Microenvironment-Responsive Polyethylene Glycol-Based Hydrogel Scaffolds for Vascularized Tissue Engineering.

Introduction: A common limitation of hydrogel-based tissue engineering scaffolds is poor vascularization, mainly because oxygen and nutrient diffusion is restricted to about 100–200 µm. As a result, cells in thicker constructs often become hypoxic. Current approaches, such as microchannel-based designs or the use of growth factors like VEGF, have shown some benefit, but they are largely static and do not reflect the dynamic nature of the extracellular matrix (ECM). In this work, attention is placed on polyethylene glycol (PEG)-based hydrogels that can respond to their surrounding microenvironment.

Methods: An ECM-inspired PEG hydrogel scaffold was designed incorporating matrix metalloproteinase (MMP)-sensitive peptide crosslinkers and oxygen-responsive elements. The system introduces a dual-responsive mechanism in which cell-secreted enzymes trigger localized degradation, while hypoxic conditions promote further structural loosening. This response increases scaffold porosity and exposes embedded pro-angiogenic cues. The framework considers how these combined responses regulate pore size, permeability, and endothelial cell infiltration during tissue regeneration.

Results: Previous experimental studies on PEG-based hydrogels show that matrix stiffness and degradability influence vascularization. Compressive modulus values ranging from approximately 30 to 110 kPa, depending on PEG concentration, have been linked to differences in cell migration, with intermediate formulations supporting more stable endothelial networks. Endothelial structures have been reported to reach lengths of up to ~700 µm and penetrate beyond 1 mm into the scaffold, although fully lumenized vessels remain limited. Enzymatically degradable hydrogels consistently demonstrate improved cell infiltration compared to non-degradable PEG systems. These findings support the rationale for combining enzyme-sensitive degradation with additional environmental responsiveness.

Conclusion: PEG hydrogels that respond to both enzymatic activity and oxygen levels offer a more adaptable way to improve vascularization. By allowing the scaffold to change in response to local conditions, this approach supports increased permeability and better endothelial infiltration, providing a practical direction for future scaffold design.