Controlled release of neurotrophin-3 from fibrin gels for spinal cord injury.
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.
Taylor
Sara J
SJ
Department of Biomedical Engineering, Washington University, St. Louis, MO, USA.
McDonald
John W
JW
Sakiyama-Elbert
Shelly E
SE
D000818:Animals; D000990:Antithrombin III / Q000737:chemistry; D001682:Biological Availability; D002642:Chick Embryo; D003692:Delayed-Action Preparations / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D005260:Female; D005337:Fibrin / Q000737:chemistry*; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology; D005782:Gels; D006493:Heparin / Q000737:chemistry; D007150:Immunohistochemistry; D008956:Models, Chemical; D009416:Nerve Regeneration / Q000187:drug effects; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D020933:Neurotrophin 3 / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry; D051381:Rats; D020318:Rats, Long-Evans; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000979:alpha-2-Antiplasmin / Q000737:chemistry
D003692:Delayed-Action Preparations; D005782:Gels; D020933:Neurotrophin 3; D010455:Peptides; D000979:alpha-2-Antiplasmin; D000990:Antithrombin III; D005337:Fibrin; D006493:Heparin