Covalently Adaptable Elastin-Like Protein-Hyaluronic Acid (ELP-HA) Hybrid Hydrogels with Secondary Thermoresponsive Crosslinking for Injectable Stem Cell Delivery
Journal article, 2017

Shear-thinning, self-healing hydrogels are promising vehicles for therapeutic cargo delivery due to their ability to be injected using minimally invasive surgical procedures. An injectable hydrogel using a novel combination of dynamic covalent crosslinking with thermoresponsive engineered proteins is presented. Ex situ at room temperature, rapid gelation occurs through dynamic covalent hydrazone bonds by simply mixing two components: hydrazine-modified elastin-like protein (ELP) and aldehyde-modified hyaluronic acid. This hydrogel provides significant mechanical protection to encapsulated human mesenchymal stem cells during syringe needle injection and rapidly recovers after injection to retain the cells homogeneously within a 3D environment. In situ, the ELP undergoes a thermal phase transition, as confirmed by coherent anti-Stokes Raman scattering microscopy observation of dense ELP thermal aggregates. The formation of the secondary network reinforces the hydrogel and results in a tenfold slower erosion rate compared to a control hydrogel without secondary thermal crosslinking. This improved structural integrity enables cell culture for three weeks postinjection, and encapsulated cells maintain their ability to differentiate into multiple lineages, including chondrogenic, adipogenic, and osteogenic cell types. Together, these data demonstrate the promising potential of ELP-HA hydrogels for injectable stem cell transplantation and tissue regeneration.

secondary crosslinking

mesenchymal stem cells

injectable hydrogels

dynamic covalent chemistry

elastin-like protein (ELP)


H. Y. Wang

Stanford University

D. Q. Zhu

Stanford University

Alexandra Paul

Chalmers, Biology and Biological Engineering, Chemical Biology

L. Cai

Stanford University

Annika Enejder

Chalmers, Biology and Biological Engineering, Chemical Biology

F. Yang

Stanford University

S. C. Heilshorn

Stanford University

Advanced Materials for Optics and Electronics

1616301x (ISSN) 1616-3028 (eISSN)

Vol. 27 28

Subject Categories

Polymer Chemistry

Cell Biology



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