THE USE OF FIBRIN HYDROGELS TO PROMOTE SALIVARY GLAND REGENERATION

ABSTRACT
According to the American Cancer Society, more than 60,000 people will develop head and neck cancer this
year and those patients must receive radiation therapy to survive. This treatment regularly destroys the salivary
glands (SG), leading to a loss of secretory function which is typically permanent. Current treatments remain
largely ineffective, with therapeutic interventions being limited to use of saliva substitutes with modest
effectiveness and medications that provide only temporary relief. In light of the high degree of need and the
limitations of current therapies, development of alternative treatments to restore SG functioning is essential. In
response to the challenges noted above, we propose introduction of FGF7 and FGF10, both of which activate
FGF2b signaling to promote SG epithelial morphogenesis and differentiation (Aims 1 and 2, in vitro and in vivo,
respectively). Having fortified our scaffold to enhance SG morphogenesis and differentiation, we will
nonetheless still be faced with absent or poorly developed vasculature and nerve systems, as indicated by
repeated studies demonstrating loss of vascularization and innervation in irradiated SG. In response to these
challenges, we will draw on our previous findings indicating VEGF and FGF9 to aid vascular formation and
neurotrophic factors (e.g., NGF) to promote innervation (Aim 3). We hypothesize that a modified FH scaffold
containing immobilized L1 peptides (L1p) and GF (L1p-GF-FH) will promote formation of functional tissue in
irradiated SG. Aim 1: will demonstrate sustained secretory function using a fortified scaffold in vitro. We will
determine whether incorporation of FGF7 and FGF10 into the L1p-FH (termed Ep-FH) scaffold allows secretory
function to remain intact for an extended duration in irradiated SG. Aim 2: will demonstrate sustained secretory
function using a fortified scaffold in vivo. We will determine whether incorporation of FGF7 and FGF10 into the
L1p-FH (termed Ep-FH) scaffold allows secretory function to remain intact for an extended duration in an
irradiated SMG mouse model. Aim 3: will restore full functionality to irradiated SG in vivo. We will combine our
Ep-FH scaffold with polymeric microparticles to release pro-angiogenic and pro-innervation GF in a temporal
sequence, mimicking the in vivo physiology, to enhance functional recovery of SMG following radiation
treatment. In summary, our proposed studies will extend our findings to date using L1p to restore SG function,
thereby allowing for both greater sustainability and a deeper degree of functionality.

Grant Number: 5R01DE022971-15
NIH Institute/Center: NIH
Principal Investigator: Olga Baker