The effects of peptide-based modification of alginate on left ventricular remodeling and function after myocardial infarction
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.
- SourceAvailable from: Kimimasa Tobita[Show abstract] [Hide abstract]
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 · 8.31 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.Der Kardiologe 08/2009; 3(4):319-325. DOI:10.1007/s12181-009-0205-2
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ABSTRACT: This study sought to determine whether alginate biomaterial can be delivered effectively into the infarcted myocardium by intracoronary injection to prevent left ventricular (LV) remodeling early after myocardial infarction (MI). Although injectable biomaterials can improve infarct healing and repair, the feasibility and effectiveness of intracoronary injection have not been studied. We prepared a calcium cross-linked alginate solution that undergoes liquid to gel phase transition after deposition in infarcted myocardium. Anterior MI was induced in swine by transient balloon occlusion of left anterior descending coronary artery. At 4 days after MI, either alginate solution (2 or 4 ml) or saline was injected selectively into the infarct-related coronary artery. An additional group (n = 19) was treated with incremental volumes of biomaterial (1, 2, and 4 ml) or 2 ml saline and underwent serial echocardiography studies. Examination of hearts harvested after injection showed that the alginate crossed the infarcted leaky vessels and was deposited as hydrogel in the infarcted tissue. At 60 days, control swine experienced an increase in left ventricular (LV) diastolic area by 44%, LV systolic area by 45%, and LV mass by 35%. In contrast, intracoronary injection of alginate (2 and 4 ml) prevented and even reversed LV enlargement (p < 0.01). Post-mortem analysis showed that the biomaterial (2 ml) increased scar thickness by 53% compared with control (2.9 +/- 0.1 mm vs. 1.9 +/- 0.3 mm; p < 0.01) and was replaced by myofibroblasts and collagen. Intracoronary injection of alginate biomaterial is feasible, safe, and effective. Our findings suggest a new percutaneous intervention to improve infarct repair and prevent adverse remodeling after reperfused MI.Journal of the American College of Cardiology 09/2009; 54(11):1014-23. DOI:10.1016/j.jacc.2009.06.010 · 15.34 Impact Factor