StarPEG-Heparin Hydrogels to Protect and Sustainably Deliver IL-4

Adv Healthc Mater. 2016 Dec;5(24):3157-3164. doi: 10.1002/adhm.201600797. Epub 2016 Nov 8.


A major limitation for the therapeutic applications of cytokines is their short half-life time. Glycosaminoglycans (GAGs), known to complex and stabilize cytokines in vivo, are therefore used to form 3D-biohybrid polymer networks capable of aiding the effective administration of Interleukin-4, a key regulator of the inflammatory response. Mimicking the in vivo situation of a protease-rich inflammatory milieu, star-shaped poly(ethylene glycol) (starPEG)-heparin hydrogels and starPEG reference hydrogels without heparin are loaded with Interleukin-4 and subsequently exposed to trypsin as a model protease. Heparin-containing hydrogels retain significantly higher amounts of the Interleukin-4 protein thus exhibiting a significantly higher specific activity than the heparin-free controls. StarPEG-heparin hydrogels are furthermore shown to enable a sustained delivery of the cytokine for time periods of more than two weeks. Primary murine macrophages adopt a wound healing supporting (M2) phenotype when conditioned with Interleukin-4 releasing starPEG-heparin hydrogels. The reported results suggest that GAG-based hydrogels offer valuable options for the effective administration of cytokines in protease-rich proinflammatory milieus such as chronic wounds of diabetic patients.

Keywords: Interleukin-4; biohybrid hydrogels; cytokines; glycosaminoglycan; stabilization; sustained release.

MeSH terms

  • Animals
  • Cells, Cultured
  • Delayed-Action Preparations / administration & dosage
  • Delayed-Action Preparations / chemistry*
  • Glycosaminoglycans / metabolism
  • Half-Life
  • Heparin / administration & dosage
  • Heparin / chemistry*
  • Hydrogels / administration & dosage
  • Hydrogels / chemistry*
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Interleukin-4 / administration & dosage
  • Interleukin-4 / chemistry*
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Polyethylene Glycols / administration & dosage
  • Polyethylene Glycols / chemistry*
  • Wound Healing / drug effects


  • Delayed-Action Preparations
  • Glycosaminoglycans
  • Hydrogels
  • Interleukin-4
  • Polyethylene Glycols
  • Heparin