Controlled release of neurotrophin-3 from fibrin gels for spinal cord injury

Sara J. Taylor, John W. McDonald, Shelly E. Sakiyama-Elbert

Research output: Contribution to journalArticlepeer-review

Abstract

The goal of this work was to assess the feasibility of using affinity-based delivery systems to release neurotrophin-3 (NT-3) in a controlled manner from fibrin gels as a therapy for spinal cord injury. A heparin-based delivery system (HBDS) was used to immobilize NT-3 within fibrin gels via non-covalent interactions to slow diffusion-based release of NT-3, thus allowing cell-activated degradation of fibrin to mediate release. The HBDS consists of three components: immobilized linker peptide, heparin and NT-3. The linker peptide contained a Factor XIIIa substrate and was covalently cross-linked to fibrin during polymerization. This immobilized linker peptide sequesters heparin within fibrin gels, and sequestered heparin binds NT-3, preventing its diffusion. Mathematical modeling was performed to examine the effect of heparin concentration on the fraction of NT-3 initially bound to fibrin. In vitro release studies confirmed that heparin concentration modulates diffusion-based release of NT-3. Fibrin gels containing the HBDS and NT-3 stimulated neural outgrowth from chick dorsal root ganglia by up to 54% versus unmodified fibrin, demonstrating that the NT-3 released is biologically active. In a preliminary in vivo study, fibrin gels containing the HBDS and NT-3 showed increased neural fiber density in spinal cord lesions versus unmodified fibrin at 9 days.

Original languageEnglish (US)
Pages (from-to)281-294
Number of pages14
JournalJournal of Controlled Release
Volume98
Issue number2
DOIs
StatePublished - Aug 11 2004

Keywords

  • Growth factor
  • Heparin
  • Nerve regeneration
  • Tissue engineering

ASJC Scopus subject areas

  • Pharmaceutical Science

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