A sulfonated reversible thermal gel for the spatiotemporal control of VEGF delivery to promote therapeutic angiogenesis

Abstract

Despite medical and surgical advancements for the treatment of cardiovascular disease, mortality and morbidity remain high. Therapeutic angiogenesis has been one approach to address the major clinical need for a more effective treatment to restoring blood flow in ischemic organs and tissues, but current progress in angiogenic drug delivery is inadequate at providing sufficient bioavailability without causing safety concerns. An injectable sulfonated reversible thermal gel composed of a polyurea conjugated with poly(N‐isopropylacrylamide) and sulfonate groups has been developed for the delivery of angiogenic factors. The thermal gel allowed for the spatiotemporal control of vascular endothelial growth factor release with a decreased initial burst release and reduced release rate in vitro. A subcutaneous injection mouse model was used to evaluate efficacious vascularization and assess the inflammatory response due to a foreign body. Thermal gel injections showed substantial vascularization properties by inducing vessel formation, recruitment and differentiation of vascular endothelial cells, and vessel stabilization by perivascular cells, while infiltrating macrophages due to the thermal gel injections decreased over time. These results demonstrated effective localization and delivery of angiogenic factors for therapeutic angiogenesis. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3053–3064, 2018.

Stimuli‐Responsive Delivery of Growth Factors for Tissue Engineering

“…Sulfonation aimed to mimic heparin in promoting electrostatic binding with VEGF while temperature responsiveness facilitated its use as a minimally invasive injection with high interstitial retention. [ 151 ]…”

“…Healthcare Mater. 2020, 9,1901714 Tissues Stimuli Materials Growth factor Application Reference pH and temperature P(NIPAm-co-PAA-co-BA) microspheres FGF Ischemic limb [52] Collagen coated PNIPAm nanoparticles VEGF hBMSCs [150] Polyurea conjugated PNIPAm VEGF Vascularization [151] NIPAm and PAA synthesized p(NIPAm-co-PAA) hydrogels temperature cycles (45 °C for 5 min and room temperature for another 15 min). They found that 60% of BSA could be released within one cycle with 5% of PNIPAM, whereas BSA release did not reach 40% after five cycles with 25% PNIPAM.…”

Evaluation of scaffolding, inflammatory response, and wound healing support of a reverse thermal gel for myelomeningocele patching

“…Mechanical elastic properties have been tested with rheological studies which show the RTG has a distinct shift from viscous to elastic gel as the temperature approaches 37°C, which fits closely with the LCST of the RTG of about 34°C. Morphological characterization by scanning electron microscopy demonstrates a porous inner polymer structure with variable pore sizes depending on polymer concentrations 8,12,14,21 . We demonstrated that the RTG can be applied with simple small gauge needle and act as an MMC patch 8 .…”

Hybrid Thermo-Responsive Polymer Systems and Their Biomedical Applications

“…The sulfonate groups within the gel created an electrostatic binding affinity to vascular endothelial growth factor (VEGF), thereby allowing the gel to bind to VEGF and localize it, facilitating its spatiotemporal control. Additionally, a decrease in the initial burst release was seen, together with a reduction in the sustained rate of release, showing the system's potential for the delivery angiogenic factors (Lee et al, 2018).…”

“…The injectability, biodegradability, and the extended and simultaneous sequential release characteristics of this system make it an attractive prospect in tissue engineering applications, particularly, intramyocardial injections following ischemic injury (Nelson et al, 2012). In another study by Lee et al (2018), conjugation of NIPAAm with sulfonated poly(serinol hexamethylene urea) (SPSHU) was undertaken to formulate a thermogel for the controlled delivery of vascular endothelial growth factor (VEGF) in the promotion of therapeutic angiogenesis. The sulfonate groups within the gel created an electrostatic binding affinity to vascular endothelial growth factor (VEGF), thereby allowing the gel to bind to VEGF and localize it, facilitating its spatiotemporal control.…”