Intra-myocardial biomaterial injection therapy in the treatment of heart failure: Materials, outcomes and challenges

Abstract

Heart failure initiated by coronary artery disease and myocardial infarction (MI) is a widespread, debilitating condition for which there are a limited number of options to prevent disease progression. Intra-myocardial biomaterial injection following MI theoretically provides a means to reduce the stresses experienced by the infarcted ventricular wall, which may alter the pathological remodeling process in a positive manner. Furthermore, biomaterial injection provides an opportunity to concurrently introduce cellular components and depots of bioactive agents. Biologically derived, synthetic and hybrid materials have been applied, as well as materials designed expressly for this purpose, although optimal design parameters, including degradation rate and profile, injectability, elastic modulus and various possible bioactivities, largely remain to be elucidated. This review seeks to summarize the current body of growing literature where biomaterial injection, with and without concurrent pharmaceutical or cellular delivery, has been pursued to improve functional outcomes following MI. The literature to date generally demonstrates acute functional benefits associated with biomaterial injection therapy across a broad variety of animal models and material compositions. Further functional improvements have been reported when cellular or pharmaceutical agents have been incorporated into the delivery system. Despite these encouraging early results, the specific mechanisms behind the observed functional improvements remain to be fully explored and future studies employing hypothesis-driven material design and selection may increase the potential of this approach to alleviate the morbidity and mortality of heart failure.

Figure 1

Ventricular dilation associated with progressive heart failure. After the initial insult, infarct expansion and ventricular wall thinning contribute to further ventricular remodeling, ultimately causing increased intraventricular pressure and decreased cardiac output.(From [1])

Figure 2

Cardiac restraint devices are used as a means to limit ventricular dilation following MI. The CorCap device (A) uses a Dacron woven mesh to maintain ventricular dimensions whereas the Heart Net (B) surrounds the ventricle in an elastic nitinol metal wrap. ((A) from [22], (B) from[20])

Figure 3

Direct epicardial injection of a fibrin-alginate composite into porcine myocardium.(A) Using a grid template, material was injected from a double-barreled syringe to distinct points across the infarcted area.(B) Myocardial cross section reveals the material present as amorphous compartments at the injection sites. (From [44])

Figure 4

Representation of mid wall ventricular fiber stress as a function of position in the heart. (A) Wall stress with an apical infarct (red is higher stress localized near the infarct). (B) Wall stress with injection of a theoretical gel material at 4 different numbered locations peripheral to the infarct region. (C) The difference in the previous two images. Marked reduction in wall stress is seen due to injection therapy (cooler colors representing reduced stress). (From [28]).

Figure 5

Two hours after intracoronary injection of alginate, the material has migrated from the vascular space and is found throughout the myocardial wall in a porcine model. The presence of this material will lead to increased wall thickness which persists after material has degraded six weeks later.(From [47])

Figure 6

Comparison between injection of fibrin or alginate into 5-week old infarcts in rats. Two days after injection both materials demonstrated equivalent improvements to FS(A), LV dimension(B)and wall thickness (C). Five weeks after treatment the fibrin group lost much of the advantage seen at two days whereas alginate retained significant improvement.(* p<0.05, From [41])

Figure 7

Demonstration of the thermal properties of NIPAAm-co-AAc-co-HEMAPTMC hydrogel. (A) aqueous polymer solution at 4 °C, (B) gel formation after 30-second incubation in 37 °C water bath, (C) after 10 minutes the gel continues to shrink and stiffen, leading to (D)a mechanically robust material with some elastic behavior.(From [101])

Figure 8

Histological evaluation of myocardium following material injection. Intracoronary injection of alginate (A) led to substantial growth of myofibroblasts that stain positive for α-smooth muscle actin (brown) into the infarct compared to saline injection (B). Direct epicardial injection of a thermally responsive NIPAAm copolymer leads to a smooth muscle layer (C, blue arrows) beneath the material that stains positive for α-smooth muscle actin (D, green stain). (Left panels from [47], scale bar = 10 μm; right panels from [101], scale bar = 100 μm)

Figure 9

Atomic force microscopy (A) of biotinylated peptide nanofibers (left), streptavidin (center) and streptavidin-bound biotinylated peptides (right) creating a beads-on-a-string appearance. IGF-1 was biotinylated and bound to biotinylated peptides through streptavidin (B). This attachment dramatically slows the release of IGF-1 from the SAP environment compared to IGF-1 that is not biotinylated or not tethered by streptavidin. (From [108], image copyright 2006 National Academy of Sciences, U.S.A.)

Figure 10

Fluorescently labeled bone marrow stem cells were injected into an infarct with or without α-CD/MPEG-PCL-MPEG hydrogel. Four weeks after injection cell engraftment in the group without the hydrogel (A) was less than half that of the hydrogel group (B) as determined both visually and quantitatively (C), thus demonstrating a benefit of material injection with cell therapy. (From [123], scale bar = 40 μm)