Naturally derived myocardial matrix as an injectable scaffold for cardiac tissue engineering. Biomaterials

Department of Bioengineering, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0412, USA.
Biomaterials (Impact Factor: 8.56). 08/2009; 30(29):5409-16. DOI: 10.1016/j.biomaterials.2009.06.045
Source: PubMed

ABSTRACT Myocardial tissue lacks the ability to significantly regenerate itself following a myocardial infarction, thus tissue engineering strategies are required for repair. Several injectable materials have been examined for cardiac tissue engineering; however, none have been designed specifically to mimic the myocardium. The goal of this study was to investigate the in vitro properties and in vivo potential of an injectable myocardial matrix designed to mimic the natural myocardial extracellular environment. Porcine myocardial tissue was decellularized and processed to form a myocardial matrix with the ability to gel in vitro at 37 degrees C and in vivo upon injection into rat myocardium. The resulting myocardial matrix maintained a complex composition, including glycosaminoglycan content, and was able to self-assemble to form a nanofibrous structure. Endothelial cells and smooth muscle cells were shown to migrate towards the myocardial matrix both in vitro and in vivo, with a significant increase in arteriole formation at 11 days post-injection. The matrix was also successfully pushed through a clinically used catheter, demonstrating its potential for minimally invasive therapy. Thus, we have demonstrated the initial feasibility and potential of a naturally derived myocardial matrix as an injectable scaffold for cardiac tissue engineering.

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Available from: Karen L Christman, Dec 31, 2013
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    • "Only patient age was provided for the six patients (p1-6) and is as follows: p1-43, p2-52, p3-63, p4-69, p5-63, and p6-34. The methods for decellularizing human myocardial tissue have been previously reported [4], and were based on methods developed for decellularizing porcine myocardium [6]. In brief, human cardiac tissue was collected from 6 different patients. "
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    ABSTRACT: The purpose of this study was to characterize and quantitatively analyze human cardiac extracellular matrix (ECM) isolated from six different cadaveric donor hearts. ECM was isolated by decellularization of six human cadaveric donor hearts and characterized by quantifying sulfated glycosaminoglycan content (sGAG) and via polyacrylamide gel electrophoresis (PAGE). The protein content was then quantified using ECM-targeted Quantitative conCATamers (QconCAT) by Liquid Chromatography - Selected Reaction Monitoring (LC-SRM) analysis using 83 stable isotope labeled (SIL) peptides representing 48 different proteins. Non-targeted global analysis was also implemented using liquid chromatography tandem mass spectrometry (LC-MS/MS). The sGAG content, PAGE, and QconCAT proteomics analysis showed significant variation between each of the six patient samples. The quantitative proteomics indicated that the majority of the protein content was composed of various fibrillar collagen components. Also, quantification of difficult to remove cellular proteins represented less than 1% of total protein content, which is very low for a decellularized biomaterial. Global proteomics identified over 200 distinct proteins present in the human cardiac ECM. In conclusion, quantification and characterization of human myocardial ECM showed significant patient-to-patient variability between the six investigated patients. This is an important outcome for the development of allogeneic derived biomaterials and for increasing our understanding of human myocardial ECM composition. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    PROTEOMICS - CLINICAL APPLICATIONS 07/2015; DOI:10.1002/prca.201500048 · 2.96 Impact Factor
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    • "It is also possible that the therapeutic potential of these cells in the acute infarct will be enhanced after co-injection with matrix proteins that are representative of the 4 week time point. Earlier work demonstrated that the injection of decellularized porcine ventricular ECM promoted angiogenesis via enhanced arteriole formation [32], and we believe the co-injection of matrix and MSCs will only further enhance this therapeutic strategy. "
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    ABSTRACT: While stem cell therapy is a promising treatment for myocardial infarction, the minimal functional improvements observed clinically limit its widespread application. There is a need to maximize the therapeutic potential of these stem cells by first understanding what factors within the infarct microenvironment impact their ability to regenerate the necrotic tissue. In this study we assessed both differentiation capacity and paracrine signaling as a function of extracellular matrix remodeling following myocardial infarction. Mechanical and compositional changes to the decellularized infarcted myocardium were characterized to understand how the extracellular environment, specifically, was altered as a function of time following coronary artery ligation in Sprague-Dawley rats. These alterations were first modeled in a polyacrylamide gel system to understand how the variables of composition and stiffness drive mesenchymal stem cell differentiation towards a cardiac lineage. Lastly, the paracrine secretome was characterized as a function of matrix remodeling through gene and protein expression and conditioned media studies. The decellularized infarct tissue revealed significant alterations in both the mechanical and compositional properties of the ECM with remodeling time post-MI. This altered microenvironment dynamically regulates the potential for early cardiac differentiation. While Nkx2.5 expression is limited in the presence of chronically remodeled matrix of increased stiffness, GATA4 expression is enhanced. In addition, the remodeled matrix promotes the expression of several pro-angiogenic, pro-survival, anti-fibrotic and immunomodulatory growth factors. In particular, an increase in HGF and SDF1 expression and secretion by mesenchymal stem cells can rescue oxidatively stressed cardiomyocytes in vitro. This study demonstrated that decellularization of diseased tissue allows for the exclusive analysis of the remodeled matrix and its ability to significantly influence the cellular phenotype. Characterization of cell fate as a function of myocardial remodeling following infarction is critical in developing the ideal strategy for cell implantation to maximize tissue regeneration and ultimately reduce the prevalence and severity of heart failure.
    Stem Cell Research & Therapy 01/2014; 5(1):14. DOI:10.1186/scrt403 · 3.37 Impact Factor
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    • "However, SHG signal intensity on a per pixel basis also increased over time, possibly as a result of increased fibril size and organization within fiber bundles [45]. In initial experiments, it was found that 1% SDS, which is standard for adult hearts [30] [33] [34], was too harsh on fetal hearts and nearly fully solubilized the tissue. Given the findings from SHG microscopy indicating that the ECM fibers were smaller and the collagen matrix was less dense, this was not surprising. "
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    ABSTRACT: A major limitation to cardiac tissue engineering and regenerative medicine strategies is the lack of proliferation of postnatal cardiomyocytes. The extracellular matrix (ECM) is altered during heart development, and studies suggest that it plays an important role in regulating myocyte proliferation. Here, the effects of fetal, neonatal and adult cardiac ECM on the expansion of neonatal rat ventricular cells in vitro are studied. At 24 h, overall cell attachment was lowest on fetal ECM; however, ∼80% of the cells were cardiomyocytes, while many non-myocytes attached to older ECM and poly-l-lysine controls. After 5 days, the cardiomyocyte population remained highest on fetal ECM, with a 4-fold increase in number. Significantly more cardiomyocytes stained positively for the mitotic marker phospho-histone H3 on fetal ECM compared with other substrates at 5 days, suggesting that proliferation may be a major mechanism of cardiomyocyte expansion on young ECM. Further study of the beneficial properties of early developmental aged cardiac ECM could advance the design of novel biomaterials aimed at promoting cardiac regeneration.
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