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Elastin-like protein hydrogels with controllable stress relaxation rate and stiffness modulate endothelial cell
Mahdis Shayan1,2, Michelle S Huang3, Renato Navarro4
1Department of Cardiothoracic Surgery, Stanford University, Palo Alto, California, USA.
Journal of Biomedical Materials Research. Part A
|March 2, 2023
Summary
Engineered hydrogels reveal that fast-relaxing, low-stiffness materials promote endothelial cell spreading and vascularization. These findings highlight the importance of matrix viscoelasticity in regulating blood vessel formation for tissue engineering applications.
Area of Science:
- Biomaterials Science
- Cell Biology
- Tissue Engineering
Background:
- Extracellular matrix (ECM) mechanical properties, including stiffness and viscoelasticity, critically influence endothelial cell (EC) behavior.
- Naturally occurring ECMs are viscoelastic and exhibit stress relaxation, a phenomenon where applied stress dissipates over time, impacting cell-matrix interactions.
Purpose of the Study:
- To engineer biomaterials with independently tunable stiffness and stress relaxation rates to investigate their effects on ECs.
- To decouple the influence of stress relaxation rate from substrate stiffness on EC morphology, proliferation, and vascularization.
- To determine the optimal mechanical cues for promoting vascular network formation in vitro and in vivo.
Main Methods:
- Development of elastin-like protein (ELP) and polyethylene glycol (PEG) based hydrogels using dynamic covalent chemistry (DCC) for reversible crosslinking.
- Independent tuning of hydrogel stiffness (500-3300 Pa) and stress relaxation rates (fast vs. slow).
- Assessment of EC spreading on 2D substrates and EC/fibroblast co-culture in 3D hydrogels, followed by in vivo subcutaneous implantation in mice.
Main Results:
- Endothelial cell spreading on 2D substrates was enhanced on fast-relaxing hydrogels compared to slow-relaxing ones at equivalent stiffness.
- In 3D co-cultures, fast-relaxing, low-stiffness hydrogels promoted the formation of wider vascular sprouts, indicating improved vessel maturity.
- In vivo studies confirmed that fast-relaxing, low-stiffness hydrogels significantly increased vascularization and capillary density compared to slow-relaxing counterparts.
Conclusions:
- Both stress relaxation rate and stiffness are critical mechanical cues that modulate endothelial cell behavior.
- Fast-relaxing, low-stiffness hydrogels provide a conducive microenvironment for enhanced EC spreading and vascular network formation.
- These findings offer valuable insights for designing biomaterials for regenerative medicine and tissue engineering applications, particularly for promoting angiogenesis.
