Injectable fibrin scaffold improves cell transplant survival, reduces infarct expansion, and induces neovasculature formation in ischemic myocardium.

OBJECTIVES: In this study, we determined whether fibrin glue improves cell transplant retention and survival, reduces infarct expansion, and induces neovasculature formation. BACKGROUND: Current efforts in restoring the myocardium after myocardial infarction (MI) include the delivery of viable cells to replace necrotic cardiomyocytes. Cellular transplantation techniques are, however, limited by transplanted cell retention and survival within the ischemic tissue. METHODS: The left coronary artery of rats was occluded for 17 min followed by reperfusion. One week later, bovine serum albumin (BSA), fibrin glue, skeletal myoblasts in BSA, or skeletal myoblasts in fibrin glue were injected into the infarcted area of the left ventricle. The animals were euthanized five weeks after injection, and their hearts were excised, fresh frozen, and sectioned for histology and immunohistochemistry. RESULTS: After five weeks, the mean area covered by skeletal myoblasts in fibrin glue was significantly greater than the area covered by myoblasts injected in BSA. Myoblasts within the infarct were often concentrated around arterioles. The infarct scar size and myoblasts in the fibrin group were significantly smaller than those in the control and BSA groups. Fibrin glue also significantly increased the arteriole density in the infarct scar as compared with the control group. CONCLUSIONS: This study indicates that fibrin glue increases cell transplant survival, decreases infarct size, and increases blood flow to ischemic myocardium. Therefore, fibrin glue may have potential as a biomaterial scaffold to improve cellular cardiomyoplasty treat and MIs.

Fibrin glue alone and skeletal myoblasts in a fibrin scaffold preserve cardiac function after myocardial infarction.

Current efforts in cardiac tissue engineering center around the use of scaffolds that deliver cells to the epicardial surface. In this study, we examined the effects of fibrin glue as an injectable scaffold and wall support in ischemic myocardium. The left coronary artery of rats was occluded for 17 min, followed by reperfusion. Echocardiography was performed 8 days after infarction. One to 2 days later, either 0.5% bovine serum albumin (BSA) in phosphate-buffered saline, fibrin glue alone, skeletal myoblasts alone, or skeletal myoblasts in fibrin glue were injected into the ischemic left ventricle. Echocardiography was again performed 5 weeks after injection. The animals were then sacrificed and the hearts were fresh frozen and sectioned for histology and immunohistochemistry. Both the fractional shortening (FS) and infarct wall thickness of the BSA group decreased significantly after 5 weeks (p = 0.0005 and 0.02, respectively). In contrast, both measurements for the fibrin glue group, cells group, and cells in fibrin glue group did not change significantly (FS: p = 0.18, 0.89, and 0.19, respectively; wall thickness: p = 0.40, 0.44, 0.43, respectively). Fibrin glue is capable of preserving infarct wall thickness and cardiac function after a myocardial infarction in rats and may be useful as a biomaterial scaffold for myocardial cell transplantation.

Pleiotrophin induces formation of functional neovasculature in vivo.

Pleiotrophin (PTN) is a heparin-binding growth/differentiation inducing cytokine that shares 50% amino acid sequence identity and striking domain homology with Midkine (MK), the only other member of the Ptn/Mk developmental gene family. The Ptn gene is expressed in sites of early vascular development in embryos and in healing wounds and its constitutive expression in many human tumors is associated with an angiogenic phenotype, suggesting that PTN has an important role in angiogenesis during development and in wound repair and advanced malignancies. To directly test whether PTN is angiogenic in vivo, we injected a plasmid to express PTN into ischemic myocardium in rats. Pleiotrophin stimulated statistically significant increases in both normal appearing new capillaries and arterioles each of which had readily detectable levels of the arteriole marker, smooth muscle cell alpha-actin. Furthermore, the newly formed blood vessels were shown to interconnect with the existent coronary vascular system. The results of these studies demonstrate directly that PTN is an effective angiogenic agent in vivo able to initiate new vessel formation that is both normal in appearance and function. The data suggest that PTN signals the more "complete" new blood vessel formation through its ability to stimulate different functions in different cell types not limited to the endothelial cell.