Spatiotemporal control of vascular endothelial growth factor delivery from injectable hydrogels enhances angiogenesis

Abstract

Summary. Therapeutic angiogenesis with vascular endothelial growth factor (VEGF) delivery may provide a new approach for the treatment of ischemic diseases, but current strategies to deliver VEGF rely on either bolus delivery or systemic administration, resulting in limited clinical utility, because of the short half‐life of VEGF in vivo and its resultant low and transient levels at sites of ischemia. We hypothesize that an injectable hydrogel system can be utilized to provide temporal control and appropriate spatial biodistribution of VEGF in ischemic hindlimbs. A sustained local delivery of relatively low amounts of bioactive VEGF (3 μg) with this system led to physiologic levels of bioactive VEGF in ischemic murine (ApoE−/−) hindlimbs for 15 days after injection of the gel, as contrasted with complete VEGF deprivation after 72 h with bolus injection. The gel delivery system resulted in significantly greater angiogenesis in these limbs as compared to bolus (266 vs. 161 blood vessels mm−2). Laser Doppler perfusion imaging showed return of tissue perfusion to normal levels by day 28 with the gel system, whereas normal levels of perfusion were never achieved with saline delivery of VEGF or in control mice. The system described in this article could represent an attractive new generation of therapeutic delivery vehicle for treatment of cardiovascular diseases, as it combines long‐term in vivo therapeutic benefit (localized bioactive VEGF for 1–2 weeks) with minimally invasive delivery.

Polymers to direct cell fate by controlling the microenvironment

“…Polymeric systems allow for independent regulation of the localization, duration, and availability of one or more soluble factors [28][29][30], while limiting the overall quantity of drug and minimizing the potential side effects of systemic dosing. Many techniques have been developed to regulate the kinetics and distribution of soluble factors, including multiple levels of encapsulation [31] as well as noncovalently bonding the bioactive factors to peptides with a range of dissociation constants mimicking ECM immobilization of growth factors [32].…”

The Role of Synthetic Extracellular Matrices in Endothelial Progenitor Cell Homing for Treatment of Vascular Disease

“…5 However, although bolus VEGF injection provided therapeutic benefit in animal studies, there was no significant improvement in clinical trials presumably due to rapid washout of the protein from bolus delivery strategies. 71 Spatiotemporal delivery of human VEGF 121 isoform within RGD-modified alginate hydrogels was shown to improve outward migration and invasion of OECs also housed within the hydrogel. 70,78 This isoform readily diffuses through the surrounding ECM unlike the VEGF 165 isoform, which binds heparin with high affinity and thus traverses more slowly.…”

“…Alternatively, decreasing the molecular weight (MW) distribution of the polymer chains used to form the gels also permits rapid degradation, but leads to mechanical weakness. 9 Investigators have previously shown that bimodal gels created from a mixture of high MW polymers and low MW polymers (prepared via gamma irradiation 71 ) maintain mechanical stability while simultaneously providing control over degradation. 9 Such bimodal gels have been used to provide spatiotemporal control of release of multiple proangiogenic factors including VEGF, platelet-derived growth factor-BB, and S1P for therapeutic angiogenesis.…”

“…34 Hydrogels are a useful class of cell delivery vehicles as they can be delivered in a minimally invasive manner and used to fill irregularly shaped defects, as opposed to scaffold transplantation. 9,71 Similarly to scaffolds, hydrogels are used to deliver cells to the desired tissue site, to provide a space for new tissue formation, and to control the structure and function of the regenerated tissue. 39 Beneficially, these highly hydrated networks strongly resemble the native ECM of tissues, facilitating better integration given their inherent biocompatibility.…”

“…9 Such bimodal gels have been used to provide spatiotemporal control of release of multiple proangiogenic factors including VEGF, platelet-derived growth factor-BB, and S1P for therapeutic angiogenesis. 26,71,85 Alginates used for cell delivery must be chemically modified to present cell adhesion ligands, such as peptides including the sequence arginine-lysine-aspartic acid (RGD). 9,39 The incorporation of EPCs within RGD-modified alginate was shown to enhance both avb5 integrin expression and epidermal growth factor (EGF) secretion as opposed to EPCs delivered without the scaffold.…”