Stepping Stone Symposia Conference on Medical Technology ...

Jeffrey HUBBELL
EPF Lausanne
jeffrey.hubbell@epfl.ch
SSSTC <strong>Stepping</strong> <strong>Stone</strong> Symposium on Medical Technologies, 27–28 September 2012
Research interests
Biomaterials; tissue engineering; regenerative medicine; immunoengineering
Educational history
BS, Chemical Engineering, Kansas State University; PhD, Chemical Engineering, Rice University
Previous positions
Previous to joining EPFL, Prof. Hubbell was on the faculty at the ETH Zurich and University of Zurich, at the
California Institute of Technology, and the University of Texas at Austin.
Jeffrey A. Hubbell
Engineering the regenerative microenvironment
Growth factor; extracellular matrix
In natural situations, angiogenic growth factors such as vascular endothelial growth factor (VEGF) are present in a
matrix-bound form, yet therapeutic use of such growth factors has focused on application in soluble form. To
explore matrix immobilization of angiogenic growth factors, we have explored two approaches, both in the
context of fibrin as a surgically-relevant matrix: enzymatic conjugation of variant forms of the growth factors, and
complexation with recombinant variants of fibronectin.
Angiogenic growth factors such as VEGF were engineered so as to contain a substrate domain for the coagulation
transglutaminase factor XIIIa, modeled after the N terminus of alpha2 plasmin inhibitor. To provide a release
mechanism, an enzymatic substrate was included in the growth factor variant between the transglutaminase
substrate and the growth factor domain, taken as either a plasmin substrate domain or a matrix
metalloproteinase domain. Thus, we have explored the activity of tripartite fusion proteins for inducing
angiogenesis. We have most thoroughly studied the variant of VEGF-A, and we have demonstrated that the variant
form of VEGF-A induces more angiogenesis than the wild type and induces a less hyperpermeable phenotype, both
in the chick chorioallantoic membrane and in mouse skin.
To explore noncovalent immobilization upon matrices, we have engineered a fibrin-binding domain of fibronectin,
containing the 12th-14th type III repeat (which was known to bind VEGF-A). In studies of the 12th-14th type III
repeat, we determined that the growth factor binding activity of this domain was rather promiscuous, binding to
VEGF-A, VEGF-C, PDGF-AA, PDGF-BB and PDGF-AB, for example, in addition to a wide number of other growth
factors. Incorporation of this domain into fibrin, also through transglutaminase activity, provides a powerful and
generalizable method to retain such growth factors into surgical matrices.
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