Covalently conjugated VEGF-fibrin matrices for endothelialization

Andreas H. Zisch, Ursula Schenk, Jason C. Schense, Shelly E. Sakiyama-Elbert, Jeffrey A. Hubbell

Research output: Contribution to journalArticle

271 Citations (Scopus)

Abstract

Vascular endothelial growth factor (VEGF) is a key factor in endothelial cell biology and blood vessel formation and a candidate therapeutic for the stimulation of angiogenesis-dependent tissue regeneration. The objective of this study was to confer the angiogenic activity of VEGF121 upon the biomaterial fibrin, a natural substrate for endothelial cell growth and clinically accepted as 'fibrin glue'. To achieve this, we engineered fibrin-based hydrogels that were covalently modified with VEGF121. Our laboratory has recently developed novel methodology that allows the covalent incorporation of exogenous bioactive peptides by the transglutaminase activity of factor XIIIa into fibrin during coagulation. Here, this ability of factor XIIIa to crosslink additional proteins within fibrin was employed to covalently incorporate VEGF121. By recombinant DNA methodology, a mutant VEGF121 variant, α2-PI1-8-VEGF121, which contains an additional factor XIIIa substrate sequence NQEQVSPL at the aminoterminus, was expressed in E. coli. In soluble form, the mutant protein fully retained its mitogenic activity for endothelial cells. Using 125I-labeled α2-PI1-8-VEGF121, its covalent incorporation and the efficiency of incorporation into fibrin was demonstrated and characterized. The immobilized, fibrin-conjugated VEGF121 protein remained an active and very efficient mitogen for human endothelial cells grown on two-dimensional VEGF121-modified fibrin surfaces, and the incorporation of increasing amounts of α2-PI1-8-VEGF121 resulted in dose-dependent enhancement of endothelial cell growth. The VEGF-modified fibrin matrices can be formed as injectable gels in a single-step reaction under physiological conditions in vivo. When used as a ingrowth matrix, such VEGF incorporating materials could be useful in a variety of clinical situations that require an angiogenic response into an ischemic region or inplant.

Original languageEnglish
Pages (from-to)101-113
Number of pages13
JournalJournal of Controlled Release
Volume72
Issue number1-3
DOIs
StatePublished - May 14 2001
Externally publishedYes

Fingerprint

Fibrin
Vascular Endothelial Growth Factor A
Factor XIIIa
Endothelial Cells
Fibrin Tissue Adhesive
Hydrogels
Transglutaminases
Recombinant DNA
Biocompatible Materials
Mutant Proteins
Growth
Mitogens
Blood Vessels
Cell Biology
Regeneration
Proteins
Gels
Escherichia coli
Peptides
Injections

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Zisch, A. H., Schenk, U., Schense, J. C., Sakiyama-Elbert, S. E., & Hubbell, J. A. (2001). Covalently conjugated VEGF-fibrin matrices for endothelialization. Journal of Controlled Release, 72(1-3), 101-113. https://doi.org/10.1016/S0168-3659(01)00266-8

Covalently conjugated VEGF-fibrin matrices for endothelialization. / Zisch, Andreas H.; Schenk, Ursula; Schense, Jason C.; Sakiyama-Elbert, Shelly E.; Hubbell, Jeffrey A.

In: Journal of Controlled Release, Vol. 72, No. 1-3, 14.05.2001, p. 101-113.

Research output: Contribution to journalArticle

Zisch, AH, Schenk, U, Schense, JC, Sakiyama-Elbert, SE & Hubbell, JA 2001, 'Covalently conjugated VEGF-fibrin matrices for endothelialization', Journal of Controlled Release, vol. 72, no. 1-3, pp. 101-113. https://doi.org/10.1016/S0168-3659(01)00266-8
Zisch AH, Schenk U, Schense JC, Sakiyama-Elbert SE, Hubbell JA. Covalently conjugated VEGF-fibrin matrices for endothelialization. Journal of Controlled Release. 2001 May 14;72(1-3):101-113. https://doi.org/10.1016/S0168-3659(01)00266-8
Zisch, Andreas H. ; Schenk, Ursula ; Schense, Jason C. ; Sakiyama-Elbert, Shelly E. ; Hubbell, Jeffrey A. / Covalently conjugated VEGF-fibrin matrices for endothelialization. In: Journal of Controlled Release. 2001 ; Vol. 72, No. 1-3. pp. 101-113.
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