【作者】 吕丰；

【导师】 刘天军；

【作者基本信息】 中国协和医科大学 ， 生物医学工程， 2008， 博士

【摘要】 透室壁性心肌血运重建术(TMR)是近些年发展起来的一项新型外科技术,主要用于治疗冠状动脉旁路移植术(CABG)或经皮腔内冠状动脉成型术(PTCA)不适应症的晚期心绞痛患者,其减轻心绞痛、提高缺血心肌灌注、改善心功能的作用已得到广泛关注。但是TMR术后短时间内,心肌管道便因凝血而闭塞,原始的心肌管道本身并不能对心肌直接供血。将心肌打孔血运重建术和支架置入方法结合起来,在缺血心肌区域进行阵列式打孔,产生多个直通心腔的隧道,置入支架后可以阻止心肌孔道自行闭合,将会增进血流灌注效果。细胞生长因子能够诱发缺血心肌的血管形成、建立侧枝循环、刺激血管再生,细胞生长因子血管再生治疗法已被用于心肌缺血性疾病的治疗,改善组织血液灌流。TMR术结合细胞生长因子血管再生法治疗冠心病等缺血性心脏病在实验研究和临床试验方面取得较好的结果,它能够提高局部心肌灌注效果,促进动脉血管生成,有助于局部心肌功能的修复。但是生长因子在血液循环中的半衰期很短,而且靶向定位差,难以发挥长久的、持续的促血管生成作用,另外,由于肝素与细胞生长因子有很高的亲和性,它能提高细胞生长因子生物活性、延长其半衰期,还有助于凝血现象的抑制。因此能够缓控释细胞生长因子类药物的肝素改性支架可以应用到透室壁性心肌血管重建术中,它不仅能阻止TMR后孔道自行闭合,又能够防止血栓形成,还可促进孔壁生成血管内皮,使之最终成为与壁间微细结构相交通的“血管”,补偿冠状动脉的供血不足,提高血运重建效果。由于心肌支架研究较少,其它用途的支架也不能完全满足于心肌血运重建的需要,而且释放的药物也有较大的差别,因此应该针对心肌血运重建的需要进行专门设计。本文对心肌内生物可降解性复合缓释支架进行深入研究,以生物可降解聚合物聚已内酯(PCL)、聚乳酸-羟基乙酸共聚物(PLGA)为支架材料,采用静电纺丝法、溶液浇注-溶剂挥发法、熔融挤出成型法等多种方式对支架制备方式进行优化;通过对PLGA药物缓释系统进行研究,分别制备了药物载体嵌入式PCL/PLGA复合支架和药物载体层支架结构层双层结构复合的PCL/PLGA药物支架,对支架结构组成与性能的关系,药物释放动力学等进行了测定和表征;为了制备抗凝血支架材料,通过化学键共价结合方式制备了肝素改性PLGA薄膜,对其结构进行了确证和分析,并测定了薄膜表面亲疏水性能及抗凝血性能;最后综合利用支架制备方式、药物缓释层、抗凝血材料制备等方面结果,制备透室壁性心肌血运重建生物可降解性药物缓释支架进行动物实验评价,通过心肌新生血管密度分析、组织化学染色分析、心功能的超声学评价和心肌灌注核素显像等手段研究生物可降解性药物缓释支架在促进血管再生以及心肌血流灌注方面的效果。实验结果表明,通过熔融挤出成型法制备的PCL支架结构层可以承受心肌压力,保持心肌孔道通畅;PCL/PLGA复合支架不仅阻止心肌孔道闭合,而且可以缓慢释放药物进行治疗;肝素修饰PLGA薄膜可以赋予支架一定的抗凝血性能;动物实验结果肯定了支架结合TMR作用后对心肌功能改善的效果,初步结果表明药物支架与TMR的结合有助于局部缺血心肌功能的改善,能够保持孔道的长期开放,显著增加新生血管密度,改善血流灌注和局部心肌收缩功能,促进心肌血运重建。本文研究的透心室壁生物可降解性药物支架不仅能阻止心肌自行闭合,又能够防止血栓形成,还可促进孔壁生成血管内皮,将是对透室壁性心肌血运重建术的优化,在心肌缺血性疾病的治疗中发挥一定的作用,为真正意义上的全心肌血运重建提供必要的基础条件。另外,该支架研究还可拓展到血管、胆管、食道、尿道等其它腔道内支架方面的应用,优化治疗效果。更多还原

【Abstract】 Transmyocardial revascularization (TMR) is a popular novel surgical treatment recently for patients with severe chronic stable angina that is refractory to coronary artery bypass graft surgery (CABG) or percutaneous transluminal coronary angioplasty (PTCA). It is paid great attention that TMR can reduce the symptoms of angina and the occurrence of ischemia, promote blood perfusion and improve heart function. But the myocardial channels are closed soon after the TMR procedure because of blood clotting. The initial channels cannot remain long-term channel patency and there is little direct blood flow through channels created. The combinations of stent and TMR are applied by arraying drilling in ischemia myocardium and putting the stent into the transmyocardial channel. Thus, they can keep long-term channels patency to improve myocardial perfusion.Angiogenic growth factor can induce angiopoiesis throughout the ischemic tissue, build collateral circulation and stimulate blood vessel growth. Therapeutic angiogenesis of growth factor have been applied to treat the ischemic heart disease and improve blood perfusion of tissue. The strategies of combining TMR with therapeutic angiogenesis augment desired experimental and clinical effects on the therapy of ischemic heart disease. They are available to recovery the region myocardial function by promoting blood perfusion and improve the formation of arterial blood. Because of the short half-life and poor target location of the growth factors, they cannot improve angiogenesis for long time continuously. Additionally, heparin has good affinity with cells and some ability of inhibiting the blood coagulation. It can enhance the biological activity and the half-life of growth factors. So the application of heparin modified stents in TMR channel can not only avoid the occlusion of TMR channels but also prevent the thrombosis and improve the formation of blood vessel endothelium to build the blood vessel linked with fine structure of endothelium. The approach can compensate the deficient of blood supplement and enhance the effect of myocardial revascularization.Up to now, there is few report about the transmyocardial stent. Other stents cannot satisfy the need of myocardial revascularization and carry the protein drugs, therefore the transmyocardial stent need to be devised especially. In this paper, the transmyocardial biodegradable drug delivery stents were studied. The stents were prepared using poly (ε-caprolactone)(PCL) and poly (D, L-lactide-co-glycolide) (PLGA) as the materials of stents by electrospinning, solution spraying or melting extrusion. The drug delivery system of PLGA was discussed. The PCL/PLGA drug delivery stents were developed by the method of embedding or compounding bilayered materials. The relations of function and structure of stent were discussed. The kinetics of drug delivery were tested and analyzed. The anticoagulated blood films of heparin modified PLGA were prepared by covalent bonding and then were checked by structure analyses. The hydrophilicity and anticoagulant properties of film were evaluated. At last the transmyocardial biodegradable drug delivery stents were prepared by optimization of all above methods .The effects of biodegradable drug delivery stents in improving revascularization and blood perfusion were evaluated by analyses of new vessels densities, histochemical stain, echocardiography, and single photon emission computed tomography (SPECT). The results are shown as follows. The melting extrusion PCL stents can sustain the pressure of myocardial muscle and keep TMR channels patency. The PCL/PLGA stents cannot only avoid the TMR channels closed but also delivery drug for long time. The heparin modified PLGA film can afford the property of anticoagulated blood. The animal experiments show the therapeutic effects of combination stent with TMR in vivo. The experimental results show the drug stents can recovery partly the function of ischemia cardiac muscle, keep TMR channels patency for a long time, enhance the densities of new vessels, improve blood perfusion and heart contraction, and encourage myocardial revascularization.Transmyocardial biodegradable drug delivery stents can not only avoid the occlusion of myocardium channel but also prevent the thrombosis and improve the formation of blood vessel endothelium. The application of the stent will be an opinion method of TMR. It can produce a marked effect in the therapy of ischemia heart disease and afford the necessary basis to fully myocardial revascularization. Moreover, the stent can be extended to the application of other conduit stents such as blood vessel stent, bile duct stent, esophagus stent and urethra stent.更多还原