Design and Characterization of Thioester Networks with Adaptable and Enzymatically Degradable Cross-Links

Area of Science:

• Biomaterials Science
• Polymer Chemistry
• Cellular Mechanics

Background:

• The extracellular matrix (ECM) is a complex network whose viscoelastic properties influence cell behavior.
• Cells actively remodel the ECM through enzymatic secretion and cytoskeletal forces.
• Designing biomaterials that replicate ECM viscoelasticity and remodeling is crucial for advanced cell delivery platforms.

Purpose of the Study:

• To design and characterize novel hydrogel networks with tunable viscoelastic properties and degradation kinetics.
• To investigate the relationship between cross-link composition and network mechanics and microstructure.
• To evaluate the potential of these hybrid networks for mimicking native ECM properties.

Main Methods:

• Synthesis of 8-arm poly(ethylene glycol) (PEG) based networks incorporating covalent adaptable and matrix metalloproteinase (MMP)-degradable cross-links.
• Characterization of network mechanical properties using bulk rheology and multiple particle tracking microrheology (MPT).
• Assessment of network degradation kinetics and microstructure evolution during degradation using rheology and MPT, including time-cure superposition (TCS).

Main Results:

• Elastic modulus increased with a higher ratio of adaptable to MMP-degradable cross-links.
• All networks exhibited similar stress relaxation, but degradation rates varied significantly.
• Networks with a 3:1 adaptable to MMP-degradable ratio showed the fastest degradation and a more open structure.
• MPT revealed distinct rearrangement behaviors during degradation based on cross-link ratios.
• High human mesenchymal stem cell (hMSC) viability (≥70%) was maintained in all tested network compositions.

Conclusions:

• Hybrid hydrogel networks with varying ratios of adaptable and degradable cross-links offer tunable mechanical properties and degradation profiles.
• The cross-link composition dictates network microstructure, rearrangement dynamics, and degradation rates.
• These findings provide a foundation for designing biomaterials that better replicate native ECM characteristics for regenerative medicine and cell-based therapies.