Mechanical cues from the extracellular matrix (ECM) regulate vascular endothelial cell (EC) morphology and function. Since naturally derived ECMs are viscoelastic, cells respond to viscoelastic matrices that exhibit stress relaxation, in which a cell‐applied force results in matrix remodeling. To decouple the effects of stress relaxation rate from substrate stiffness on EC behavior, we engineered elastin‐like protein (ELP) hydrogels in which dynamic covalent chemistry (DCC) was used to crosslink hydrazine‐modified ELP (ELP‐HYD) and aldehyde/benzaldehyde‐modified polyethylene glycol (PEG‐ALD/PEG‐BZA). The reversible DCC crosslinks in ELP‐PEG hydrogels create a matrix with independently tunable stiffness and stress relaxation rate. By formulating fast‐relaxing or slow‐relaxing hydrogels with a range of stiffness (500–3300 Pa), we examined the effect of these mechanical properties on EC spreading, proliferation, vascular sprouting, and vascularization. The results show that both stress relaxation rate and stiffness modulate endothelial spreading on two‐dimensional substrates, on which ECs exhibited greater cell spreading on fast‐relaxing hydrogels up through 3 days, compared with slow‐relaxing hydrogels at the same stiffness. In three‐dimensional hydrogels encapsulating ECs and fibroblasts in coculture, the fast‐relaxing, low‐stiffness hydrogels produced the widest vascular sprouts, a measure of vessel maturity. This finding was validated in a murine subcutaneous implantation model, in which the fast‐relaxing, low‐stiffness hydrogel produced significantly more vascularization compared with the slow‐relaxing, low‐stiffness hydrogel. Together, these results suggest that both stress relaxation rate and stiffness modulate endothelial behavior, and that the fast‐relaxing, low‐stiffness hydrogels supported the highest capillary density in vivo.
Hydrogels are promising scaffolds for adipose tissue regeneration. Currently, the incorporation of bioactive molecules in hydrogel system is used, which can increase the cell proliferation rate or improve adipogenic differentiation performance of stromal stem cells but often suffers from high expense or cytotoxicity because of light/thermal curing used for polymerization. In this study, decellularized adipose tissue is incorporated, at varying concentrations, with a thiol‐acrylate fraction that is then polymerized to produce hydrogels via a Michael addition reaction. The results reveal that the major component of isolated adipose‐derived extracellular matrix (ECM) is Collagen I. Mechanical properties of ECM polyethylene glycol (PEG) are not negatively affected by the incorporation of ECM. Additionally, human adipose‐derived stem cells (hASCs) are encapsulated in ECM PEG hydrogel with ECM concentrations varying from 0% to 1%. The results indicate that hASCs maintained the highest viability and proliferation rate in 1% ECM PEG hydrogel with most lipids formation when cultured in adipogenic conditions. Furthermore, more adipose regeneration is observed in 1% ECM group with in vivo study by Day 14 compared to other ECM PEG hydrogels with lower ECM content. Taken together, these findings suggest the ECM PEG hydrogel is a promising substitute for adipose tissue regeneration applications.
more » « less- NSF-PAR ID:
- 10075897
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Macromolecular Bioscience
- Volume:
- 18
- Issue:
- 11
- ISSN:
- 1616-5187
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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