Effect of Injectable Alginate Implant on Cardiac Remodeling and Function After Recent and Old Infarcts in Rat

Abstract

Background-Adverse cardiac remodeling and progression of heart failure after myocardial infarction are associated with excessive and continuous damage to the extracellular matrix. We hypothesized that injection of in situ-forming alginate hydrogel into recent and old infarcts would provide a temporary scaffold and attenuate adverse cardiac remodeling and dysfunction. Methods and Results-We developed a novel absorbable biomaterial composed of calcium-crosslinked alginate solution, which displays low viscosity and, after injection into the infarct, undergoes phase transition into hydrogel. To determine the outcome of the biomaterial after injection, calcium-crosslinked biotin-labeled alginate was injected into the infarct 7 days after anterior myocardial infarction in rat. Serial histology studies showed in situ formation of alginate hydrogel implant, which occupied up to 50% of the scar area. The biomaterial was replaced by connective tissue within 6 weeks. Serial echocardiography studies before and 60 days after injection showed that injection of alginate biomaterial into recent (7 days) infarct increased scar thickness and attenuated left ventricular systolic and diastolic dilatation and dysfunction. These beneficial effects were comparable and sometimes superior to those achieved by neonatal cardiomyocyte transplantation. Moreover, injection of alginate biomaterial into old myocardial infarction (60 days) increased scar thickness and improved systolic and diastolic dysfunction. Conclusions-We show for the first time that injection of in situ-forming, bioabsorbable alginate hydrogel is an effective acellular strategy that prevents adverse cardiac remodeling and dysfunction in recent and old myocardial infarctions in rat.

Injectable Acellular Hydrogels for Cardiac Repair

“…Unlike fibrin, alginate must be modified with adhesive peptides to facilitate cell binding. Both non-modified alginate and alginate modified with adhesive peptides such as Arg-Gly-Asp (RGD) or Tyr-Ile-Gly-Ser-Arg (YIGSR) have been explored as bulking agents [26,31,34,50,51], and comparisons have been performed between the two [31,51]. Yu et al compared modified alginate to non-modified alginate using a rat reperfusion-MI model with injections 5 weeks post-MI, more indicative of a chronic response [51].…”

“…If anything, these results reveal the complexity in the material interaction with the myocardial tissue, including both the biological (e.g., material remodeling and inflammatory response) and mechanical (e.g., stress reduction) responses. Variable results from these studies indicate that material thickness [21,26,29,34], infarct size [22] [34], and/or increased angiogenesis [19,24,64] do not necessarily correlate directly with improved heart function. However, discrepancies in results could be due to inconsistencies in methodology (Table 1; e.g., animal models, infarct, amount of material injected, and timing of injection), and material properties and the importance of these parameters should be considered when investigating LV remodeling.…”

“…Material injection in these studies has been performed as early as immediately post-MI [21,25] and as late at 8 weeks post-MI [26]. In separate studies with fibrin, injection at 1 week was more effective in improving myocardium function [18] versus injection 5 weeks post-MI [34].…”

“…In separate studies with fibrin, injection at 1 week was more effective in improving myocardium function [18] versus injection 5 weeks post-MI [34]. Utilizing a permanent ligation rat model, Landa et al directly compared injections into new (1 week post-MI) and old (2 months post-MI) infarcts and demonstrated the efficacy of alginate in both (although to different extents) [26]. Recent infarcts resulted in improvements in wall thickening and LV dilation; while older infarcts also showed improvements, results were more pronounced in new infarcts, implying that post-MI therapies are more effective when applied early in the LV remodeling process, before irreversible processes have occurred.…”

“…However, these approaches are limited by the invasive procedure in which they are applied, and clinical adoption has not occurred. In order to circumvent the invasive surgical placement of restraining devices early post-MI, our group and others have begun to explore the use of injectable materials, and specifically hydrogels, to limit infarct expansion and normalize the regional stress distribution [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35].…”