Spatiotemporal delivery of basic fibroblast growth factor to directly and simultaneously attenuate cardiac fibrosis and promote cardiac tissue vascularization following myocardial infarction

Abstract

Following myocardial infarction (MI), the destruction of vasculature in the infarcted heart muscle and progression of cardiac fibrosis lead to cardiac function deterioration. Vascularization of the damaged tissue and prevention of cardiac fibrosis represent promising strategies to improve cardiac function. Herein we have developed a bFGF release system with suitable release kinetics to simultaneously achieve the two goals. The release system was based on an injectable, thermosensitive, and fast gelation hydrogel and bFGF. The hydrogel had gelation time < 7 s. It can quickly solidify upon injection into tissue so as to increase drug retention in the tissue. Hydrogel complex modulus can be tuned by hydrogel solution concentration. The complex modulus of 176.6 Pa and lower allowed cardiac fibroblast to maintain its phenotype. Bioactive bFGF was able to gradually release from the hydrogel for 4 weeks. The released bFGF promoted cardiac fibroblast survival under ischemic conditions mimicking those of the infarcted hearts. It also attenuated cardiac fibroblasts from differentiating into myofibroblasts in the presence of TGFβ when tested in 3D collagen model mimicking the scenario when the bFGF release system was injected into hearts. Furthermore, the released bFGF stimulated human umbilical endothelial cells to form endothelial lumen. After 4 weeks of implantation into infarcted hearts, the bFGF release system significantly increased blood vessel density, decreased myofibroblast density and collagen content, augmented cardiac cell survival/proliferation, and reduced macrophage density. In addition, the bFGF release system significantly increased cardiac function. These results demonstrate that delivery of bFGF with appropriate release kinetics alone may represent an efficient approach to control cardiac remodeling after MI.

Garcinoic Acid Improves Cardiac Function and Enhances Angiogenesis&nbsp;Following Myocardial Infarction

“…The presence of HIF-1α-bFGF pathway enhances survival and sprouting of ECs under hypoxic conditions. Spatiotemporal delivery of bFGF promotes cardiac tissue vascularization and improves cardiac function following MI (Calvani et al, 2006;Fan et al, 2019). Intriguingly, our data con rmed that GA can promotes the expression of HIF-1α, VEGF and bFGF in vivo and in vitro experiments.…”

Dual-peptide functionalized acetalated dextran-based nanoparticles for sequential targeting of macrophages during myocardial infarction

“…The advent of nanomedicine has brought new insights in innovative treatment strategies, currently at the pre-clinical stage, of CVD, in particular MI. [5][6][7][8][9][10] Such approaches are very promising, but there is urgent need for smart targeting strategies. The infarcted tissue is challenging to address due to mechanical obstacles, like the constant pumping of the organ and the restless massive exchange of blood.…”

The Roles of Noncardiomyocytes in Cardiac Remodeling

“…A newly constructed bFGF release system with adequate release kinetics may solve these problems. A bFGF-encapsulating hydrogel not only served as a drug carrier, but also effectively preserved fibroblast phenotypes so that the pro-angiogenesis and anti-fibrotic functions of CFs were maintained [39]. Additionally, some cardioprotective molecules associated with CFs have been discovered, for example, a novel agent, NM922, of therapeutic value could inhibit the conversion of the CF phenotype in a murine TAC model by preventing the activation of several profibrotic pathways (including pathways involving mTOR/STAT3/E4-BP1, FAK-Akt-P70S6K, and the generation of COX-2) [40].…”