Engineering approaches to study fibrosis in 3-D in vitro systems

Porras, Ana Maria; Hutson, Heather N.; Berger, Anthony J.; Masters, Kristyn S.

doi:10.1016/j.copbio.2016.02.006

Cited by 24 publications

(15 citation statements)

References 61 publications

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“…Here we provide a human lung fibrotic microtissue array that allows multi-parameter, phenotypic screening of the anti-fibrosis drug candidates in a relatively high-throughput manner. The adoption of the microtissue array format offers orders of magnitude scale-up advantages over tissue biopsy samples and conventional engineered tissues 10 , 11 , leading to improved experimental throughput. Further integration of the microtissue array with multi-well plate enabled parallel analysis of multiple drug conditions.…”

Section: Discussionmentioning

confidence: 99%

Fibrotic microtissue array to predict anti-fibrosis drug efficacy

et al. 2018

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Fibrosis is a severe health problem characterized by progressive stiffening of tissues which causes organ malfunction and failure. A major bottleneck in developing new anti-fibrosis therapies is the lack of in vitro models that recapitulate dynamic changes in tissue mechanics during fibrogenesis. Here we create membranous human lung microtissues to model key biomechanical events occurred during lung fibrogenesis including progressive stiffening and contraction of alveolar tissue, decline in alveolar tissue compliance and traction force-induced bronchial dilation. With these capabilities, we provide proof of principle for using this fibrotic tissue array for multi-parameter, phenotypic analysis of the therapeutic efficacy of two anti-fibrosis drugs recently approved by the FDA. Preventative treatments with Pirfenidone and Nintedanib reduce tissue contractility and prevent tissue stiffening and decline in tissue compliance. In a therapeutic treatment regimen, both drugs restore tissue compliance. These results highlight the pathophysiologically relevant modeling capability of our novel fibrotic microtissue system.

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Section: Discussionmentioning

confidence: 99%

Fibrotic microtissue array to predict anti-fibrosis drug efficacy

et al. 2018

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“…Because SHG does not require tissue fixation or staining, its use could advance current efforts to engineer fibrotic environments in vitro [ 50 ]. The combination of fibrosis tissue engineering with SHG may offer the ability to gain insight into fibrogenic processes through the non-invasive visualization of ECM dynamics in living cultures [ 51 ]. Recent work has also shown that SHG imaging of collagen alterations may be combined with machine learning algorithms to characterize the extent of fibrosis in clinical samples, as well as provide automated, high-throughput diagnoses of fibrotic disease [ 52 – 56 ]…”

Section: Discussionmentioning

confidence: 99%

Calcific Aortic Valve Disease Is Associated with Layer-Specific Alterations in Collagen Architecture

et al. 2016

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Disorganization of the valve extracellular matrix (ECM) is a hallmark of calcific aortic valve disease (CAVD). However, while microarchitectural features of the ECM can strongly influence the biological and mechanical behavior of tissues, little is known about the ECM microarchitecture in CAVD. In this work, we apply advanced imaging techniques to quantify spatially heterogeneous changes in collagen microarchitecture in CAVD. Human aortic valves were obtained from individuals between 50 and 75 years old with no evidence of valvular disease (healthy) and individuals who underwent valve replacement surgery due to severe stenosis (diseased). Second Harmonic Generation microscopy and subsequent image quantification revealed layer-specific changes in fiber characteristics in healthy and diseased valves. Specifically, the majority of collagen fiber changes in CAVD were found to occur in the spongiosa, where collagen fiber number increased by over 2-fold, and fiber width and density also significantly increased. Relatively few fibrillar changes occurred in the fibrosa in CAVD, where fibers became significantly shorter, but did not otherwise change in terms of number, width, density, or alignment. Immunohistochemical staining for lysyl oxidase showed localized increased expression in the diseased fibrosa. These findings reveal a more complex picture of valvular collagen enrichment and arrangement in CAVD than has previously been described using traditional analysis methods. Changes in fiber architecture may play a role in regulating the pathobiological events and mechanical properties of valves during CAVD. Additionally, characterization of the ECM microarchitecture can inform the design of fibrous scaffolds for heart valve tissue engineering.

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“…In case of cardiac disease, the heart is subject to changes in composition and structure, often leading to cardiac fibrosis. While at first, fibrogenesis is an effective mechanism of tissue repair, ongoing adverse remodeling will lead to a decrease in cardiac functionality and eventually to the development of heart failure [ 1 ]. To halt or reverse this process, anti-fibrotic therapies are being developed [ 2 ], so far with limited success, due to the fact that the extent and distribution of fibrosis vary according to the underlying pathology.…”

Section: Introductionmentioning

confidence: 99%

Mimicking Cardiac Fibrosis in a Dish: Fibroblast Density Rather than Collagen Density Weakens Cardiomyocyte Function

Spreeuwel

Bax

Nierop

et al. 2017

J. of Cardiovasc. Trans. Res.

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Cardiac fibrosis is one of the most devastating effects of cardiac disease. Current in vitro models of cardiac fibrosis do not sufficiently mimic the complex in vivo environment of the cardiomyocyte. We determined the local composition and mechanical properties of the myocardium in established mouse models of genetic and acquired fibrosis and tested the effect of myocardial composition on cardiomyocyte contractility in vitro by systematically manipulating the number of fibroblasts and collagen concentration in a platform of engineered cardiac microtissues. The in vitro results showed that while increasing collagen content had little effect on microtissue contraction, increasing fibroblast density caused a significant reduction in contraction force. In addition, the beating frequency dropped significantly in tissues consisting of 50% cardiac fibroblasts or higher. Despite apparent dissimilarities between native and in vitro fibrosis, the latter allows for the independent analysis of local determinants of fibrosis, which is not possible in vivo. Electronic supplementary materialThe online version of this article (doi:10.1007/s12265-017-9737-1) contains supplementary material, which is available to authorized users.

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Engineering approaches to study fibrosis in 3-D in vitro systems

Cited by 24 publications

References 61 publications

Fibrotic microtissue array to predict anti-fibrosis drug efficacy

Fibrotic microtissue array to predict anti-fibrosis drug efficacy

Calcific Aortic Valve Disease Is Associated with Layer-Specific Alterations in Collagen Architecture

Mimicking Cardiac Fibrosis in a Dish: Fibroblast Density Rather than Collagen Density Weakens Cardiomyocyte Function

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