Injectable hydrogel properties influence infarct expansion and extent of postinfarction left ventricular remodeling in an ovine model

A recent trend has emerged that involves myocardial injection of biomaterials, containing cells or acellular, following myocardial infarction (MI) to influence the remodeling response through both biological and mechanical effects. Despite the number of different materials injected in these approaches, there has been little investigation into the importance of material properties on therapeutic outcomes. This work focuses on the investigation of injectable hyaluronic acid (MeHA) hydrogels that have tunable mechanics and gelation behavior. Specifically, two MeHA formulations that exhibit similar degradation and tissue distribution upon injection but have differential moduli (~8 versus ~43 kPa) were injected into a clinically relevant ovine MI model to evaluate the associated salutary effect of intramyocardial hydrogel injection on the remodeling response based on hydrogel mechanics. Treatment with both hydrogels significantly increased the wall thickness in the apex and basilar infarct regions compared with the control infarct. However, only the higher-modulus (MeHA High) treatment group had a statistically smaller infarct area compared with the control infarct group. Moreover, reductions in normalized end-diastolic and end-systolic volumes were observed for the MeHA High group. This group also tended to have better functional outcomes (cardiac output and ejection fraction) than the low-modulus (MeHA Low) and control infarct groups. This study provides fundamental information that can be used in the rational design of therapeutic materials for treatment of MI.

[1]  Maythem Saeed,et al.  Restoration of left ventricular geometry and improvement of left ventricular function in a rodent model of chronic ischemic cardiomyopathy. , 2009, The Journal of thoracic and cardiovascular surgery.

[2]  T. Miura,et al.  Limitation of myocardial infarct size in the clinical setting: current status and challenges in translating animal experiments into clinical therapy , 2008, Basic Research in Cardiology.

[3]  J. B. Garrison,et al.  Regional cardiac dilatation after acute myocardial infarction: recognition by two-dimensional echocardiography. , 1979, The New England journal of medicine.

[4]  T. Guy,et al.  Infarct restraint attenuates remodeling and reduces chronic ischemic mitral regurgitation after postero-lateral infarction. , 2002, The Annals of thoracic surgery.

[5]  Smadar Cohen,et al.  Effect of Injectable Alginate Implant on Cardiac Remodeling and Function After Recent and Old Infarcts in Rat , 2008, Circulation.

[6]  J. Bavaria,et al.  Large animal model of left ventricular aneurysm. , 1989, The Annals of thoracic surgery.

[7]  James J Pilla,et al.  Theoretic impact of infarct compliance on left ventricular function. , 2009, The Annals of thoracic surgery.

[8]  J. Pilla,et al.  Early postinfarction ventricular restraint improves borderzone wall thickening dynamics during remodeling. , 2005, The Annals of thoracic surgery.

[9]  J. Weiss,et al.  Early dilation of the infarcted segment in acute transmural myocardial infarction: role of infarct expansion in acute left ventricular enlargement. , 1984, Journal of the American College of Cardiology.

[10]  I. Palacios,et al.  Impact of Time of Presentation on the Care and Outcomes of Acute Myocardial Infarction , 2008, Circulation.

[11]  Richard T. Lee,et al.  Local myocardial insulin-like growth factor 1 (IGF-1) delivery with biotinylated peptide nanofibers improves cell therapy for myocardial infarction. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Randall J Lee,et al.  Fibrin glue alone and skeletal myoblasts in a fibrin scaffold preserve cardiac function after myocardial infarction. , 2004, Tissue engineering.

[13]  Robert C Gorman,et al.  Border zone geometry increases wall stress after myocardial infarction: contrast echocardiographic assessment. , 2003, American journal of physiology. Heart and circulatory physiology.

[14]  R. Kloner,et al.  New Insights Into the Open Artery Hypothesis , 2008, Circulation research.

[15]  J. Gorman,et al.  Early ventricular restraint after myocardial infarction: extent of the wrap determines the outcome of remodeling. , 2005, The Annals of thoracic surgery.

[16]  Christine N. Koval,et al.  Targeted myocardial microinjections of a biocomposite material reduces infarct expansion in pigs. , 2008, The Annals of thoracic surgery.

[17]  Stuart S Berr,et al.  MR tagging early after myocardial infarction in mice demonstrates contractile dysfunction in adjacent and remote regions , 2002, Magnetic resonance in medicine.

[18]  J. Hochman,et al.  Limitation of myocardial infarct expansion by reperfusion independent of myocardial salvage. , 1987, Circulation.

[19]  Smadar Cohen,et al.  Intracoronary injection of in situ forming alginate hydrogel reverses left ventricular remodeling after myocardial infarction in Swine. , 2009, Journal of the American College of Cardiology.

[20]  Robert C Gorman,et al.  Extension of borderzone myocardium in postinfarction dilated cardiomyopathy. , 2002, Journal of the American College of Cardiology.

[21]  I. Palacios,et al.  Get with the guidelines steering committee and investigators. Impact of time of presentation on the care and outcome of acute myocardial infarction , 2008 .

[22]  H. Weisman,et al.  Myocardial infarct expansion, infarct extension, and reinfarction: pathophysiologic concepts. , 1987, Progress in cardiovascular diseases.

[23]  Robert C Gorman,et al.  The potential role of ventricular compressive therapy. , 2004, The Surgical clinics of North America.

[24]  J. Gorman,et al.  Dermal filler injection: a novel approach for limiting infarct expansion. , 2009, The Annals of thoracic surgery.

[25]  J. Pilla,et al.  Infarct Size Reduction and Attenuation of Global Left Ventricular Remodeling with the CorCapTM Cardiac Support Device Following Acute Myocardial Infarction in Sheep , 2005, Heart Failure Reviews.

[26]  T BITTER,et al.  A modified uronic acid carbazole reaction. , 1962, Analytical biochemistry.

[27]  Loren E Wold,et al.  Thickening of the infarcted wall by collagen injection improves left ventricular function in rats: a novel approach to preserve cardiac function after myocardial infarction. , 2005, Journal of the American College of Cardiology.

[28]  M. Marber,et al.  Restraining infarct expansion preserves left ventricular geometry and function after acute anteroapical infarction. , 1999, Circulation.

[29]  D. Mann,et al.  Mechanisms and models in heart failure: A combinatorial approach. , 1999, Circulation.

[30]  L Axel,et al.  Regional differences in function within noninfarcted myocardium during left ventricular remodeling. , 1993, Circulation.

[31]  R. Bonow,et al.  Chronic heart failure in the United States: a manifestation of coronary artery disease. , 1998, Circulation.

[32]  Jennifer M. Singelyn,et al.  Naturally derived myocardial matrix as an injectable scaffold for cardiac tissue engineering. , 2009, Biomaterials.

[33]  Theo Kofidis,et al.  Novel Injectable Bioartificial Tissue Facilitates Targeted, Less Invasive, Large-Scale Tissue Restoration on the Beating Heart After Myocardial Injury , 2005, Circulation.

[34]  D. Bogen,et al.  Restraining infarct expansion preserves left ventricular geometry and function after acute anteroapical infarction. , 1999, Circulation.

[35]  Peter Zilla,et al.  A synthetic non-degradable polyethylene glycol hydrogel retards adverse post-infarct left ventricular remodeling. , 2009, Journal of cardiac failure.

[36]  J. Weiss,et al.  Impaired thickening of nonischemic myocardium during acute regional ischemia in the dog. , 1985, Circulation.

[37]  Randall J Lee,et al.  Injectable fibrin scaffold improves cell transplant survival, reduces infarct expansion, and induces neovasculature formation in ischemic myocardium. , 2004, Journal of the American College of Cardiology.

[38]  Samuel T Wall,et al.  Theoretical Impact of the Injection of Material Into the Myocardium: A Finite Element Model Simulation , 2006, Circulation.

[39]  Robert Langer,et al.  Controlled degradation and mechanical behavior of photopolymerized hyaluronic acid networks. , 2005, Biomacromolecules.

[40]  K. Tobita,et al.  Synthesis, characterization and therapeutic efficacy of a biodegradable, thermoresponsive hydrogel designed for application in chronic infarcted myocardium. , 2009, Biomaterials.