3D printed human fibrotic model for studying how abnormal mechano-environment may affect fibroblast collagen remodelling

Fibrosis involves the overgrowth, hardening, and/or scarring of various tissues and is attributed to excessive deposition of extracellular matrix components, especially collagen. Fibrosis can occur in many tissues including lungs, liver, heart, and brain, and is a hallmark of several diseases such as idiopathic pulmonary fibrosis (IPF), liver cirrhosis, systemic sclerosis, dermal and cardiovascular fibrosis. Collagen accumulation and remodelling are also contributing factors in several other conditions such as asthma, atherosclerosis, hepatitis C, including certain types of cancer. For example, idiopathic pulmonary fibrosis (IPF) is one of the most aggressive forms of interstitial lung disease (ILD), characterized by chronic, progressive fibrosis, and respiratory failure. The prevalence of IPF in Canada is 41.8 persons /100,000, with a reported median survival of 3 years from diagnosis.

Over the last five years, antifibrotic therapies, have been approved for the management of IPF, but accurate and early diagnosis is essential to optimize treatment selection. Alongside the clinical progression of the above-mentioned diseases, fibrosis imposes a heavy humanistic impact in terms of morbidity and quality of life, which also translates into a significant economic burden to the healthcare system.

The critical cellular mediator of fibrosis is the myofibroblast – a cell lying between a fibroblast and a smooth muscle cell in phenotype. Upon injury, fibroblasts are stimulated mechanically (by altered activation patterns) and chemically (by inflammatory mediators) to undergo differentiation into the myofibroblast phenotype. Myofibroblasts are then activated as the primary collagen-producing cell, mediating tissue repair.

Repairing extracellular matrix (ECM) is the most important function of (myo)fibroblasts and, therefore, they are strongly associated with tissue remodelling (the reorganization or renovation of existing tissues) and function loss. While variability in collagen deposition and ECM stiffness are known to modulate cellular behaviour, these processes are not well understood. In particular, the molecular mechanisms by which myofibroblast differentiation occurs in vivo remains unclear. Evidence suggests that fibrosis results from chronic inflammatory reactions induced by various stimuli including persistent infections, autoimmune reactions, allergic responses, radiation, and tissue injury. Although current treatments for fibrotic diseases typically target the inflammatory response, there is mounting evidence that factors other than those regulating inflammation could be causing fibrosis. Furthermore, some studies have suggested that ongoing inflammation is needed to reverse established and progressive fibrosis. The overarching scientific questions are to determine if fibrosis causes inflammation or if inflammation causes fibrosis. Which should be the therapeutic target? Fibrosis or inflammation?

Using label-free NLOM to visualize key ECM molecules (collagen and elastin), I recently demonstrated that accumulation of disorganized and fragmented fibrillar collagen is an early feature of airway remodelling, and occur early during disease progression. I further demonstrated that the potential mechanism driving disorganized fibrillar collagen in asthma involves low decorin expression (decorin is essential for normal collagen formation). Alterations in ECM structural properties are known to influence the cell microenvironment and could affect the cells implicated in fibrosis. However, our current fibrosis model is limited by the lack of accurate control over the mechanical, structural, and biochemical characteristics of the ECM where the cells are localized.

Related selected publications

  • Wight TN, Potter-Perigo S. The extracellular matrix: an active or passive player in fibrosis?. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2011 Dec;301(6):G950-5.
  • Cox TR, Erler JT. Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer. Disease models & mechanisms. 2011 Mar 1;4(2):165-78.
  • López‐Novoa JM, Nieto MA. Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO molecular medicine. 2009 Sep 1;1(6‐7):303-14.
  • Fibroblasts and myofibroblasts: their source, function and role in disease. The international journal of biochemistry & cell biology. 2007 Jan 1;39(4):666-71.
  • Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nature reviews Molecular cell biology. 2002 May;3(5):349-63.
  • Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nature medicine. 2012 Jul;18(7):1028.
  • Wynn TA. Cellular and molecular mechanisms of fibrosis. The Journal of Pathology: A Journal of the Pathological Society of Great Britain and Ireland. 2008 Jan;214(2):199-210.
  • Mostaço-Guidolin LB, Osei ET, Ullah J, Hajimohammadi S, Fouadi M, Li X, Li V, Shaheen F, Yang CX, Chu F, Cole DJ. Defective fibrillar collagen organization by fibroblasts contributes to airway remodeling in asthma. American Journal of Respiratory and Critical Care Medicine. 2019 Aug 15;200(4):431-43.


Dr. Sangeeta Murugkar, Department of Physics, Carleton University

Dr. Anna Jezierski, Human Health Therapeutics Research Centre, National Research Council Canada

Dr. Tillie-Louise Hackett, Centre for Heart Lung Innovation, University of British Columbia