Bioengineered sequential growth factor delivery stimulates brain tissue regeneration after stroke

J Control Release. 2013 Nov 28;172(1):1-11. doi: 10.1016/j.jconrel.2013.07.032. Epub 2013 Aug 9.


Stroke is a leading cause of disability with no effective regenerative treatment. One promising strategy for achieving tissue repair involves the stimulation of endogenous neural stem/progenitor cells through sequential delivery of epidermal growth factor (EGF) followed by erythropoietin (EPO). Yet currently available delivery strategies such as intracerebroventricular (ICV) infusion cause significant tissue damage. We designed a novel delivery system that circumvents the blood brain barrier and directly releases growth factors to the brain. Sequential release of the two growth factors is a key in eliciting tissue repair. To control release, we encapsulate pegylated EGF (EGF-PEG) in poly(lactic-co-glycolic acid) (PLGA) nanoparticles and EPO in biphasic microparticles comprised of a PLGA core and a poly(sebacic acid) coating. EGF-PEG and EPO polymeric particles are dispersed in a hyaluronan methylcellulose (HAMC) hydrogel which spatially confines the particles and attenuates the inflammatory response of brain tissue. Our composite-mediated, sequential delivery of EGF-PEG and EPO leads to tissue repair in a mouse stroke model and minimizes damage compared to ICV infusion.

Keywords: Controlled delivery; Epidermal growth factor; Erythropoietin; Hydrogel composite; Stroke; Tissue regeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Absorbable Implants
  • Animals
  • Brain / drug effects*
  • Brain / physiology
  • Brain / physiopathology
  • Delayed-Action Preparations / chemistry
  • Drug Delivery Systems / methods*
  • Epidermal Growth Factor / administration & dosage*
  • Epidermal Growth Factor / therapeutic use
  • Erythropoietin / administration & dosage*
  • Erythropoietin / therapeutic use
  • Humans
  • Lactic Acid / chemistry
  • Male
  • Methylcellulose / chemistry
  • Mice
  • Mice, Inbred C57BL
  • Nanoparticles / chemistry
  • Polyglycolic Acid / chemistry
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / therapeutic use
  • Regeneration
  • Stroke / drug therapy*
  • Stroke / physiopathology
  • Stroke / surgery


  • Delayed-Action Preparations
  • Recombinant Proteins
  • Erythropoietin
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polyglycolic Acid
  • Lactic Acid
  • Epidermal Growth Factor
  • Methylcellulose