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Experimental Study Of Acute Myocardial Infarction Treated By Needleless Jetting Two Growth Factors Controlled-Release Alginate Hydrogel

Posted on:2012-12-12Degree:DoctorType:Dissertation
Country:ChinaCandidate:Z Y ZhouFull Text:PDF
GTID:1114330335487151Subject:Internal Medicine
Abstract/Summary:PDF Full Text Request
Ischemic heart disease is a common disease which threatens human health. Although percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) can be performed successfully in most lesions, several difficult complex lesions continue to present unique technical challenges.Therefore, new treatments are being looked for continuously, such as transmyocardial laser revasculariazation(TMLR), cytokines treatment, gene therapy, stem cell therapy etc. TMLR has been accepted because of intractable angina pectoris relief and quality of life improvement. Thus, its clinical application was approved in 1998 by the U.S. FDA. But, it can't avoid myocardium thermal injury which is unfavorable for myocardial revascularization, patent channels and survival rate improvement. To solve the problems, we hypothesized that using needle-free injector could create transventricular channels which can avoid thermal injury by laser. When creating channels, soluble biogel were jetted into channels to avoid channels getting close during recovery stage. With the degradation of gel, VEGF and PDGF were slowly released which may promote endothelial cells and smooth muscle cells to migrate to inner walls of channels. Therefore, patent channels were realized and ischemic myocardium could be perfused directly by intraventricular oxygenated blood.Left ventricular remodeling and heart failure after myocardial infarction is often associated with excessive damage of the cardiac extracellular matrix (ECM). Several recent reports have suggested that direct injection of biomaterials such as fibrin, collagen, and selfassembling peptide into the infarct zone could replace the damaged ECM and prevent left ventricular (LV) remodeling and heart failure. Alginate, a polysaccharide found in brown seaweed, has been used extensively in the field of drug delivery systems and tissue engineering. Its combination with divalent cations can be formed into three-dimensional scaffolds structure with a certain viscosity and mechanical strength. It is biocompatible, non-toxic and biodegradable, in the form of crosslinked hydrogel, and has a structure similar to that of ECM. Therefore, we hypothesized that needleless jetting two growth factor alginate gel in the infarct zone and the infarct border zone could improve left ventricular remodeling and heart function after myocardial infarction.To summary, needleless jetting alginate hydrogel incorporated with two growth factors could induce patent channels and improve left ventricular remolding, which may improve heart function. Therefore, the results of this study may provide a new strategy for ischemic heart disease.The study included the following three parts.PARTⅠ: Preparation and detection of two growth factors controlled-release alginate hydrogel carrierObjective The aim of this study was to prepare two growth factors controlled-release alginate hydrogel carrier and detect their characteristics. Methods Sodium alginate were modified though oxidization and cobalt-60 source irradiation. Two growth factors controlled-release alginate hydrogel carrier were prepared. After alginate modification and gelling process, gels were incubated in 1.0 ml PBS at 37°C. Gel degradation behaviour was monitored by measuring the dry weight loss over time and degradation curve was obtained. 100μl two growth factors alginate hydrogel was jetted into the myocardium of 18 rabbits using needle-free injector. Myocardium was received over time point and were stained with hematoxylin and eosin. Gel degradation in vivo were obtained. Cytotoxicity of gels was measured by MTT assay. Results Two growth factors controlled-release alginate hydrogels exhibited a relatively rapid degradation in vitro; In the first week, approximately 50% of the initial gel mass was lost. After 3 weeks, approximately 100% of the initial gel mass was lost. Following injection in vivo, gels were decreased gradually. No gel fragments were found in histological sections 5 weeks after delivery. For gels, there was no significant effect to cytoactive. Conclusion Two growth factors controlled-release alginate hydrogel carrier were successfully prepared with satisfied delegation and safety, which can supply following experiment.PARTⅡ: Channel effects of needleless jetting alginate hydrogels with two growth factorsObjective The aim of this study was to investigate channel effects of needleless jetting alginate hydrogels with two growth factors. Methods Alginate hydrogel incorporated with two growth factors(vascular endothelial growth factor and platelet-derived growth factor) were prepared. 22 rabbits were randomly assigned into three groups after myocardial infarction models were prepared. Alginate hydrogels incorporated with two growth factors were given to gel + growth factors group (n=8). Alginate hydrogels were given to gel group (n=8). Normal saline was given to saline group (n=6). Ultrasound diagnostic equipment was used to monitor the progress of needless jetting. Eight weeks after procedure, contrast echocardiography was used to detect patent channel. Myocardial histological sections were stained with HE stain and Masson stain. Results White pasty gels were viewed in channels. Jetting progress was monitored by ultrasound diagnostic equipment. Contrast echocardiography demonstrated that patent channels in gel + growth factors group were perfused by ultrasound contrast agent. There were no ultrasound contrast agent perfusing in the other two groups. HE stain showed patent channels were observed in gel + growth factors group, while no patent channels were observed in the other two groups. Masson stain showed there was much blue collagen fiber around the channels in gel + growth factors group and much lumen was left in the channels, while the channels in the other two groups had been filled by fibers. Conclusion Needleless jetting alginate hydrogel incorporated with two growth factors could induce patent channels. Ishemic myocardium can be perfused directly by intraventricular oxygenated blood through patent channels.PARTⅢ: Effect of needleless jetting two growth factors controlled-release alginate hydrogel on cardiac remodeling and function after myocardial infarctionObjective The aim of this study was to investigate whether needleless jetting two growth factors controlled-release alginate hydrogel can improve left ventricular remodeling and cardiac function after myocardial infarction. Methods After myocardial infarction models were prepared, 40 rabbits were randomly assigned into five groups: saline group, gel group, VEGF-A165 gel group, PDGF-BB gel group and two growth factors gel group. 8 weeks after procedure, morphological analysis was processed by measuring average scar thickness. Cardiac function was evaluated by echocardiography. The expression of CD34 andα-SMA was detected using immunohistochemistry(IHC). Results Results of morphological analysis showed that the average scar thickness of gel group, VEGF-A165 gel group, PDGF-BB gel group and two growth factors gel group was significantly thicker than the average scar thickness of saline group (P<0.05). The cardiac function was improved significantly in two growth factors gel group(P<0.05). The results of immunohistochemistry showed density of microvessels and small arteries was increased in VEGF-A165 gel group, PDGF-BB gel group and two growth factors gel group, while the most obvious in two growth factors gel group (P<0.05). Conclusion Needleless jetting two growth factors controlled-release alginate hydrogel can improve left ventricular remodeling and cardiac function after myocardial infarction and increase the density of myocardial vessels, which may provide a new strategy for the treatment of ischemic heart disease.
Keywords/Search Tags:Needleless jetting, Controlled-release, Growth factors, Alginate hydrogel, Myocardial infarction
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