Intracoronary Injection of In Situ Forming Alginate Hydrogel Reverses Left Ventricular Remodeling After Myocardial Infarction in Swine
Jonathan Leor, MD*,1,
Shmuel Tuvia, PhD ,
Victor Guetta, MD*,
Ferenc Manczur, PhD, DVM ,
David Castel, DVM*,
Udi Willenz, DVM*,
Örs Petneházy, DVM ,
Natali Landa, PhD*,
Micha S. Feinberg, MD*,
Eli Konen, MD||,
Orly Goitein, MD||,
Orna Tsur-Gang, PhD¶,
Mazal Shaul, PhD,
Lea Klapper, PhD and
Smadar Cohen, PhD¶,2
* Neufeld Cardiac Research Institute, Sheba Medical Center, Tel-Aviv University, Tel-Hashomer, Israel
BiolineRx, Jerusalem, Israel
Department of Internal Medicine Faculty of Veterinary Science Szent István University, Budapest, Hungary
Institute of Diagnostic Imaging and Radiation Oncology Kaposvár University, Kaposvár, Hungary
|| Department of Diagnostic Imaging, Sheba Medical Center, Tel-Hashomer, Israel
¶ Department of Biotechnology Engineering, Ben-Gurion University of the Negev, Beer-Sheva, Israel
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Figure 1 Macroscopic View of the Infarcted Heart After Intracoronary Injection of Calcium Cross-Linked Alginate Solution
(A) Two hours after injection, the alginate hydrogel was identified on the infarct surface (arrows). (B) Macroscopic view of heart sections revealed hemorrhagic infarct and in situ deposition of the alginate hydrogel (white areas, arrows) and consistent distribution of the biomaterial in the granulation tissue. LAD = left anterior descending; LV = left ventricular.
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Figure 2 Microscopic View of Infarcted Myocardium, 2 h After Intracoronary Injection of 2 ml Biotin-Labeled Alginate Solution or Saline
Upper panels show low-power (x12.5) microscopic view of infarcted myocardium 2 h after intracoronary injection of 2 ml biotin-labeled alginate solution (A) or saline (B). (A) Positive brown staining confirms extensive and effective delivery of the alginate solution into the infarcted heart. Nuclei of cardiac cells are stained blue by hematoxylin. (B) Positive brown staining was absent in saline-treated hearts (x12.5). (C) High-power (x100) view of A. Note typical inflammation after myocardial infarction. Positive brown staining of avidin-biotin complex indicates effective delivery of the biotin-labeled alginate solution into the infarcted heart. (D) In 1 specimen, the alginate biomaterial (brown staining) was embedded at the extracellular matrix of the border zone, and did not affect viable cardiomyocytes (x200).
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Figure 3 Masson Trichrome Staining in Naive Pig Hearts, 72 h After Alginate (2 ml) Injection
Viable myocardium is stained bright red. Fibrosis should be stained bright blue. (A) There are no signs of fibrosis in samples from animals treated with intracoronary injection of alginate solution (x100). Only the connective tissue that surrounds the artery (tunica adventitia) is stained blue. (B) Higher magnification (x200) confirmed that intracoronary injection of alginate solution does not injure the myocardium.
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Figure 4 Effect of Intracoronary Injection of Various Volumes of Alginate on LV Dilation 30 and 60 Days After MI
Comparison of the therapeutic effects of intracoronary delivery of 1, 2, and 4 ml of alginate solution or saline (2 ml) into recent (4-day-old) scar. All volumes of alginate attenuate or prevent left ventriculat (LV) diastolic (A) and systolic (B) dilation compared with control. Relative change was calculated as ([30 or 60 day measure – 3 day measure]/3 day measure) x 100. Individual values and mean (±SEM). The p values are for treatment effect versus control by repeated-measures analysis of variance (ANOVA) and Bonferroni post hoc test adjusted for multiple comparisons. MI = myocardial infarction.
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Figure 5 Diastolic Properties Were Improved in Alginate Biomaterial-Treated Animals by Doppler Echocardiography
Diastolic properties were evaluated by serial Doppler echocardiography tests. During a 60-day follow-up, control animals maintained a trend for restrictive LV filling pattern presented by increased E/A ratio. In contrast, the E/A ratio decreased in alginate-treated animals (p = 0.02 for treatment over time interaction by a linear mix model). Abbreviations as in Figure 4.
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Figure 6 Alginate Solution (1 and 2 ml) Does Not Affect TFG and MPG 3 Min and 60 Days After Intracoronary Injection
MPG = myocardial perfusion grade; TFG = Thrombolysis In Myocardial Infarction flow grade; TIMI = Thrombolysis In Myocardial Infarction.
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Figure 7 Alginate Implant Increases Scar Thickness by Post-Mortem Morphometry, 60 Days After MI
Representative sections of heart treated with alginate (upper left panel) or saline (upper right panel). Morphometry shows that injection of alginate solution (2 ml) increases scar thickness (arrows) as well as anterior wall thickness (lower panels). Abbreviations as in Figure 4.
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-SMA, 60 Days After Either Alginate or Saline Injection