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Adv Healthc Mater. 2015 Jan 7;4(1):121-30. doi: 10.1002/adhm.201400029. Epub 2014 Jun 24.

Directing valvular interstitial cell myofibroblast-like differentiation in a hybrid hydrogel platform.

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Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of MedicineBrigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Center of Excellence in Vascular Biology, Department of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Cardiothoracic Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.


Three dimensional (3D) hydrogel platforms are powerful tools, providing controllable, physiologically relevant microenvironments that could aid in understanding how various environmental factors direct valvular interstitial cell (VIC) phenotype. Continuous activation of VICs and their transformation from quiescent fibroblast to activated myofibroblast phenotype is considered to be an initiating event in the onset of valve disease. However, the relative contribution VIC phenotypes is poorly understood since most 2D culture systems lead to spontaneous VIC myofibroblastic activation. Here, a hydrogel platform composed of photocrosslinkable versions of native valvular extracellular matrix components-methacrylated hyaluronic acid (HAMA) and methacrylated gelatin (GelMA)-is proposed as a 3D culture system to study VIC phenotypic changes. These results show that VIC myofibroblast-like differentiation occurs spontaneously in mechanically soft GelMA hydrogels. Conversely, differentiation of VICs encapsulated in HAMA-GelMA hybrid hydrogels, does not occur spontaneously and requires exogenous delivery of TGFβ1, indicating that hybrid hydrogels can be used to study cytokine-dependent transition of VICs. This study demonstrates that a hybrid hydrogel platform can be used to maintain a quiescent VIC phenotype and study the effect of environmental cues on VIC activation, which will aid in understanding pathobiology of valvular disease.


hydrogels; methacrylated gelatin; methacrylated hyaluronic acid; valvular disease model; valvular interstitial cells

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