In Vivo Models for the Study of Fibrosis

Abstract

Significance: Fibrosis and scar formation pose a substantial physiological and psychological burden on patients and a significant public health burden on the economy, estimated to be up to $12 billion a year. Fibrosis research is heavily reliant on in vivo models, but variations in animal models and differences between animal and human fibrosis necessitates careful selection of animal models to study fibrosis. There is also an increased need for improved animal models that recapitulate human pathophysiology. Recent Advances: Several murine and porcine models, including xenograft, drug-induced fibrosis, and mechanical load-induced fibrosis, for different types of fibrotic disease have been described in the literature. Recent findings have underscored the importance of mechanical forces in the pathophysiology of scarring. Critical Issues: Differences in skin, properties of subcutaneous tissue, and modes of fibrotic healing in animal models and humans provide challenges toward investigating fibrosis with in vivo models. While porcine models are typically better suited to study cutaneous fibrosis, murine models are preferred because of the ease of handling and availability of transgenic strains. Future Directions: There is a critical need to develop novel murine models that recapitulate the mechanical cues influencing fibrosis in humans, significantly increasing the translational value of fibrosis research. We advocate a translational pipeline that begins in mouse models with modified biomechanical environments for foundational molecular and cellular research before validation in porcine models that closely mimic the human condition.

Keywords: animal model; burn; fibrosis; foreign body reaction; hypertrophic scar; scar.

Geoffrey C. Gurtner, MD, FACS

Figure 1.

Schematic of fibroblast lineages. Fibroblasts are a heterogeneous population of cells with multipotent and differentiated cells. Reticular fibroblasts, located in the lower dermis, are primarily responsible for fibrosis, while papillary fibroblasts in the upper dermis support epithelization and hair follicle formation. Adapted from Driskell et al. Color images are available online.

Figure 2.

Differences in skin elasticity between species inspired the design of a murine HTS model. (A) Human skin demonstrates greater intrinsic tension at rest compared to adult and fetal murine skin as measured by microtensiometry (n = 5 for each group, error bars indicate SD; **p < 0.01) (B) Stress loading curves as measured by microtensiometry demonstrate human skin is relatively stiff compared with murine adult and fetal skin (n = 5 for each group, error bars indicate SD) (C) The biomechanical loading device was engineered from expansion screws and titanium surgical Luhr plates. (D) Loading devices were placed over each of two 2 cm linear incisions on the mouse dorsum. One wound was left unloaded and served as the internal control, while the other was subjected to mechanical loading and served as the experimental wound. Adapted from Aarabi et al. HTS, hypertrophic scar.

Figure 3.

Schematic of FAK mechanotransduction in fibrosis. Schematic of the proposed vicious cycle of hypertrophic scarring driven by mechanical activation of local and systemic fibroproliferative pathways through fibroblast FAK. Adapted from Wong et al. FAK, focal adhesion kinase. Color images are available online.

Figure 4.

Porcine HTS formation 5 months after creation of excisional wounds of various depths. Acute wounds of various depths (TDS) lead to HTS formation of various thicknesses after 5 months in female red Duroc pigs. Adapted from Zhu et al. TDS, total dermatome settings. Color images are available online.

Figure 5.

Schematic of the foreign body response. Thrombotic agents and other blood proteins adsorb to the surface of implanted biomaterials to form a provisional matrix. Activated platelets, fibrinogen, and biochemical agents within the matrix direct neutrophils and monocyte-derived macrophages to the implantation site. At the tissue/implant interface, macrophages fuse to form foreign body giant cells. Persistent inflammatory signaling activates collagen-secreting fibroblasts at the biomaterial site, resulting in the formation of a fibrous capsule that can persist for the life of the implant. Adapted from Major et al. Color images are available online.