Quantifying heart valve interstitial cell contractile state using highly tunable poly(ethylene glycol) hydrogels

Date Issued
2019-09Publisher Version
10.1016/j.actbio.2019.07.010Author(s)
Khang, Alex
Gonzalez Rodriguez, Andrea
Schroeder, Megan E.
Sansom, Jacob
Lejeune, Emma
Anseth, Kristi S.
Sacks, Michael S.
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Show full item recordPermanent Link
https://hdl.handle.net/2144/41392Version
Accepted manuscript
Citation (published version)
Alex Khang, Andrea Gonzalez Rodriguez, Megan E Schroeder, Jacob Sansom, Emma Lejeune, Kristi S Anseth, Michael S Sacks. 2019. "Quantifying heart valve interstitial cell contractile state using highly tunable poly(ethylene glycol) hydrogels." Acta Biomaterialia, Volume 96, pp. 354 - 367. https://doi.org/10.1016/j.actbio.2019.07.010Abstract
Valve interstitial cells (VIC) are the primary cell type residing within heart valve tissues. In many valve
pathologies, VICs become activated and will subsequently profoundly remodel the valve tissue extracellular matrix (ECM). A primary indicator of VIC activation is the upregulation of a-smooth muscle actin
(aSMA) stress fibers, which in turn increase VIC contractility. Thus, contractile state reflects VIC activation
and ECM biosynthesis levels. In general, cell contraction studies have largely utilized two-dimensional
substrates, which are a vastly different micro mechanical environment than 3D native leaflet tissue. To
address this limitation, hydrogels have been a popular choice for studying cells in a three-dimensional
environment due to their tunable properties and optical transparency, which allows for direct cell visualization. In the present study, we extended the use of hydrogels to study the active contractile behavior
of VICs. Aortic VICs (AVIC) were encapsulated within poly(ethylene glycol) (PEG) hydrogels and were subjected to flexural-deformation tests to assess the state of AVIC contraction. Using a finite element model
of the experimental setup, we determined the effective shear modulus l of the constructs. An increase in
l resulting from AVIC active contraction was observed. Results further indicated that AVIC contraction
had a more pronounced effect on l in softer gels (72 ± 21% increase in l within 2.5 kPa gels) and was
dependent upon the availability of adhesion sites (0.5–1 mM CRGDS). The transparency of the gel allowed
us to image AVICs directly within the hydrogel, where we observed a time-dependent decrease in volume
(time constant s ¼ 3:04 min) when the AVICs were induced into a hypertensive state. Our results indicated that AVIC contraction was regulated by both the intrinsic (unseeded) gel stiffness and the CRGDS
peptide concentrations. This finding suggests that AVIC contractile state can be profoundly modulated
through their local micro environment using modifiable PEG gels in a 3D micromechanical-emulating
environment. Moving forward, this approach has the potential to be used towards delineating normal
and diseased VIC biomechanical properties using highly tunable PEG biomaterials.
Description
Published in final edited form as:
Acta Biomater. 2019 September 15; 96: 354–367. doi:10.1016/j.actbio.2019.07.010.
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