The effects of peptide-based modification of alginate on left ventricular remodeling and function after myocardial infarction

Department of Biotechnology Engineering, Ben-Gurion University of Negev, Beer Sheva, Israel.
Biomaterials (Impact Factor: 8.56). 11/2008; 30(2):189-95. DOI: 10.1016/j.biomaterials.2008.09.018
Source: PubMed

ABSTRACT Adverse cardiac remodeling and dysfunction after myocardial infarction (MI) is associated with (BioLineRx, BL-1040 myocardial implant) excessive damage to the extracellular matrix. Biomaterials, such as the in situ-forming alginate hydrogel, provide temporary support and attenuate these processes. Here, we tested the effects of decorating alginate biomaterial with cell adhesion peptides, containing the sequences RGD and YIGSR, or a non-specific peptide (RGE), in terms of therapeutic outcome soon after MI. The biomaterial (i.e., both unmodified and peptide-modified alginate) solutions retained the ability to flow after cross-linking with calcium ions, and could be injected into 7-day infarcts, where they underwent phase transition into hydrogels. Serial echocardiography studies performed before and 60 days after treatment showed that alginate modification with the peptides reduced the therapeutical effects of the hydrogel, as revealed by the extent of scar thickness, left ventricle dilatation and function. Histology and immunohistochemistry revealed no significant differences in blood vessel density, scar thickness, myofibroblast or macrophage infiltration or cell proliferation between the experimental groups BioLineRx BL-1040 myocardial implant. Our studies thus reveal that the chemical and physical traits of the biomaterial can affect its therapeutical efficacy in attenuating left ventricle remodeling and function, post-MI.

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    • "Compared with other materials, a major advantage of the injectable alginate biomaterial solution is its non-thrombogenicity. Tsur-Gang et al. [159] recently showed that a solution of calcium cross-linked alginate biomaterial with cell adhesion peptides, containing the sequences RGD and YIGSR, or a non-specific peptide (RGD), can be injected via a needle into the infarct, where it undergoes phase transition into hydrogel for left ventricular remodelling and function of post-MI. This alginate hydrogel implant provides temporary physical support to the damaged cardiac tissue by replacing some of the functions of damaged ECM while preventing adverse cardiac remodelling and dysfunction after recent and old MI in rat. "
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    ABSTRACT: World Health Organization estimated that heart failure initiated by coronary artery disease and myocardial infarction (MI) leads to 29 per cent of deaths worldwide. Heart failure is one of the leading causes of death in industrialized countries and is expected to become a global epidemic within the twenty-first century. MI, the main cause of heart failure, leads to a loss of cardiac tissue impairment of left ventricular function. The damaged left ventricle undergoes progressive 'remodelling' and chamber dilation, with myocyte slippage and fibroblast proliferation. Repair of diseased myocardium with in vitro-engineered cardiac muscle patch/injectable biopolymers with cells may become a viable option for heart failure patients. These events reflect an apparent lack of effective intrinsic mechanism for myocardial repair and regeneration. Motivated by the desire to develop minimally invasive procedures, the last 10 years observed growing efforts to develop injectable biomaterials with and without cells to treat cardiac failure. Biomaterials evaluated include alginate, fibrin, collagen, chitosan, self-assembling peptides, biopolymers and a range of synthetic hydrogels. The ultimate goal in therapeutic cardiac tissue engineering is to generate biocompatible, non-immunogenic heart muscle with morphological and functional properties similar to natural myocardium to repair MI. This review summarizes the properties of biomaterial substrates having sufficient mechanical stability, which stimulates the native collagen fibril structure for differentiating pluripotent stem cells and mesenchymal stem cells into cardiomyocytes for cardiac tissue engineering.
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    ABSTRACT: Injection of a bulking material into the ventricular wall has been proposed as a therapy to prevent progressive adverse remodeling due to high wall stresses that develop after myocardial infarction. Our objective was to design, synthesize and characterize a biodegradable, thermoresponsive hydrogel for this application based on copolymerization of N-isopropylacrylamide (NIPAAm), acrylic acid (AAc) and hydroxyethyl methacrylate-poly(trimethylene carbonate) (HEMAPTMC). By evaluating a range of monomer ratios, poly(NIPAAm-co-AAc-co-HEMAPTMC) at a feed ratio of 86/4/10 was shown to be ideal since it formed a hydrogel at 37 degrees C, and gradually became soluble over a 5 month period in vitro through hydrolytic cleavage of the PTMC residues. HEMAPTMC, copolymer and degradation product chemical structures were verified by NMR. No degradation product cytotoxicity was observed in vitro. In a rat chronic infarction model, the infarcted left ventricular (LV) wall was injected with the hydrogel or phosphate buffered saline (PBS). In the PBS group, LV cavity area increased and contractility decreased at 8 wk (p<0.05 versus pre-injection), while in the hydrogel group both parameters were preserved during this period. Tissue ingrowth was observed in the hydrogel injected area and a thicker LV wall and higher capillary density were found for the hydrogel versus PBS group. Smooth muscle cells with contractile phenotype were also identified in the hydrogel injected LV wall. The designed poly(NIPAAm-co-AAc-co-HEMAPTMC) hydrogel of this report may thus offer an attractive biomaterial-centered treatment option for ischemic cardiomyopathy.
    Biomaterials 05/2009; 30(26):4357-68. DOI:10.1016/j.biomaterials.2009.04.055 · 8.56 Impact Factor
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    ABSTRACT: Die Injektion von Biomaterialien nach Myokardinfarkt stellt ein neues Therapiekonzept dar, bei dem durch das Einbringen einer artifiziellen Matrix eine Verbesserung des ventrikulären Remodelings erzielt werden soll. Mehrere tierexperimentelle Studien ergaben, dass Infarktexpansion und Ventrikeldilatation im Vergleich zu einer Kontrollgruppe verringert und die Pumpfunktion durch die Injektion von Biomaterialien verbessert werden können. Basierend auf umfangreichen tierexperimentellen Daten, wurde kürzlich die erste klinische Phase-I-Studie zur Injektion eines Biomaterials begonnen. Bei dieser Studie wird Alginat verwendet, das in flüssigem Zustand intrakoronar injiziert und durch die erhöhte Kalziumkonzentration im Infarktgebiet in einen gelförmigen Zustand überführt wird. Bislang konnten keine Nebenwirkungen beobachtet werden. Vor einem Einsatz in der klinischen Routine muss der therapeutische Effekt der Alginatinjektion jedoch in kontrollierten klinischen Studien nachgewiesen werden. Sollten sich die vielversprechenden tierexperimentellen Daten in der Klinik bestätigen, könnte sich die Alginatinjektion zu einer wichtigen Therapieoption für Patienten mit akutem Myokardinfarkt entwickeln. The injection of biomaterials after myocardial infarction is a new therapeutic concept aimed at improving ventricular remodeling by implanting an artificial matrix. Several animal studies showed that infarct expansion and ventricular dilation can be reduced and function can be improved compared with controls. Based on the exciting experimental animal data, an initial clinical phase I trial was recently started. This trial uses alginate, which is injected in liquid form and transformed to a gel-like state by the high calcium concentration in the area of infarction. No side effects have been observed so far. Before alginate can be injected in clinical routine, the therapeutic effect must be confirmed in controlled clinical trials. If the promising data obtained in animal studies can be translated into a clinical setting, the injection of alginate after myocardial infarction may prove to be an important therapeutic option in patients with acute myocardial infarction.
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