Inducible nerve growth factor delivery for peripheral nerve regeneration in vivo.
BACKGROUND
HEK-293 cells can be genetically modified to release and regulate nerve growth factor (NGF) in vitro. The aim of this study was to evaluate the impact of this NGF delivery system on peripheral nerve regeneration in vivo.


METHODS
HEK-293 cells were transfected with an ecdysone receptor, NGF cDNA, and herpes simplex virus-thymidine kinase suicide vector. NGF production is induced by ponasterone A and stopped by ganciclovir. A 13-mm sciatic nerve gap was bridged with Silastic conduits in 120 nude rats, and transfected HEK-293 cells were added, induced, and boostered to secrete bioactive NGF.


RESULTS
The induction of the cell line and additional booster with ponasterone A demonstrated significantly higher levels of bioactive NGF, enhanced macroscopic nerve growth, improved functional recovery, and histologic regeneration when compared with control groups after 7, 14, and 21 days, and 2 and 4 months. The treatment with ganciclovir resulted in suppression of the NGF production and decreased functional and histologic outcomes.


CONCLUSIONS
Transfected HEK-293 cells can be regulated to inducibly produce bioactive NGF in vivo over prolonged periods. This tissue-engineered nerve construct including the NGF delivery system is able to improve peripheral nerve regeneration and functional recovery and appears to be superior to nerve isografts.
Orange, Calif. From the Aesthetic and Plastic Surgery Institute, University of California, Irvine.
Thomas
T
Scholz
Jason M
JM
Rogers
Alisa
A
Krichevsky
Sanjay
S
Dhar
Gregory R D
GRD
Evans
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001369:Axons / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D004441:Ecdysterone / Q000031:analogs & derivatives / Q000494:pharmacology; D015774:Ganciclovir / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D020932:Nerve Growth Factor / Q000378:metabolism* / Q000494:pharmacology*; D009416:Nerve Regeneration / Q000187:drug effects*; D009431:Neural Conduction / Q000187:drug effects; D010525:Peripheral Nerves / Q000187:drug effects*; D051381:Rats; D011923:Rats, Nude; D012584:Sciatic Nerve / Q000187:drug effects; D023822:Tissue Engineering / Q000379:methods*
D000998:Antiviral Agents; D004441:Ecdysterone; C008999:ponasterone A; D020932:Nerve Growth Factor; D015774:Ganciclovir