Bioengineered in Vitro Tissue Model of Fibroblast Activation for Modeling Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a complex disease of unknown etiology with no current curative treatment. Modeling pulmonary fibrotic (PF) tissue has the potential to improve our understanding of IPF disease progression and treatment. Rodent animal models do not replicate human fibroblastic foci (Hum-FF) pathology, and current iterations of in vitro model systems (e.g., collagen hydrogels, polyacrylamide hydrogels, and fibrosis-on-chip systems) are unable to replicate the three-dimensional (3D) complexity and biochemical composition of human PF tissue. Herein, we fabricated a 3D bioengineered pulmonary fibrotic (Eng-PF) tissue utilizing cell laden silk collagen type I dityrosine cross-linked hydrogels and Flexcell bioreactors. We show that silk collagen type I hydrogels have superior stability and mechanical tunability compared to other hydrogel systems. Using customized Flexcell bioreactors, we reproduced Hum-FF-like pathology with airway epithelial and microvascular endothelial cells. Eng-PF tissues can model myofibroblast differentiation and permit evaluation of antifibrotic drug treatments. Further, Eng-PF tissues could be used to model different facets of IPF disease, including epithelial injury with the addition of bleomycin and cellular recruitment by perfusion of cells through the hydrogel microchannel.

Mechanical and Physical Regulation of Fibroblast–Myofibroblast Transition: From Cellular Mechanoresponse to Tissue Pathology

“…Interestingly, fibroblasts were shown to sense the biochemical stimuli released by cancer cells, indicating a complex interplay between both cell types that affects the capability of fibroblasts to remodel the ECM and the capability of cancer cells to invade the surrounding tissue (Kalluri, 2016;Erdogan et al, 2017;Richards et al, 2017). A more physiological 3D environment can also be reproduced using gels, such as collagen I hydrogels to model pulmonary fibrotic tissues coupled to a fibrosis-on-chip model (Sundarakrishnan et al, 2018(Sundarakrishnan et al, , 2019. It is also noteworthy that such 3D in-vitro microenvironments are also generally amenable to long-term culturing, enabling dynamic alteration of their properties to mimic the properties of tissue pathologies to study the fibroblast activation, which is still missing in 2D approaches.…”

Effects of Gelatin Methacrylate Bio-ink Concentration on Mechano-Physical Properties and Human Dermal Fibroblast Behavior

“…Fibroblasts are commonly seeded into the scaffold because they have the ability to secrete and degrade proteins during skin reconstruction and regeneration, thus leading to extracellular matrix (ECM) remodeling. Furthermore, fibroblasts can secrete various growth factors and cytokines, which in turn lead to enhanced regeneration and healing [ 5 ]. However, it is worth noting that even with our current knowledge and technology, a full-thickness skin substitute with appropriate vascularization is still currently not available.…”

Biomaterial-based immunoengineering to fight COVID-19 and infectious diseases

“…Several tissue model systems have been developed to recapitulate key aspects of the respiratory system, such as the airliquid interfaces and differentiated cell types, and have been characterized for COVID-19 infection. 136,137 Integration with in vitro models of fibroblast-mediated scarring 138 may serve to better understand COVID-19-induced fibrosis and evaluate potential therapeutic agents to properly heal scar tissues.…”