Endomyocardial Catheter Delivery of Artificial Biopolymer Matrices for Enhanced C

心内膜心肌导管输送人工生物聚合物基质以增强 C

• 批准号: 7600670
• 负责人: Didier B Rouy
• 金额: $ 10万
• 依托单位: BIOCARDIA, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7600670
• 关键词: Acute myocardial infarction; Aftercare; Alginates; Animals; Arteries; Attention; Biodistribution; Biological Response Modifier Therapy; Biopolymers; Bone Marrow; Cardiac; Cardiovascular system; Catheters; Cell Survival; Cell Therapy; Cells; Cerebrum; Characteristics; Chronic; Clinical; Colloids; Control Groups; Data; Detection; Development; Devices; Drug Formulations; Drug or chemical Tissue Distribution; EFRAC; Economic Inflation; Electrodes; Embolism; Engineering; Ensure; Extravasation; Family suidae; Fibrin; Goals; Heart; Heart Transplantation; Heart failure; Histopathology; Holter Electrocardiography; Hour; Image; In Vitro; Infarction; Injection of therapeutic agent; Injury; Label; Left; Left ventricular structure; Literature; Liver; Lung; Mechanics; Methodology; Microspheres; Modeling; Monitor; Mononuclear; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Needles; Neutrons; Organ; PET/CT scan; Pancreas; Pathology; Pattern; Phase; Polymers; Population; Preparation; Procedures; Process; Property; Proteins; Protocols documentation; Publishing; Radiolabeled; Reagent; Safety; Signal Transduction; Site; Skeletal Muscle; Solid; Spinal; Spleen; Stem cells; System; Technology; Testing; Therapeutic; Time; Tissue Engineering; Tissue Sample; Tissues; Variant; Ventricular; Viscosity; Work; base; brain tissue; electric impedance; heart function; improved; in vivo; meetings; migration; novel; novel therapeutic intervention; polymerization; pressure; programs; prototype; public health relevance; radiotracer; repaired; safety study

DESCRIPTION (provided by applicant): In the literature to date, cardiac regeneration strategies using stem cells have repeatedly had inefficient cell retention in the target zone. Our group has developed a catheter based technology that enables accurate and controlled delivery of biopolymers, with or without cells, into target zones in the myocardium. Overall procedure: Commercially available alginate and fibrin two part biopolymers will be assessed for material properties (which may be modified to keep the viscosity below a threshold to passage through a microcatheter lumen and to provide for the greatest and most uniform mechanical integrity after delivery and polymerization). Selected formulations at specific volumes (0.1ml to 5ml) will be delivered through specific flow rates (0.1ml/min to 1ml/min) and into swine left ventricular tissues ex vivo while pressure is monitored. Post delivery, three dimensional distributions within tissues will be qualitatively analyzed using sectioning and imaging. Additional testing evaluating the inclusion of bone marrow derived mononuclear cells (MNC's) from swine for viability in single part reagents and through the polymerization process will also be performed in preparation for a preliminary large animal safety study. The large animal study will evaluate a single polymer formulation and delivery protocol for safety in a healthy swine. Five formulation deliveries incorporating one of five different 15 um neutron activated microsphere populations will enable the resulting distribution of each delivery to be assessed in vivo at each of the three time points at which the animals are sacrificed (1 hour, 1 day, and 7 days). Heart, lung, liver, spleen, skeletal muscle, and brain tissue samples will be collected to assess distributions. Safety will be assessed by holter monitoring, histopathology, and biodistribution studies. Perspectives: This study is intended to establish feasibility and preliminary safety for percutaneous transendocardial delivery of two part biopolymer matrices for enhancing cell a new multi-lumen catheter at retention in vivo in large animals this goal material property analysis, flow characteristics, local tissue distribution studies, and safety parameters will be assessed in detail. using a new multiple-lumen delivery catheter. To achieve further studies will assess the safety on infarcted myocardium and assess the good conditions to avoid embolism. PUBLIC HEALTH RELEVANCE: Existing strategies for restoring heart function after myocardial injury are practically limited to cardiac transplantation. Since the supply of donor hearts is limited, tissue engineering appears to be a promising approach for the formation of new functional tissue to replace lost or failing tissue. Novel therapeutic approaches using cell therapy that may contribute to grow new vessels and repair the cardiac tissue have shown great promise and are intuitively appealing. However, successful retention of therapeutic cells in the target tissue after delivery is an important challenge that remains in that up to 98% of the cells delivered in the heart are lost very soon after delivery. The proposal here seeks to improve cell retention by incorporating biopolymer tissue matrix strategies with catheter delivery technologies appropriate for routine clinical use, with a special focus on this strategy safety. The results of this work may prove critical to enabling cardiovascular tissue engineering strategies broadly, and should also have important implications for other local tissue engineering therapies.

描述（由申请人提供）：在迄今为止的文献中，使用干细胞的心脏再生策略反复在靶区中具有低效的细胞保留。我们的团队已经开发出一种基于导管的技术，该技术能够将生物聚合物（有或没有细胞）准确和受控地输送到心肌中的靶区。总体程序：将评估市售藻酸盐和纤维蛋白两部分生物聚合物的材料特性（可对其进行改性，以保持粘度低于通过微导管腔的阈值，并在输送和聚合后提供最大和最均匀的机械完整性）。特定体积（0.1 ml-5 ml）的选定制剂将通过特定流速（0.1 ml/min-1 ml/min）递送至离体猪左心室组织中，同时监测压力。输送后，将使用切片和成像对组织内的三维分布进行定性分析。在准备初步大型动物安全性研究时，还将进行额外的试验，以评价单组分试剂和聚合过程中猪骨髓源单核细胞（MNC）的活力。大型动物研究将评价单一聚合物制剂和递送方案在健康猪中的安全性。掺入五种不同的15 μ m中子活化微球群之一的五种制剂递送将使得能够在处死动物的三个时间点（1小时、1天和7天）中的每一个时间点在体内评估每种递送的所得分布。将采集心脏、肺、肝、脾、骨骼肌和脑组织样本以评估分布。将通过霍尔特监测、组织病理学和生物分布研究评估安全性。观点：本研究旨在确定经皮经血管内输送两部分生物聚合物基质的可行性和初步安全性，以增强大型动物体内保留的新型多腔导管的细胞，将详细评估该目标材料特性分析、流动特性、局部组织分布研究和安全性参数。使用新的多腔输送导管。为实现进一步的研究，将评估对梗死心肌的安全性，并评估避免栓塞的良好条件。公共卫生相关性：心肌损伤后恢复心脏功能的现有策略实际上仅限于心脏移植。由于供体心脏的供应是有限的，组织工程似乎是一个有前途的方法，形成新的功能组织，以取代失去或失败的组织。使用细胞疗法的新治疗方法可能有助于生长新血管和修复心脏组织，已经显示出巨大的前景，并且直观上具有吸引力。然而，在递送后将治疗性细胞成功保留在靶组织中是一个重要的挑战，因为在心脏中递送的高达98%的细胞在递送后很快就丢失了。该提案旨在通过将生物聚合物组织基质策略与适用于常规临床使用的导管输送技术相结合来改善细胞保留，特别关注该策略的安全性。这项工作的结果可能被证明是至关重要的，使心血管组织工程战略广泛，也应该有重要的影响，其他地方的组织工程治疗。