Dual delivery of VEGF and ANG-1 in ischemic hearts using an injectable hydrogel.

Acute myocardial infarction (MI) caused by ischemia is the most common cause of cardiac dysfunction. While growth factor therapy is promising, the retention in the highly vascularized myocardium is limited and prevents sustained activation needed for adequate cellular responses. Here, we demonstrated the use of polyethylene glycol-fibrinogen (PF) hydrogels for sustained dual delivery of vascular endothelial growth factor (VEGF) and angiopoietin-1 (ANG-1) to enhance myocardial repair and function. VEGF and ANG-1 were incorporated in PF hydrogels and their in vitro characteristics were studied. Acute MI was generated in a rodent model with rats randomly assigned to 4 groups; sham, saline, PF and PF-VEGF-ANG1 (n=10 each group). Saline or hydrogel was injected in infarct and peri-infarct areas of the myocardium. After 4weeks, myocardial function was assessed using echocardiography. Tissue samples were harvested for Hematoxylin and Eosin, Masson Trichrome and capillary staining to assess the extent of fibrotic scar and arteriogenesis. Both VEGF and ANG-1 were released in a sustained and controlled manner over 30days. PF-VEGF-ANG1 treated animals showed the best improvement in cardiac function, highest degree of cardiac muscle preservation, and arteriogenesis. This study demonstrates that PF hydrogels can simultaneously provide mechanical support to attenuate adverse myocardial remodelling, and a pro-angiogenic benefit from the sustained VEGF and ANG1 delivery that culminates in a restorative effect following MI. The utility of this synergistic, biomaterial-based growth factor delivery may have clinical implications in the prevention of post-MI cardiac dysfunction. STATEMENT OF SIGNIFICANCE: Acute myocardial infarction (MI) caused by ischemia is the most common cause of cardiac dysfunction. Here, we demonstrated the use of polyethylene glycol-fibrinogen (PF) hydrogels for sustained dual delivery of vascular endothelial growth factor (VEGF) and angiopoietin-1 (ANG-1) to enhance myocardial repair and function. Treated animals showed the best improvement in cardiac function, highest degree of cardiac muscle preservation, and arteriogenesis. This study demonstrates that PF hydrogels can simultaneously provide mechanical support to attenuate adverse myocardial remodelling, and a pro-angiogenic benefit from the sustained VEGF and ANG1 delivery that culminates in a restorative effect following MI.

Feasibility of transapical cardioscopic surgery in a pig model.

BACKGROUND AND AIM: We introduced a cardioscopic surgical platform for a wide range of cardiac procedures, to address various intracardiac pathologies, through the left ventricular (LV) apex on the arrested heart. The method involves endoscopic access into the LV cavity; hence the term "transapical cardioscopic surgery (TACS)." METHODS: For this proof-of-concept study, we obtained transapical access to the left ventricle in five pigs. A right minithoracotomy was used for cannulation and cardiopulmonary bypass A purse string-secured incision at the apex allows for introduction of a self-made intracavitary expander, 5 mm steerable-tip endoscopic camera as well as 5 and 3 mm endoscopic instruments. RESULTS: The trans-apical approach provided a good exposure and an adequate surgical field, which allowed us to perform mitral valve repair, mitral valve replacement, and aortic valve replacement. This approach also enabled excellent access and visualization for atrial ablation and intra-aortic procedures. All animals were rewarmed and weaned off bypass. CONCLUSIONS: The proposed transapical cardioscopic platform is feasible for major intra-cardiac procedures.

The effect of matrix stiffness of injectable hydrogels on the preservation of cardiac function after a heart attack.

This study compares the effect of four injectable hydrogels with different mechanical properties on the post-myocardial infarction left ventricle (LV) remodeling process. The bioactive hydrogels were synthesized from Tetronic-fibrinogen (TF) and PEG-fibrinogen (PF) conjugates; each hydrogel was supplemented with two levels of additional cross-linker to increase the matrix stiffness as measured by the shear storage modulus (G'). Infarcts created by ligating the left anterior descending coronary artery in a rodent model were treated with the hydrogels, and all four treatment groups showed an increase in wall thickness, arterial density, and viable cardiac tissue in the peri-infarct areas of the LV. Echocardiography and hemodynamics data of the PF/TF treated groups showed significant improvement of heart function associated with the attenuated effects of the remodeling process. Multi-factorial regression analysis indicated that the group with the highest modulus exhibited the best rescue of heart function and highest neovascularization. The results of this study demonstrate that multiple properties of an injectable bioactive biomaterial, and notably the matrix stiffness, provide the multifaceted stimulation necessary to preserve cardiac function and prevent adverse remodeling following a heart attack.

Enhanced infarct stabilization and neovascularization mediated by VEGF-loaded PEGylated fibrinogen hydrogel in a rodent myocardial infarction model.

Most tissue engineering therapies require biomaterials that are able to induce an angiogenic response to support tissue regeneration. In addition angiogenic growth factor signaling plays an essential role in controlling the process of angiogenesis and matrices have the potential of regulating the concentration of growth factors within the cellular microenvironment. Here we demonstrated myocardial protection and improved post-infarct vascularization of the infarcted hearts using a biosynthetic injectable hydrogel consisting of polyethylene glycol and fibrinogen (PEG-fibrinogen) loaded with vascular endothelial growth factor-A (VEGF-A). Our data revealed PEG-fibrinogen hydrogel was able to store and release VEGF-A in a sustained and controlled fashion. Upon injection after coronary artery ligation, the VEGF-loaded hydrogel significantly improved arteriogenesis and cardiac performance at 4 weeks post-infarction. The results support the future application of PEG-fibrinogen for regulating growth factor signaling in cellular microenvironment and may demonstrates a new strategy for cardiovascular repair with potential for future clinical applications.