Cell retention and biodistribution after transendocardial delivery in cardiovascu

描述(申请人提供)：概述在过去的几十年里，细胞移植疗法在心肌梗死和缺血性心力衰竭的组织再生和功能恢复方面显示出积极的有效性和相对安全性。然而，超过95%的细胞被注入冠状动脉，并且在分娩后成功地将治疗细胞保留在靶部位仍然是这种方法的主要缺点。BioCardia开发了一种基于螺旋针的导管技术，能够准确和可控地将各种可释放物注射到心肌中的目标部位，与直接基于针的直接或导管输送到心肌中的靶区相比，这在增加保留量方面具有很大的前景。本提案旨在通过证明与使用直针的直接手术输送相比，使用螺旋形针的导管介导的经心内膜输送在健康和心肌梗死后的猪模型中显示出高效的输送和更好的基于细胞的治疗药物的保留，从而推动细胞治疗领域的发展。本研究的目的是比较通过带螺旋尖端的BioCardia螺旋针尖经心内膜给药导管心肌内注射与使用直针直接心肌内注射时的细胞保留率和生物分布。如果观察到滞留增加，这将证明目前正在通过心外膜途径实施的基于细胞的治疗方法的未来经心内膜临床开发的合理性，以及在输送导管的远端具有螺旋尖端的更大价值。第二阶段将详细说明这些结果，包括一项大型药代动力学研究、一项长期安全性研究和一项使用自体骨髓单个核细胞的疗效研究。这将为进一步开发螺旋针导管与自体骨髓单个核细胞联合治疗奠定基础。研究设计与方法从猪骨髓中提纯自体单个核细胞，18F-FDG放射性标记，分别用BioCardia经心内膜螺旋针输送装置和开胸直针心外膜输送装置在健康和心肌梗死后的猪体内输送，以比较细胞滞留率。体内注射的18F-FDG-MNCs的生物分布将通过全身PET-CT扫描进行量化，心脏内的注射部位将在尸检后识别和验证。 公共卫生相关性：细胞移植是心力衰竭或心肌梗死后恢复心功能的新型心血管疗法的新兴策略之一。这项研究旨在改进目前的给药技术，包括使用直针给药，通过使用新型的心肌内螺旋针尖端导管增加细胞滞留。这项研究工作可能对极大地提高持续靶向和将细胞捕获到受损心脏内特定位置的治疗效果具有重要意义，并可能提供一种方法，以避免背部渗漏进入脑室，同时允许安全和有效地输送治疗药物，包括再生医学领域的细胞以及蛋白质、基因和其他药物。

DESCRIPTION (provided by applicant): Overview Over the past few decades, cell transplantation therapies have shown positive signs of efficacy and relative safety for tissue regeneration and functional recovery of myocardial infarction and ischemic heart failure. However, more than 95% of the cells infused in the coronary arteries are lost and successful retention of therapeutic cells in the target sites after delivery remains a major shortcoming to this approach. BioCardia has developed a helical needle-based catheter technology that enables accurate and controlled injection of various deliverables into targeted sites in the myocardium and that has great promise for increasing retention compared to straight needle-based direct or catheter delivery into target zones in the myocardium. Description The proposal here seeks to advance the field of cell therapy by demonstrating that compared to direct surgical delivery using straight needle, catheter-mediated transendocardial delivery using a helical shaped needle shows efficient delivery and superior retention of cell based therapeutics in healthy and post-myocardial infarction swine models. The objectives of this study are to compare cell retention rates and biodistribution when injected intramyocardially through BioCardia helical needle-tipped transendocardial delivery catheter with a helical tip versus when injected intramyocardially directly using a straight needle. If increased retention is observed, it will justify future transendocardial clinical development of cell based therapies that are currently being administered with a transepicardial approach and the increased value of having a helical tip at the distal end of the delivery catheter. A phase 2 will elaborate on these results to include a large pharmacokinetics study, a long term safety study and an efficacy study using autologous bone marrow mononuclear cells. This will lay the foundation for further clinical development of a combination treatment using the helical needle catheter and autologous bone marrow mononuclear cells. Research Design and Methods Autologous mononuclear cells will be purified from swine bone marrow, radiolabeled with 18F-FDG and delivered in healthy and post-myocardial infarction swines using both BioCardia transendocardial helical needle delivery device, and an open chest straight needle epicardial delivery process in order to compare cell retention rates. Biodistribution of the injected 18F-FDG-MNCs will be quantified by whole body PET-CT scan in vivo, and the injection sites within the heart will be identified and validated post necropsy. PUBLIC HEALTH RELEVANCE: Cell transplantation is one of the emerging strategies in novel cardiovascular therapies for restoring heart function in heart failure or after myocardial infarction. This research seeks to improve on the current delivery technologies which include delivery using a straight needle by increasing cell retention via their delivery using a novel intramyocardial helical needle tipped catheter. This research work could have critical implications in greatly improving the therapeutic effects of consistent targeting and trapping cells to specific sites within the injured heart and could provide a means to avoid back leak into the ventricular chamber while allowing for safe and efficient delivery of therapeutic agents including cells but also proteins, genes and other agents in the field of regenerative medicine.