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. 2014 Jan 13;15(1):1-11.
doi: 10.1021/bm4010639. Epub 2014 Jan 2.

Intramyocardial Injection of a Synthetic Hydrogel With Delivery of bFGF and IGF1 in a Rat Model of Ischemic Cardiomyopathy

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Free PMC article

Intramyocardial Injection of a Synthetic Hydrogel With Delivery of bFGF and IGF1 in a Rat Model of Ischemic Cardiomyopathy

Devin M Nelson et al. Biomacromolecules. .
Free PMC article

Abstract

It is increasingly appreciated that the properties of a biomaterial used in intramyocardial injection therapy influence the outcomes of infarcted hearts that are treated. In this report the extended in vivo efficacy of a thermally responsive material that can deliver dual growth factors while providing a slow degradation time and high mechanical stiffness is examined. Copolymers consisting of N-isopropylacrylamide, 2-hydroxyethyl methacrylate, and degradable methacrylate polylactide were synthesized. The release of bioactive basic fibroblast growth factor (bFGF) and insulin-like growth factor 1 (IGF1) from the gel and loaded poly(lactide-co-glycolide) microparticles was assessed. Hydrogel with or without loaded growth factors was injected into 2 week-old infarcts in Lewis rats and animals were followed for 16 weeks. The hydrogel released bioactive bFGF and IGF1 as shown by mitogenic effects on rat smooth muscle cells in vitro. Cardiac function and geometry were improved for 16 weeks after hydrogel injection compared to saline injection. Despite demonstrating that left ventricular levels of bFGF and IGF1 were elevated for two weeks after injection of growth factor loaded gels, both functional and histological assessment showed no added benefit to inclusion of these proteins. This result points to the complexity of designing appropriate materials for this application and suggests that the nature of the material alone, without exogenous growth factors, has a direct ability to influence cardiac remodeling.

Figures

Figure 1
Figure 1
Release profiles of 125I-bFGF from poly(NIPAAm-co-HEMA-co-MAPLA) hydrogels. The presence of heparin allowed more bFGF to be released during gel formation (A). Proliferation of rat smooth muscle cells in response to bFGF released from the hydrogel (B) or IGF1 released from microparticles inside the hydrogel (C). bFGF release caused proliferation in the first few weeks of release whereas IGF1 caused proliferation over a longer time with a peak after four weeks: *shows significance (p < 0.05) compared to controls (100%); †denotes value significantly higher than all other time points.
Figure 2
Figure 2
Effect of gel injection on fractional area change 16 weeks after treatment (top). Gel injection prevented the decreased function observed in hearts receiving PBS injection. Addition of growth factors did not improve upon the results of the plain hydrogel: *denotes a significant change from preinjection; †denotes differences between groups over time. Representative M-mode echocardiographic images of the left ventricle for each group (bottom). An image from an age-matched healthy heart is from the data set used in ref 9. Scale bar: 1 cm and 0.2 s.
Figure 3
Figure 3
Measurements of dilation in hearts receiving injection of hydrogels with or without growth factors: *denotes a significant change from preinjection; †denotes differences between groups over time.
Figure 4
Figure 4
Representative Masson’s trichrome stained cardiac cross sections 16 weeks after injection of unloaded material (A), or material loaded with bFGF (B), IGF1-loaded microparticles (C), or both (D). Arrows point to residual hydrogel infiltrated with cells, which are presented in the insets at a higher magnification. Scale bars = 500 µm.
Figure 5
Figure 5
Representative images of αSMA (green), macrophage CD68 (red), and DNA (blue) staining from hearts receiving injection of hydrogel with and without growth factors at 16 wk. There is marked infiltration of macrophages into the hydrogel and presence of smooth muscle cells near the gel. Scale bar = 100 µm for all images; epi designates the epicardial surface; end designates the endocardial surface; dashed line shows edge of hydrogel material; *shows which side of the line has the gel.
Figure 6
Figure 6
Total content of bFGF (A) and IGF1 (B) in the left ventricular free wall of rat hearts injected with either bFGF-loaded hydrogel or hydrogel loaded with microparticles encapsulating IGF1, respectively. Increased levels for both growth factors are shown up to 2 weeks after injection: *denotes significance compared to injection of plain gel at the same time point.

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