Intracoronary device and method of use thereof

Abstract

Engraftment of therapeutic cells and agents to a target site in an organism is enhanced by mechanical, chemical and biological methods and systems.

1 . A method of enhancing engraftment of therapeutic cells at a target site in a mammal comprising conditioning the cells to provide cells having an altered number of adhesion molecules as compared to corresponding cells not subjected to the conditioning, wherein the conditioning increases the probability of engraftment of the cell at the target site; and delivering a composition comprising the conditioned therapeutic cells to the target site using an intracoronary delivery device.  
     
     
         2 . The method of  claim 1 , wherein the therapeutic cells comprise pluripotent or totipotent cells.  
     
     
         3 . The method of  claim 1 , wherein the therapeutic cells comprise autologous cells, non-autologous cells, or xenogenic cells.  
     
     
         4 . The method of  claim 1 , wherein the mammal is a human.  
     
     
         5 . The method of  claim 1 , wherein conditioning comprises biological conditioning, chemical conditioning, mechanical conditioning, or any combination thereof.  
     
     
         6 . The method of  claim 1 , wherein the adhesion molecule is CD44, P-selectin glycoprotein ligand-1 (PSGL-1; CD 162), hematopoietic cell E-/L-selectin ligand (HCELL), E-selectin ligand-1, Very Late Antigen-4 (VLA-4; CD49d), Leukocyte Function Associated Antigen-1 (LFA-1), an integrin, such as an α4 integrin or a β2 integrin, CD31, VE-Cadherin (CD144), PECAM (CD31), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule (ICAM)-1, a selectin such as P-Selectin (CD62P), E-Selectin (CD62E), L-selectin, α4β7, Mac-1, cutaneous lymphocyte antigen, CD34, CD133, VEGF receptor 1 (flt-1/flk-2), VEGF receptor 2 (flk-1/KDR), or CXCR4.  
     
     
         7 . The method of  claim 1 , wherein the surface density of adhesion molecules on the cells is increased as a result of conditioning.  
     
     
         8 . The method of  claim 1 , wherein the conditioning comprises mechanical conditioning.  
     
     
         9 . The method of  claim 8 , wherein the mechanical conditioning comprises subjecting the therapeutic cells to a mechanical shear.  
     
     
         10 . The method of  claim 9 , wherein the mechanical shear is induced by a programmable pump.  
     
     
         11 . The method of  claim 9 , wherein the mechanical shear in the range of about 5 dynes/cm 2  up to about 100 dynes/cm 2 .  
     
     
         12 . The method of  claim 1 , wherein the conditioning comprises biological conditioning.  
     
     
         13 . The method of  claim 12 , wherein the biological conditioning comprises contacting the cell with at least one chemokine.  
     
     
         14 . The method of  claim 13 , wherein the chemokine is Il-1beta, TNF-alpha, IL-4, IL-8, SDF-1, MIP-1, MCP-1/2/3/4 or lymphoactin.  
     
     
         15 . The method of  claim 12 , wherein the biological conditioning comprises contacting the cell with at least one cytokine.  
     
     
         16 . The method of  claim 15 , wherein the cytokine is a platelet derived cytokine, granulocyte colony-stimulating factor (G-CSF), oxidized LDL, tumor necrosis factor-alpha, interleukin-1, or stem cell factor (SCF).  
     
     
         17 . The method of  claim 12 , wherein the biological conditioning comprises contacting the cell with at least one growth factor.  
     
     
         18 . The method of  claim 17 , wherein at least one growth factor is VEGF, FGF, Insulin Growth Factor (IGF), bFGF, Hepatocyte Growth Factor, acidic fibroblast growth factor, fibroblast growth factor-4, fibroblast growth factor-5, epidural growth factor, or platelet-derived growth factor.  
     
     
         19 . The method of  claim 12 , wherein the biological conditioning comprises contacting the cell with PR39, HIF 1 alpha, HIF 2 alpha, Insulin Growth Factor (IGF), VEGF, bFGF, Hepatocyte Growth Factor, eNOS enhancers, P38 inhibitors, statins or S1P agonists.  
     
     
         20 . The method of  claim 12 , wherein the biological conditioning comprises contacting the cell with an exogenous agent.  
     
     
         21 . The method of  claim 20 , wherein the exogenous agent comprises a biological conjugate, linker, or an expression cassette encoding an adhesion molecule gene product.  
     
     
         22 . The method of  claim 12 , wherein the biological conditioning comprises subjecting the cells to periods of hypoxia.  
     
     
         23 . The method of  claim 1 , wherein the conditioning comprises chemical conditioning.  
     
     
         24 . The method of  claim 23 , wherein the chemical conditioning comprises conjugating a molecule or molecular moiety to the surface of the cell.  
     
     
         25 . The method of  claim 23 , wherein the chemical conditioning comprises attaching a molecule or molecular moiety to the surface of the cell.  
     
     
         26 . The method of  claim 23 , wherein the chemical conditioning comprises contacting the therapeutic cells with at least one irritant.  
     
     
         27 . The method of  claim 23 , wherein the chemical conditioning comprises contacting the therapeutic cells with at least one stimulant.  
     
     
         28 . The method of  claim 1 , wherein the composition further comprises a viscous agent.  
     
     
         29 . The method of  claim 28 , wherein the viscous agent is tocopherol, a lipid emulsion such as an emulsified vegetable oil, a surfactant, a hydrophilic polymer, or any combination thereof.  
     
     
         30 . The method of  claim 1 , wherein the composition further comprises an activated platelet or a platelet-derived microparticle.  
     
     
         31 . The method of  claim 1 , wherein the composition further comprises a calcium ionophore, oleic acid, histamine, DMSO, histamine, bradykinin, serotonin, thrombin, VEGF, a leukotriene or a vasodilator.  
     
     
         32 . The method of  claim 31 , wherein the vasodilator is an ACE inhibitor or a nitrate.  
     
     
         33 . The method of  claim 1 , wherein the composition further comprises at least one agent that increases bumping frequency.  
     
     
         34 . The method of  claim 33 , wherein the agent to increase the bumping frequency is a microbubble, a liposome, a lipid vesicle, a vesicle with membranes formed from di-block or tri-block co-polymers, a platelet-derived microparticle, or a microparticle.  
     
     
         35 . The method of  claim 1 , wherein the conditioning comprises contacting the cells with a magnetically responsive particle.  
     
     
         36 . The method of  claim 35 , further comprising applying an external magnetic field gradient to the mammal following delivery of the composition.  
     
     
         37 . The method of  claim 35 , wherein the magnetic particle is labeled.  
     
     
         38 . The method of  claim 37 , wherein the magnetic particle is labeled with CD44, P-selectin glycoprotein ligand-1 (PSGL-1; CD 162), hematopoietic cell E-/L-selectin ligand (HCELL), E-selectin ligand-1, Very Late Antigen-4 (VLA-4; CD49d), Leukocyte Function Associated Antigen-1 (LFA-1), an integrin, such as an α4 integrin or a β2 integrin, CD31, VE-Cadherin (CD144), PECAM (CD31), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule (ICAM)-1, a selectin such as P-Selectin (CD62P), E-Selectin (CD62E), L-selectin, α4β7, Mac-1, cutaneous lymphocyte antigen, CD34, CD133, VEGF receptor 1 (flt-1/flk-2), VEGF receptor 2 (flk-1/KDR) or CXCR4.  
     
     
         39 . The method of  claim 1 , wherein the composition further comprises a gaseous agent.  
     
     
         40 . The method of  claim 39 , wherein the gaseous agent induces transient, localized ischemia at the target site.  
     
     
         41 . The method of  claim 39 , wherein the gaseous agent is carbon dioxide.  
     
     
         42 . The method of  claim 1 , further comprising conditioning cells associated with the target site to provide target cells having an altered number of adhesion molecules as compared to corresponding target cells not subjected to the conditioning, wherein the conditioning increases the probability of engraftment of the therapeutic cells at the target site.  
     
     
         43 . The method of  claim 1 , wherein the composition further comprises a pharmaceutically acceptable carrier.  
     
     
         44 . The method of  claim 1 , wherein the therapeutic cells are delivered after the cells are conditioned.  
     
     
         45 . A method of enhancing engraftment of a therapeutic cell at a target site in a mammal comprising: 
 delivering a composition comprising the therapeutic cell and one or more engraftment enhancing agents, wherein the composition is delivered to the target site using an intracoronary delivery device.    
     
     
         46 . The method of  claim 45 , wherein at least one engraftment enhancing agent is gaseous and provides transient, localized ischemia at the target site.  
     
     
         47 . The method of  claim 46 , wherein the gaseous engraftment enhancing agent is carbon dioxide.  
     
     
         48 . The method of  claim 45 , wherein at least one engraftment enhancing agent is a viscous agent.  
     
     
         49 . The method of  claim 48 , wherein the viscous agent is tocopherol, a lipid emulsion such as an emulsified vegetable oil, a surfactant, a hydrophilic polymer, or any combination thereof.  
     
     
         50 . The method of  claim 45 , wherein at least one engraftment enhancing agent is a bumping agent.  
     
     
         51 . The method of  claim 45 , wherein at least one engraftment enhancing agent is an activated platelet or a platelet-derived microparticle.  
     
     
         52 . The method of  claim 45 , wherein at least one engraftment enhancing agent is a calcium ionophore, oleic acid, histamine, DSMO, a vasodilator or any combination thereof.  
     
     
         53 . The method of  claim 52 , wherein the vasodilator is an ACE inhibitor or a nitrate.  
     
     
         54 . The method of  claim 45 , wherein at least one engraftment enhancing agent is an agent that increases bumping frequency.  
     
     
         55 . The method of  claim 54 , wherein the agent to increase the bumping frequency is a microbubble, a liposome, a lipid vesicle or a vesicle with membranes formed from di-block or tri-block co-polymers.  
     
     
         56 . The method of  claim 45 , wherein at least one engraftment enhancing agent is a chemokine.  
     
     
         57 . The method of  claim 56 , where in the chemokine is IL-1β, TNF-α, IL-4, IL-8, SDF-1, MIP-1, MCP-1/2/3/4 or lymphoactin.  
     
     
         58 . The method of  claim 56 , wherein the chemokine is SDF-1.  
     
     
         59 . The method of  claim 45 , wherein at least one engraftment enhancing agent is a cytokine.  
     
     
         60 . The method of  claim 59 , wherein the cytokine is a platelet derived cytokine, granulocyte colony-stimulating factor (G-CSF), oxidized LDL, tumor necrosis factor-alpha, interleukin-1, or stem cell factor (SCF).  
     
     
         61 . The method of  claim 45 , wherein at least one engraftment enhancing agent is a growth factor.  
     
     
         62 . The method of  claim 61 , wherein at least one growth factor is VEGF, FGF Insulin Growth Factor (IGF), bFGF, Hepatocyte Growth Factor, acidic fibroblast growth factor, fibroblast growth factor-4, fibroblast growth factor-5, epidermal growth factor, or platelet-derived growth factor.  
     
     
         63 . The method of  claim 45 , wherein at least one engraftment enhancing agent is a magnetically responsive particle.  
     
     
         64 . The method of  claim 63 , further comprising modifying the target site to include magnetically responsive particles.  
     
     
         65 . The method of  claim 63 , further comprising applying an external magnetic field gradient to the mammal following delivery of the composition.  
     
     
         66 . The method of  claim 63 , wherein the magnetic particle is labeled.  
     
     
         67 . The method of  claim 66 , wherein the magnetic particle has a receptor for CD34, CD133, CD44, P-selectin glycoprotein ligand-1 (PSGL-1; CD 162), hematopoietic cell E-/L-selectin ligand (HCELL), E-selectin ligand-1, Very Late Antigen-4 (VLA-4; CD49d), Leukocyte Function Associated Antigen-1 (LFA-1), an integrin, such as an α4 integrin or a β2 integrin, CD31, VE-Cadherin (CD144), VEGF receptor 2 (KDR), CXCR4, α4β7, Mac-1, or cutaneous lymphocyte antigen.  
     
     
         68 . A method of enhancing engraftment of a therapeutic cell at a target site in a mammal comprising: 
 delivering a composition comprising the therapeutic cell and one or more engraftment enhancing agents, wherein the composition is delivered to the target site using an implantable delivery device, and wherein the one or more engraftment enhancing agents is biocompatible and provides transient, localized ischemia at the target site.    
     
     
         69 . The method of  claim 68 , wherein the biocompatible engraftment enhancing agent is a liposome.  
     
     
         70 . A method of enhancing engraftment of a therapeutic cell at a target site in a mammal comprising: 
 delivering a composition comprising the therapeutic cell and one or more engraftment enhancing agents, wherein the composition is delivered to the target site using an implantable delivery device, and wherein the one or more engraftment enhancing agents is biodegradable and provides transient, localized ischemia at the target site.    
     
     
         71 . The method of  claim 70 , wherein the biodegradable engraftment enhancing agent includes a microsphere.  
     
     
         72 . The method of  claim 71 , wherein the microsphere is made of polycaprolactone, PLGA poly(lactide-co-glycolide), polyester-amide, polyphosphazine, or tyrosine carbonate.  
     
     
         73 . The method of  claim 71 , wherein the microsphere is made of alginate crosslinked with divalent Ca, Ba or Sr cations.  
     
     
         74 . The method of  claim 71 , wherein the microsphere comprises an extra-cellular matrix protein crosslinked with glutaraldehyde.  
     
     
         75 . A method of enhancing engraftment of a therapeutic cell at a target site in a mammal comprising: 
 subjecting the therapeutic cell to in vitro conditioning, wherein the conditioning increases the probability of engraftment of the therapeutic cell at the target site; and    delivering a composition comprising the conditioned therapeutic cell, wherein the composition is delivered to the target site using an implantable delivery device.    
     
     
         76 . A catheter comprising: 
 a catheter body having a dual lumen;    a mixing chamber at a terminus of the catheter body, the mixing chamber having an outlet;    a porous material coupled to a first lumen to generate bubbles within the mixing chamber;    a discharge port coupled to the second lumen to introduce a cell into the mixing chamber; and    a bypass port to admit blood into the mixing chamber.    
     
     
         77 . The catheter of  claim 76 , wherein the first lumen is configured to receive a gas.  
     
     
         78 . The catheter of  claim 76 , further including a pump configured to generate the bubbles within the mixing chamber at a first predetermined time.  
     
     
         79 . The catheter of  claim 76 , further including pump configured to deliver the cell to the mixing chamber at a second predetermined time.  
     
     
         80 . The catheter of  claim 76 , wherein the porous material includes a sponge.  
     
     
         81 . A method comprising: 
 inducing ischemia at a target site for a transitory period of time;    delivering a therapeutic cell and a viscous agent to the target site, the viscous agent selected to increase the viscosity of the therapeutic cell injection medium; and    restoring normal blood flow to the target site.    
     
     
         82 . The method of  claim 81 , wherein inducing ischemia includes introducing a flow resistor.  
     
     
         83 . The method of  claim 81 , wherein inducing ischemia includes delivering an irritant or stimulant to the target site.  
     
     
         84 . The method of  claim 81 , wherein the viscous agent includes at least one of microparticles, PEG, vitamin E, PVA, PVP, dextran, and dextran sulfate.  
     
     
         85 . A method of delivering a therapeutic cell to a target site in a mammal comprising introducing a solution including the therapeutic cell and an agent, wherein the agent is tailored to enhance engraftment of the therapeutic cell to the target site, and wherein the solution is introduced using an implantable catheter.  
     
     
         86 . The method of  claim 85 , wherein the agent induces transient, localized ischemia at the target site.  
     
     
         87 . The method of  claim 85 , wherein the agent includes at least one of a microparticle, a liposome and a CO 2  bubble.  
     
     
         88 . A method comprising: 
 modifying a target cell to upregulate an adhesion molecule counter-receptor;    subjecting a therapeutic cell to mechanical conditioning so as to provide an increased number of adhesion molecules on the cell surface as compared to a non-conditioned cell; and    delivering the therapeutic cell to the site of the target cell.    
     
     
         89 . The method of  claim 88 , wherein modifying includes inducing ischemia.  
     
     
         90 . The method of  claim 89 , wherein inducing ischemia includes introducing a flow resistor in a vessel coupled to the target site.  
     
     
         91 . The method of  claim 87 , wherein shearing includes agitating with a fluid pump.  
     
     
         92 . A method comprising: 
 combining a magnetic particle and a therapeutic cell;    applying a static magnetic field to a target site of a mammal, the static magnetic field having a gradient oriented in a direction normal to a vessel wall at the target site; and    introducing the therapeutic cell.    
     
     
         93 . A method of enhancing engraftment of therapeutic cells at a target site in a mammal comprising contacting the therapeutic cells with a biological linker, wherein at the linker is attached to the cell membrane of a therapeutic cell, and wherein at least one functionality of the linker molecule has affinity to the surface of the therapeutic cell, and wherein at least one other functionality of the linker has affinity to the surface of the lumen surface of the target area vasculature.  
     
     
         94 . The method of  claim 93 , wherein the linker is irreversibly attached to the therapeutic cell.  
     
     
         95 . The method of  claim 93 , wherein the linker is reversibly attached to the therapeutic cell.  
     
     
         96 . The method of  claim 93 , wherein the linker is a biological conjugate.  
     
     
         97 . The method of  claim 93 , wherein the linker is a multifunctional linker.  
     
     
         98 . The method of  claim 93 , wherein the linker is a bi-functional linker.  
     
     
         99 . The method of  claim 93 , wherein the linker molecule comprises at least one of an antibody, an antibody fragment, a peptide, or an affibody.  
     
     
         100 . The method of  claim 93 , wherein the functionalities may be separated by a spacer.  
     
     
         101 . The method of  claim 100 , wherein the spacer is a hydrophilic polymer.  
     
     
         102 . The method of  claim 101 , wherein the spacer is PEG.  
     
     
         103 . The method of  claim 100 , wherein the spacer has branches or is of star form.  
     
     
         104 . The method of  claim 93 , wherein the linker comprises linked antibodies, fragments of antibodies (F ab  fragments), affibodies, peptides or other molecules with affinity to receptor molecules on the target surface.