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Abstract: Given the lack of a unified theory of heart failure, future research efforts will be required to unify and synthesize our current understanding of the multiple mechanisms that control remodeling in the failing heart. Matrix remodeling and the associated activation of inflammatory cytokines and MMPs have emerged as key pathways in the development of heart failure. As such, attempts to understand the integrated control of ECM homeostasis with the bioactivation of inflammatory cytokines may be of particular relevance to the development of effective anti-remodeling approaches. Notably, the implantation of isolated populations of cells in failing myocardium has a profound and consistent anti-remodeling effect that limits the progression to CHF. These observations were consistently identified in numerous studies using diverse experimental animal models and varied cell types. Accordingly, multicenter clinical trials are underway, and the preliminary data in patients with CHF are encouraging. Despite the enormous promise of cell transplantation to restore and regenerate failing myocardium, the mechanisms underlying these profound biological effects are not understood. An improved understanding of the myocardial response to cell implantation, particularly on parameters of matrix remodeling, may help unify our current understanding of the progression of heart failure and optimize the development of this technique for its evolving therapeutic use. The following review outlines recent advances in medical and surgical approaches to control the remodeling process that underlies the progression of heart failure. [Copyright &y& Elsevier]

Cardiac tissue engineering is of particular importance in the combination of contracting cells with a biomaterial scaffold, which serves as a cell-delivery construct, to replace cardiomyocytes (CMs) that are lost as a result of an infarction, to restore heart function. However, most biomaterial scaffolds are nonconductive and may delay regional conduction, potentially causing arrhythmias. In this study, a conductive CM-delivery construct that consists of a gelatin-based gelfoam that is conjugated with a self-doped conductive polymer (poly-3-amino-4-methoxybenzoic acid, PAMB) is proposed as a cardiac patch (PAMB-Gel patch) to repair an infarcted heart. A nonconductive plain gelfoam (Gel patch) is used as a control. The electrical conductivity of the PAMB-Gel patch is approximately 30 times higher than that of the Gel patch; as a result, the conductive PAMB-Gel patch can substantially increase electrical conduction between distinct clusters of beating CMs, facilitating their synchronous contraction. In vivo epicardial implantation of the PAMB-Gel patch that is seeded with CMs (the bioengineered patch) in infarcted rat hearts can significantly enhance electrical activity in the fibrotic tissue, improving electrical impulse propagation and synchronizing CM contraction across the scar region, markedly reducing its susceptibility to cardiac arrhythmias. Echocardiography shows that the bioengineered conductive patch has an important role in the restoration of cardiac function, perhaps owing to the synergistic effects of its conductive construct and the synchronously beating CMs. These experimental results reveal that the as-proposed bioengineered conductive patch has great potential for repairing injured cardiac tissues. Implantation of the bioengineered conductive patch in infarcted hearts improves electrical impulse propagation and synchronizes cardiomyocyte contraction across the scar region, reducing susceptibility such hearts to cardiac arrhythmias and restoring heart function. Unlabelled Image [ABSTRACT FROM AUTHOR]

Introduction: After myocardial infarction, necrosed cardiomyocytes are replaced with fibrotic tissue (FT) which dampens electrical activity and impedes impulse conduction in the heart, increasing the risk of cardiac arrhythmias. Polypyrrole-chitosan (PPY:CHI) hydrogel is a conductive biomaterial designed to restore the heart's conduction pathways to improve function and limit arrhythmias. Previously, we demonstrated that an injection of PPY:CHI into rat FT after an infarct shortened QRS interval duration. However, the underlying mechanisms were not investigated. In the current study, we injected PPY:CHI into FT to increase conductive potential and velocity towards the conduction seen in healthy myocardium. Methods: Gelatin, a resistive material, was used to model FT. We used three approaches to understand how PPY:CHI electrically works within FT. Groups of increasing concentrations of PPY:CHI and chitosan (CHI) control were used in this model: 5, 10, 20, 40, 60, 80 and 100%. 1) Impedance spectroscopy determined the effect PPY:CHI has on the impedance of the model. 2) Multi-electrode array (MEA) identified electrical potentials traveling through PPY:CHI when in contact with contracting cardiac tissue. 3) MEA and multi-channel systems were used to identify the conduction velocity of PPY:CHI, model concentrations, and healthy and infarct scar tissue. Results: 1) At concentrations ≥20%, PPY:CHI reduced the impedance of the model to a level similar to that of healthy myocardium. At a concentration of 10%, PPY:CHI reduced the impedance of the model by half compared to 40% CHI. 2) When in contact with contracting myocardium at concentrations ≥20%, PPY:CHI influenced the model to transmit field potentials >0.5 mV, mimicking healthy myocardium. The control and model had a potential of <0.5 mV, which resembles cardiac FT. 3) At concentrations >40%, PPY:CHI influenced the model to generate a velocity of 0.4-0.6 m/s, which resembles healthy myocardium. The control and model generated a velocity of <0.15 m/s, which is very similar to cardiac FT. Conclusions: PPY:CHI influenced our FT model to electrically resemble healthy cardiac tissue. Electrically coupling the left ventricle may not only induce synchronous contraction, but also limit fatal arrhythmias. [ABSTRACT FROM AUTHOR]

Background Both stable and biodegradable biomaterials have been used to surgically repair congenital cardiac defects. However, neither type of biomaterial can conduct electrical activity. We evaluated the conductivity and efficacy of a newly synthesized conductive polypyrrole–chitosan (Ppy+Chi) gelfoam patch to support cardiomyocyte (CM) viability and function in vitro and to surgically repair a cardiac defect in vivo. Methods Ppy+Chi was incorporated into gelfoam (Gel) to form a 3-dimensional conductive patch. In vitro, patch characteristics were evaluated and biocompatibility and bioconductivity were investigated by culturing neonatal rat CMs on the patches. In vivo, a full-thickness right ventricular outflow tract defect was created in rats and the patches were implanted. Four weeks after patch repair, cardiac electrical activation and conduction velocity were evaluated using an optical mapping system. Results In vitro, the Ppy+Chi+Gel patch had a higher mean breaking stress than the Gel or Chi+Gel patches, and the highest conductivity. None of the patches altered cell growth. The Ca 2+ transient velocity of CMs cultured on the Ppy+Chi+Gel patch was 2.5-fold higher than that of CMs cultured on the Gel or Chi+Gel patches. In vivo, optical mapping at 4 weeks post-implantation demonstrated that Ppy+Chi+Gel patch-implanted hearts had faster conduction velocities, as measured on the epicardial surface. Continuous electrocardiographic telemetry did not reveal any pathologic arrhythmias after patch implantation. Ex-vivo patch conductivity testing also revealed that the Ppy+Chi+Gel patch was more conductive than the Gel and Chi+Gel patches. Conclusions The Ppy+Chi+Gel patch was biocompatible, safe and conductive, making it an attractive candidate for a new biomaterial platform for cardiac surgical repair to preserve synchronous ventricular contraction. [ABSTRACT FROM AUTHOR]

Abstract: The goal of cardiac tissue engineering is to restore function to the damaged myocardium with regenerative constructs. Human embryonic stem cell–derived cardiomyocytes (hESC-CMs) can produce viable, contractile, three-dimensional grafts that function in vivo. We sought to enhance the viability and functional maturation of cardiac tissue constructs by cyclical stretch. hESC-CMs seeded onto gelatin-based scaffolds underwent cyclical stretching. Histological analysis demonstrated a greater proportion of cardiac troponin T–expressing cells in stretched than non-stretched constructs, and flow sorting demonstrated a higher proportion of cardiomyocytes. Ultrastructural assessment showed that cells in stretched constructs had a more mature phenotype, characterized by greater cell elongation, increased gap junction expression, and better contractile elements. Real-time PCR revealed enhanced mRNA expression of genes associated with cardiac maturation as well as genes encoding cardiac ion channels. Calcium imaging confirmed that stretched constructs contracted more frequently, with shorter calcium cycle duration. Epicardial implantation of constructs onto ischemic rat hearts demonstrated the feasibility of this platform, with enhanced survival and engraftment of transplanted cells in the stretched constructs. This uniaxial stretching system may serve as a platform for the production of cardiac tissue-engineered constructs for translational applications. [Copyright &y& Elsevier]

Abstract: Vascularization of engineered tissues in vitro and in vivo remains a key problem in translation of engineered tissues to clinical practice. Growth factor signalling can be prolonged by covalent tethering, thus we hypothesized that covalent immobilization of vascular endothelial growth factor (VEGF-165) to a porous collagen scaffold will enable rapid vascularization in vivo. Covalent immobilization may be preferred over controlled release or cell transfection if the effects are desired within the biomaterial rather than the surrounding tissue. Scaffolds were prepared with 14.5 ± 1.4 ng (Low) or 97.2 ± 8.0 ng (High) immobilized VEGF, or left untreated (control), and used to replace a full right ventricular free wall defect in rat hearts. In addition to rapid vascularization, an effective cardiac patch should exhibit neither thinning nor dilatation upon implantation. In vitro, VEGF enhanced the growth of endothelial and bone marrow cells seeded onto scaffolds. In vivo, High VEGF patches had greater blood vessel density (p < 0.01) than control at Day 7 and 28 due to increased cell recruitment and proliferation (p < 0.05 vs. control). At Day 28, VEGF-treated patches were significantly thicker (p < 0.05) than control, and thickness correlated positively with neovascularization (r = 0.67, p = 0.023). Importantly, angiogenesis in VEGF scaffolds contributed to improved cell survival and tissue formation. [ABSTRACT FROM AUTHOR]

Abstract: Injectable scaffolds made of biodegradable biomaterials can stabilize a myocardial infarct and promote cardiac repair. Here, we describe the synthesis of a new, temperature-sensitive, aliphatic polyester hydrogel (HG) conjugated with vascular endothelial growth factor (VEGF) and evaluate its effects on cardiac recovery after a myocardial infarction (MI). Seven days after coronary ligation in rats, PBS, HG, or HG mixed or conjugated with VEGF (HG + VEGF or HG-VEGF, respectively) was injected around the infarct (n = 8–11/group). Function was evaluated by echocardiography at multiple time points. Pressure–volume measurements were taken and infarct morphometry and blood vessel density were assessed at 35 days after injection. HG-VEGF provided localized, sustained VEGF function. Compared with outcomes in the PBS group, fractional shortening, ventricular volumes, preload recruitable stroke work, and end-systolic elastance were all preserved (p < 0.05) in the HG and HG + VEGF groups, and further preserved in the HG-VEGF group. Conjugated VEGF also produced the highest blood vessel density (p < 0.05). The infarct thinned and dilated after PBS injection, but was smaller and thicker in hearts treated with HG (p < 0.05). Our temperature-sensitive HG attenuated adverse cardiac remodeling and improved ventricular function when injected after an MI. VEGF delivery enhanced these effects when the VEGF was conjugated to the HG. [ABSTRACT FROM AUTHOR]

Abstract: Late after a myocardial infarction (MI), surgical ventricular restoration (SVR) can reduce left ventricular volumes, but an enhanced cardiac patch may be required to restore function. We developed a new, biodegradable patch (modified gelfoam, MGF) consisting of a spongy inner core (gelfoam) to encourage cell engraftment and an outer coating (poly ε-caprolactone) to provide sufficient strength to permit ventricular repair. Two weeks after coronary ligation in rats, SVR was performed using one of the following: gelfoam, MGF, MGF patches with hydrogel alone, or with hydrogel and cytokines (stem cell factor, stromal cell-derived factor-1α), bone marrow mesenchymal stem cells, or both. Cardiac function and morphology were evaluated by echocardiography, conduction catheterization, magnetic resonance imaging, and histology. Animals whose hearts were repaired with untreated gelfoam died of ventricular rupture. The MGF groups had significantly improved myocardial systolic function vs. MI controls. Enhancement with cytokines and/or cells promoted more α-smooth muscle actin-positive cells, more capillaries, greater wall thickness, a more ellipsoid shape, greater fractional shortening, and better-preserved systolic elastance than MGF alone. This combination of the new, reinforced, biodegradable biomaterial and cytokine/cell treatment created a viable tissue after SVR and produced better functional outcomes than un-reinforced gelfoam or MGF alone. [ABSTRACT FROM AUTHOR]