The challenge of translating pro-angiogenic growth factors for therapeutic purposes has stimulated a myriad of biomaterials-based, delivery approaches. Many techniques rely on incorporating a growth factor into a hydrogel. The kinetics of release can be tuned based on the physiochemical properties of the growth factor and scaffold. We have developed an acoustically-responsive scaffold (ARS), whereby release of a growth factor is non-invasively and spatiotemporally controlled in an on-demand manner using focused ultrasound. An ARS consists of a fibrin matrix doped with a growth factor-loaded, sonosensitive emulsion. In this study, we used an ARS to investigate the impact of basic fibroblast growth factor (bFGF) release on endothelial tubule formation. The co-culture model of angiogenic sprouting consisted of endothelial cell-coated microbeads and dispersed fibroblasts. bFGF release correlated with the acoustic pressure applied while sprout length correlated with both the volume of bFGF-loaded emulsion in the ARS and acoustic pressure. Minimal bFGF release and sprouting were observed in the absence of ultrasound exposure. Staggering the release of bFGF via multiple ultrasound exposures did not affect sprouting. Additionally, sprouting did not display a dependence on the distance between each microbead and the ARS. Overall, these results highlight the potential of using ultrasound to control regenerative processes via the controlled delivery of a growth factor. STATEMENT OF SIGNIFICANCE: Due to the ineffectiveness of conventional routes of administration, implantable hydrogels are often used as matrices to deliver growth factors (GFs). Spatial control of release is typically realized using anisotropic constructs while temporal control is obtained by modifying matrix properties and GF-scaffold interactions. In this study, we demonstrate how focused ultrasound can be used to non-invasively and spatiotemporally control release of basic fibroblast growth factor (bFGF), in an on-demand manner, from a composite hydrogel. The acoustically-responsive scaffold (ARS) consists of a bFGF-loaded, monodispersed double emulsion embedded within a fibrin matrix. We demonstrate how controlled release of bFGF can stimulate endothelial network formation. These results may be of interest to groups working on controlled release strategies for GFs, especially in the context of stimulating angiogenesis.
Keywords: Acoustic droplet vaporization; Angiogenesis; Controlled release; Drug delivery; Endothelial cells; Fibrin; Ultrasound.
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