Effect of Injectable Alginate Implant on Cardiac Remodeling and Function After Recent and Old Infarcts in Rat
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.
Received July 13, 2007; accepted January 18, 2008.
An emerging paradigm links adverse remodeling and progression of heart failure after myocardial infarction (MI) to excessive damage to the cardiac extracellular matrix (ECM).1 This paradigm has potential therapeutic implications because several recent reports have suggested that direct injection of biomaterials such as fibrin, collagen, and self-assembling peptide into the infarct, alone or together with cells, immediately or a few days after MI could replace the damaged ECM and prevent adverse left ventricular (LV) remodeling and heart failure.2–8 However, no study so far has investigated whether such a treatment also could be associated with improved cardiac function in chronic heart failure resulting from an old MI with an established scar.
Clinical Perspective p 1396
In recent years, we investigated the therapeutic potential of alginate biomaterial for myocardial tissue engineering.9,10 Alginate, a polysaccharide found in brown seaweed, has been used extensively in the food, pharmaceutical, and medical device industries. It is biocompatible and, in the form of crosslinked hydrogel, has a structure similar to that of ECM.9,11 Transplantation of biografts from alginate scaffolds reduced remodeling and dysfunction in a rat model of MI.9 Recently, we developed an aqueous solution of calcium-crosslinked alginate displaying relatively low viscosity at room temperature. The biomaterial solution can be injected by a needle into the infarct where it undergoes phase transition into hydrogel as the calcium ion concentration in the solution locally increases. The aim of the present study was to determine whether this novel injectable biomaterial could temporarily replace the damaged ECM and improve LV remodeling and function in a rat model of recent and old infarcts.
The study was performed in accordance with the guidelines of the Animal Care and Use Committee of Sheba Medical Center, Tel-Aviv University, which conforms to the policies of the American Heart Association and the Guide for the Care and Use of Laboratory Animals (Department of Health and Human Services, National Institutes of Health publication No. 85-23). All animal work was approved by the Institutional Review Board and was supervised by institutional animal protection officials.
Preparation of Calcium-Crosslinked Alginate Solution
Calcium-crosslinked alginate solution was prepared from an aqueous solution of 30 to 50 kDa sodium alginate (LVG, NovaMatrix FMC Biopolymers, Drammen, Norway) by mixing it with calcium gluconate solution using homogenization to distribute the calcium ions throughout the solution. Several parameters such as alginate molecular weight and solution concentration and the weight ratio of calcium ions and alginate were consistently adjusted to yield a calcium-crosslinked alginate solution displaying low apparent viscosity. The viscosity of the solution was measured on a Rheometer AR 2000 (TA Instruments, West Sussex, UK) operated in the cone-plate mode (cone angle, 1° and 4° with a 60- and 40-mm diameter, respectively).
For temporal tracking of the injectable alginate biomaterial in infarcted hearts, biotin-labeled alginate was synthesized using the carbodiimide chemistry. The modification of the uronic acid residues on alginate was <3%, and the calcium-crosslinked, biotin-labeled alginate solution retained the same viscosity as the nonmodified formulation.
The in vivo studies included 3 sets of experiments designed to determine (1) the outcome and distribution of biotin-labeled, calcium-crosslinked alginate solution after injection into the infarcted heart (n=10); (2) the effect of early administration (7 days after MI) of alginate biomaterial on LV remodeling and function compared with neonatal (1 day) cardiomyocyte (1×106) transplantation or saline injection (n=67); and (3) the effect of late administration (2 months) of alginate biomaterial on progressive LV remodeling and function in old MI (n=40).
Rat Model of MI and Injection of Biomaterial or Neonatal Cardiomyocytes
Our model of MI has been described previously.9,12 Male Sprague-Dawley rats (≈250 g) were anesthetized with a combination of 40 mg/kg ketamine and 10 mg/kg xylazine, intubated, and mechanically ventilated. The chest was opened by left thoracotomy; the pericardium was removed; and the proximal left coronary artery was permanently occluded with an intramural stitch. Seven days (second experiment) or 2 months (third experiment) after MI, the rats were randomized for a single injection of 100 to 150 μL calcium-crosslinked alginate solution or saline using a 29-gauge needle. In the second experiment, an additional group of rats was randomized for transplantation of 1×106 neonatal (1 day) cardiomyocytes. The infarcted area was identified visually as a pale surface scar with wall-motion akinesis. Rat cardiomyocytes were isolated, purified, and cultured as previously described.9,12
Temporal Tracking of Calcium-Crosslinked Biotin-Labeled Alginate in Heart
One week after MI, rats were treated with injection of 150 μL calcium-crosslinked, biotin-labeled alginate solution or 150 μL saline (control) directly into the infarct. Animals were euthanized with an overdose of pentobarbital, and hearts were removed and fixed at 1 hour (n=2, alginate), 1 week (n=2, alginate), 4 weeks (n=3; 2 alginate, 1 saline), and 6 weeks (n=3; 2 alginate, 1 saline) after treatment.
Histological and Morphometric Analyses
Eight weeks after injection into recent or old infarcts, the hearts were arrested with 15% KCl and sectioned into 3 to 4 transverse slices parallel to the atrioventricular ring. Each slice was fixed with 10% buffered formalin, embedded in paraffin, and sectioned into 5-μm slices. In the first experiment, the slides were immunostained with avidin-peroxidase (Vector Laboratories, Burlingame, Calif) to detect the biotin-labeled alginate. The immunostained slides were digitally photographed, and the areas of avidin-biotin–positive staining were analyzed using manual planimetry with Sigma Scan Pro version 5 (SPSS Inc, Chicago, Ill). In other experiments, serial sections were stained with hematoxylin and eosin and immunolabeled with antibodies against α-smooth muscle actin isoform (Sigma, St Louis, Mo).
Postmortem morphometric analysis was performed on hearts from the third experiment (old infarcts). The hearts were perfused with 4% formaldehyde (15 mm Hg) for 20 minutes, and measurements were performed on slices obtained 5 mm from the apex of the heart. The slides were stained with hematoxylin and eosin, photographed, and analyzed with planimetry software (Sigma Scan Pro version 5). We measured LV maximal diameter defined as the longest diameter perpendicular to a line connecting the insertions of the septum to the ventricular wall, average wall thickness from 3 measurements of septum thickness, average scar thickness from 3 measurements of scar thickness, LV muscle area (including the septum), LV cavity area, whole LV area, epicardial scar length (millimeters), and endocardial scar length (millimeters). Relative scar thickness was calculated as average scar thickness divided by average wall thickness. Expansion index was calculated as follows: expansion index=[LV cavity area/whole LV area]/relative scar thickness.
Echocardiography to Evaluate Remodeling and Function
In the second experiment (recent infarcts), transthoracic echocardiography was performed within 24 hours (baseline echocardiogram) and 8 weeks after MI. In the third set of experiments (old infarcts), transthoracic echocardiography was performed within 3 days after MI (baseline echocardiogram), after 2 months (before alginate injections), and 4 months later (2 months after injection). Echocardiograms were performed with a commercially available echocardiography system (Sonos 5500, Philips, Andover, Mass) equipped with a 12-MHz phased-array transducer as previously reported.13
To evaluate diastolic function, pulsed-wave Doppler interrogation of mitral inflow was performed in a modified 4-chamber view to evaluate LV diastolic filling properties. The early mitral inflow E wave was repeatedly available, and the peak E-wave velocity and deceleration time were measured. All measurements were averaged for 3 consecutive cardiac cycles, were performed by an experienced technician, and were reviewed by a cardiologist and an echocardiography expert (M.S.F.) who were blinded to treatment groups.
Statistical analysis was performed with GraphPad Prism version 5.00 for Windows (GraphPad Software, San Diego, Calif). All variables are expressed as mean±SEM. Normality was tested with the Kolmogorov-Smirnov test. If normally distributed, differences between baseline and 8 weeks were assessed with 2-tail paired t tests. In the experiment on old MI, percent of change from baseline measurement was calculated for each animal as follows: [(follow-up parameter−baseline parameter)/baseline parameter]×100. The difference between means of groups was compared by a 2-tail unpaired t test. A Kruskal-Wallis test was performed if data were not normally distributed. To test the hypothesis that changes in measures of LV function over time varied among the experimental groups, a general linear model 2-way repeated-measures ANOVA was used. The model included the effects of treatment, time, and treatment-by-time interaction. In the recent MI experiment, the Bonferroni correction was used to assess the significance of predefined comparisons at specific time points. A simple linear regression analysis was used to estimate the relationship between alginate resorption in the scar and time from injection. In addition, a simple linear regression was used to assess the relationship between diastolic properties (E/A ratio) and time from MI, as well as a time-by-group interaction.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
Overall, 117 rats were included in the study. In the first experiment, 10 rats were included in testing designed to determine the outcome and distribution of the calcium-crosslinked, biotin-labeled alginate solution in the scar. The second experiment (effect of biomaterial on recent infarct) included 67 rats; the perioperative mortality was 25 of 67. In the third experiment (effect of biomaterial on old infarcts), 40 rats were subjected to MI; 10 rats died after MI, and 9 rats died after injections during the follow-up period. Thus, the final echocardiography analysis was performed in 73 rats.
The Calcium-Crosslinked Alginate Solution
An aqueous solution of calcium-crosslinked alginate was developed by judiciously selecting the alginate molecular weight, the initial concentration of the sodium alginate solution, and the weight ratio of the crosslinking calcium ions and the alginate backbone. Furthermore, the calcium ions were added to the sodium alginate solution using extensive homogenization to facilitate a homogeneous distribution and crosslinking of the alginate. In this study, the calcium-crosslinked alginate solution displayed a viscosity of 10 to 50 cP and was composed of 1% (wt/vol) alginate and 0.3% (wt/vol) calcium gluconate. As a low-viscosity solution, the alginate biomaterial was injected easily by a needle into the infarct where it underwent phase transition into hydrogel as the calcium ion concentration locally increased at the infarct.
Temporal Tracking of Biotin-Labeled Alginate in the Infarcted Rat Heart
The labeled biomaterial solution was injected into the infarct without evidence of arrhythmias or thrombus formation at the injection sites. Heart sections were stained for alginate-biotin complex at different times after injection. Macroscopic examination showed that the alginate biomaterial implant occupied nearly 45±4% of the infarct 1 hour after injection (Figure 1). The areas of positive biotin staining, as a percentage of the scar area, were decreased significantly to 29±4%, 13±3%, and 6±1% at 1, 4, and 6 weeks after injection (Figure 2; P<0.0001). At 6 weeks, only rare, weak brown staining spots were identified (Figure 1D). No positive biotin staining was visible in control saline-injected hearts. Microscopic examination of the tissue specimens showed robust positive biotin-alginate staining (brown) at the infarct 1 hour and 1 week after injection (Figure 3). However, 4 and 6 weeks after injection, only isolated islands of biomaterial were detected in the infarct, and the biomaterial was replaced completely by connective tissue and myofibroblasts (Figures 3 and 4⇓).
Alginate Biomaterial Improved LV Remodeling and Function Similar to Neonatal Cardiomyocyte Transplantation
Serial echocardiography studies showed that the in situ–forming alginate implant significantly increased scar thickness (from 0.14±0.01 cm to 0.16±0.01 cm; P<0.01; Table 1 and Figures 4 and 5⇓), as well as diastolic and systolic anterior wall thicknesses, compared with both cardiomyocyte transplantation and saline injection. Both alginate implant and cardiomyocyte transplantation attenuated the typical course of LV systolic and diastolic dilatation and dysfunction compared with control (Table 1 and Figure 5). In contrast, control animals developed significant LV dysfunction, as assessed by LV fractional shortening and fractional area change (Table 1).
Injection of biomaterial into the heart could increase stiffness and interfere with the relaxation (diastolic) and elastic properties of the heart. To address this issue, we analyzed diastolic function by Doppler echocardiography before and 2 months after treatment in 11 animals without missing Doppler data (6 treated with alginate, 5 treated with saline). The diastolic properties were not affected over time by the injection of calcium-crosslinked alginate solution and hydrogel formation at the infarct (P=0.13). E/A wave ratios before versus after injection were 1.4±0.1 versus 1.8±0.2 in biomaterial-treated animals (P=0.08) and 2.97±0.94 versus 2.7±0.74 in controls (P=0.68). Deceleration time before and after injection was 53±4 versus 54±4 ms (P=0.7) in biomaterial-treated animals and 58±6 versus 46±7 ms in controls (P=0.15).
Two months after injection, microscopic examination of the sections from alginate biomaterial–treated hearts showed numerous myofibroblasts that populated the scar tissue at the injection site and increased scar thickness (Figure 4A and 4B). Traces of the injected biomaterial were not detected at the injection site. The robust α-actin staining for myofibroblasts was absent in control hearts (Figure 4C). Two months after cardiomyocyte transplantation, engrafted neonatal cells were detected in 4 of the 14 cell-treated hearts (Figure 4D).
Effect of Alginate Biomaterial on Remodeling and Dysfunction After Old MI
The third experiment was designed to determine whether the alginate implant could improve remodeling and function in old (2 months) MI (Table 2). Analysis of the relative changes from baseline (before injection) is presented in Table 3 and shows higher anterior wall thickening in the biomaterial group than in the control group (Table 3; diastolic by 25±4.4% versus 6.9±6.7% [P=0.03] and systolic by 30.9±6.2% versus 2.7±6.9% [P=0.007]). In addition, deterioration in LV fractional area change and fractional shortening after injection was attenuated in the biomaterial group compared with the control group.
Subgroup analysis (alginate, n=11; saline, n=6) of diastolic properties shows improvement in biomaterial-treated animals and deterioration in the control animals by transmitral Doppler echocardiography (Figure 6). Increased E/A ratio (P=0.01) resulting from a markedly elevated left arterial pressure that offsets the slowing of LV relaxation was observed in all control rats (Figure 6). In contrast, alginate-treated animals experienced improved E/A ratio after injection (P=0.01; P<0.0001 for time-by-group interaction).
Table 4 shows the results of postmortem morphometric analysis. Sections from infarcted hearts treated with alginate biomaterial showed markedly increased scar thickness (P=0.01) and reduction in expansion index (P=0.03) than control (Table 4 and Figure 7). Although no difference was noted in LV cavity area, scar length was shorter and muscle area was greater in the alginate-treated animals than in the control group.
The present study shows, for the first time, that injection of in situ–forming alginate hydrogel into recent and old infarcts increases scar thickness and attenuates adverse cardiac remodeling and systolic and diastolic dysfunction.
The bioresorbable alginate hydrogel implant is presumed to provide mechanical and physical support to the damaged cardiac tissue after MI, replacing some of the functions of the damaged ECM. Its presence during the LV remodeling period after MI provides physical scaffolding and stabilizes the infarct, preventing it from dilating and expanding. With time, the dissolvable hydrogel gradually disappears, and the water-soluble alginate chains are evacuated and excreted by the kidneys.14
Most encouraging was the finding that these beneficial effects of alginate implant were comparable and sometimes superior to those achieved by neonatal cardiomyocyte transplantation in recent infarcts. This finding supports previous evidence suggesting that cell therapies can increase wall thickness and prevent ventricular dilation and dysfunction by restoring the ECM independently of systolic activation of the implanted cells.12,15 This represents a significant component of benefits from both cell therapy and tissue engineering.2,16
Injectable Biomaterials for Heart Repair
Enlargement and spherical deformation of the left ventricle with a concomitant increase in wall stress are key elements in the pathogenesis of adverse remodeling after MI. Injectable biomaterials can reduce wall stress by increasing scar thickness and stabilizing chamber size.2,3,5–7 Several recent reports show that biomaterials with or without cells can be injected directly into the infarcted heart of small animals and improve healing, remodeling, and function. Such biomaterials include fibrin glue,17,18 collagen,7 self-assembled nanopeptide,4 and alginate.2,19,20 The most likely mechanisms are increased scar thickness and reduced wall stress, which lead to progressive adverse remodeling and heart failure. By thickening the scar, wall stress is reduced (Laplace law) and the degree of outward motion of the infarct that occurs during systole (paradoxical systolic bulging) is reduced. This is a significant effect because one of the most important predictors of mortality in patients with MI is the degree of LV systolic dilatation.21 Wall et al6 recently presented computational models that suggest that the injection of passive materials alone may improve ejection fraction and reduce wall stress in the ventricle. Returning wall stress closer to its normal value might improve the stress-induced changes in the electric and mechanical properties of myocytes.22 Furthermore, injectable biomaterial also can generate an improved environment for myocardial repair,3,5 as well as a platform for controlled delivery of therapeutic genes and proteins.19,23–25
It is notable that the favorable effect of the biomaterial on remodeling was seen with injection 7 days after MI, and even some effect was seen in an old scar. In a rat model of MI, healing is completed over 3 weeks (see Reference 1 for review). Previous experiments with cells and biograft transplantation have shown that 7 days after MI, after inflammation has subsided and the healing period has started, infarct stabilization by biomaterial or cells attenuates subsequent LV remodeling and dysfunction.9,12,26 It is possible that earlier injection may achieve a better effect on the prevention of early remodeling, but the optimal time for implant delivery requires further research.
Although the beneficial effects of alginate biomaterial implant in old MI are less impressive compared with recent MI, they may suggest a role for this strategy in ischemic cardiomyopathy and chronic heart failure. Compared with control, the diastolic properties were not affected by the injection of biomaterial into recent infarcts but were improved by injection into old scar. The mechanism responsible for this observation is unclear and needs further research. It is possible that the contribution of the biomaterial with myofibroblast accumulation to elasticity and relaxation of LV is relatively more significant in old fibrous scar than recent infarct.
First, the follow-up in the present study was up to 2 months after injection. A longer follow-up may be needed to confirm that the beneficial effects on remodeling and function are preserved for a longer time after the disappearance of the alginate biomaterial from the scar. Second, tissue Doppler imaging for diastolic function was not used in the present study because tissue Doppler and the E/E′ measure require imaging from the apical view. In the present study, it was impossible to achieve this image in many rats. In addition, because of technical difficulties, assessment of diastolic function was not performed in all animals, which may have created a bias. Third, postmortem morphometric analysis was performed on chronic infarcts and not on a recent infarct model. Finally, the present study did not include a sham group.
Implications and Future Research
Our experiments provide a novel proof of concept for an acellular approach of injectable, bioresorbable alginate implant to preserve cardiac function after recent and old MI. The injectable implant increases scar thickness and provides physical support for improved healing and repair to attenuate early and late LV remodeling. The alginate solution is nonthrombogenic and can be delivered into the infarct by a catheter-based approach. Future clinical frontiers lie in the development of “smart” biomaterials that not only will provide physical support but also will guide the healing and self-repair after infarct.
Dr Cohen holds the Clair and Harold Oshry Professor Chair in Biotechnology. We thank Pat Benjamin (echocardiography) for excellent technical assistance; Valentina Boyko, MSc, for statistical advice; and Vivienne York for skillful editing of the manuscript.
Sources of Funding
The research was supported by a grant from the Israel Science Foundation (793/04) and an applied research grant from Ben-Gurion University.
Drs Leor and Cohen applied for a patent on injectable alginate for myocardial repair via Ben-Gurion University. Dr Leor is a medical consultant for Bioline Innovations, Jerusalem, Israel.
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The present study describes a novel acellular approach consisting of an injectable, bioresorbable, calcium-crosslinked alginate solution that, when deployed into the infarcted region, undergoes phase transition into a hydrogel implant that prevents infarct expansion. Mechanistically, this hydrogel scaffold can stabilize degradation of the extracellular matrix, increase scar thickness, and reduce myocardial wall stress. These structural alterations act in concert to mitigate ventricular dilation. From a therapeutic perspective, preventing infarct expansion after acute myocardial infarction and/or preventing the possible formation of a ventricular aneurysm long term are beneficial in limiting progressive left ventricular enlargement, chamber sphericity, and their adverse sequelae. Controlling ventricular size and shape after MI is likely to prevent or retard the development of congestive heart failure and may possibly improve long-term outcome in this patient population. This cell-free approach to ventricular reconstruction after myocardial infarction may represent an alternative to biological approaches such as stem cell–based therapy, particularly in high-risk elderly patients and in patients with significant comorbidities.
↵*The first 2 authors contributed equally.