Regenerative Applications

Our research group uses biomaterial-based platforms and tissue engineering strategies to design in vitro models that capture the complexities of the changing tissue microenvironment in development, regeneration, and disease. One particular complexity of interest is fibrosis, which occurs during wound healing and disease. The fibrotic tissue microenvironment experiences increased extracellular matrix (ECM) deposition, crosslinking, and linearization of ECM fibers, while undergoing degradation over time. This dynamic ECM remodeling produces an altered ECM with heterogeneity in stiffness, architecture, and biodegradability at the micro- and macroscales. Yet, current preclinical in vitro models of disease or regeneration often lack relevant features to reflect the spatial and temporal events that drive fibrotic and repair processes in vivo. We have proposed a series of engineered tissue platforms that incorporate the progressive elements of fibrosis and related ECM heterogeneity to increase the physiological relevance of our models.

At a fundamental level, our focus is on our ability to independently and simultaneously control progressive stiffening and heterogeneity in ECM architecture and stiffness to embrace the collective effects of fibrosis. We primarily use natural biomaterials (e.g., type I collagen, hyaluronic acid) to explore techniques such as photopolymerization to control ECM stiffness over time and macromolecular crowding to control architecture. In both approaches, we are interested in bulk and local ECM changes in biophysical properties and how cells sense and respond to those changes. When considering our platforms in the context of disease, we focus on pancreatic ductal adenocarcinoma (PDAC) and lymphedema, two diseases with significant fibrotic mechanisms that influence disease progression and treatment. For PDAC, we use biomaterials that reflect in vivo tissue composition and focus on how progressive stiffening and heterogeneous architecture drive metastatic events and immunosuppression. We believe that the fibrotic tumor microenvironment drives those events by promoting invasive cell phenotypes and regulating cancer and stromal cell trafficking through lymphatic vessels. In lymphedema studies, we seek to improve models of lymphatic growth by decoupling system responses (e.g., chemokine signaling) from fibrotic elements (e.g., progressive stiffening) to resolve discrepancies between in vitro and in vivo results and gain insight into therapeutic approaches to restore lymphatic function. Finally, we have entered into a collaboration to explore opportunities in additive manufacturing of biodegradable metal-polymer composites that can be used to improve our understanding of processes in bone remodeling and regeneration. Moreover, we see these additively manufactured platforms as a potential way to resolve fundamental questions about the interplay between pore structure (e.g., size, shape, distribution, gradient), surface topography, and mechanics in regulating the behaviors of cell types involved in various stages of bone regeneration.

With a combination of controlled manipulation of biomaterial properties cell-mediated events, and fabrication techniques, we aim to generate a portfolio of approaches by which we can generate context-specific engineered tissues. This approach to improve in vitro model design will increase our overall understanding of the fundamental role of fibrosis in a host of situations. Moreover, successful models will provide further insight into how diseases develop and progress and how to control regenerative processes, particularly at the interface between repair and fibrosis, for improved patient care.