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.
Public Health Relevance Statement: Narrative 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.
Project Terms: Acute myocardial infarct; Acute myocardial infarction; After Care; After-Treatment; Aftercare; Alginates; Animals; Arteries; Attention; Biodistribution; Biologic Therapy; Biological Response Modifier Therapy; Biological Therapy; Biopolymers; Body Tissues; Bone Marrow; Cardiac; Cardiac infarction; Cardiovascular; Cardiovascular Body System; Cardiovascular system; Cardiovascular system (all sites); Catheters; Cell Communication and Signaling; Cell Signaling; Cell Survival; Cell Therapy; Cell Viability; Cells; Cerebrum; Characteristics; Chronic; Clinical; Colloids; Control Groups; Data; Detection; Development; Devices; Drug Formulations; Drug or chemical Tissue Distribution; EFRAC; Economic Inflation; Ejection Fraction; Electrical Impedance; Electrodes; Embolism; Embolus; Engineering; Engineerings; Ensure; Extravasation; Family suidae; Fibrin; Formulation; Formulations, Drug; Gastrointestinal Tract, Pancreas; Goals; Grafting, Heart; Heart; Heart Transplantation; Heart failure; Histopathology; Holter Electrocardiography; Holtmon; Hour; Image; Impedance; In Vitro; Infarction; Inflation; Injection of therapeutic agent; Injections; Injury; Intracellular Communication and Signaling; Label; Leakage; Left; Left Ventricles; Left ventricular structure; Literature; Liver; Lung; Mechanics; Method LOINC Axis 6; Methodology; Microbeads; Microspheres; Modeling; Monitor; Monitoring, Holter; Mononuclear; Mother Cells; Muscle, Cardiac; Muscle, Heart; Muscle, Skeletal; Muscle, Voluntary; Myocardial; Myocardial Infarct; Myocardial Infarction; Myocardium; Natural regeneration; Needles; Neutrons; Organ; Organ System, Cardiovascular; PET/CT; PET/CT scan; Pancreas; Pancreatic; Pathology; Pattern; Phase; Pigs; Polymers; Population; Preparation; Pressure; Pressure- physical agent; Procedures; Process; Progenitor Cells; Programs (PT); Programs [Publication Type]; Property; Property, LOINC Axis 2; Proteins; Protocol; Protocols documentation; Publishing; Radiolabeled; Reagent; Regeneration; Respiratory System, Lung; Reticuloendothelial System, Bone Marrow; Reticuloendothelial System, Spleen; Safety; Signal Transduction; Signal Transduction Systems; Signaling; Site; Skeletal Muscle Tissue; Skeletal muscle structure; Solid; Spillage; Spinal; Spleen; Stem cells; Suidae; Swine; System; System, LOINC Axis 4; Technology; Testing; Therapeutic; Therapy, Cell; Time; Tissue Distribution; Tissue Engineering; Tissue Sample; Tissues; Transplantation, Cardiac; Variant; Variation; Vascular, Heart; Ventricular; Viscosity; Work; base; biological signal transduction; biotherapeutics; biotherapy; body system, hepatic; brain tissue; cardiac failure; cardiac graft; cardiac infarct; cardiac muscle; cell-based therapy; circulatory system; coronary attack; coronary infarct; coronary infarction; electric impedance; engineered tissue; gene product; heart attack; heart function; heart infarct; heart infarction; heart muscle; heart transplant; imaging; improved; in vivo; infarct; meetings; migration; novel; novel therapeutic intervention; organ system, hepatic; polymerization; porcine; pressure; programs; prototype; public health relevance; pulmonary; radiolabel; radiotracer; regenerate; repair; repaired; safety study; suid
