Patent Application
20070100323
1. Field of the Invention
Inhibiting intravascular thrombosis, vascular smooth muscle cell proliferation or restenosis.
2. Background
Balloon angioplasty is utilized as an alternative to bypass surgery for treatment early in the development of stenosis or occlusion of blood vessels due to the abnormal build-up of plaque on the endothelial wall of a blood vessel. Angioplasty typically involves guiding a catheter that is usually fitted with a balloon through an artery to the region of stenosis or occlusion, followed by brief inflation of the balloon to push the obstructing intravascular material or plaque against the endothelial wall of the vessel, thereby compressing and/or breaking apart the plaque and reestablishing blood flow. In some cases, particularly where a blood vessel may be perceived to be weakened, a stent may be deployed.
Balloon angioplasty and stent deployment may result in injury to a wall of a blood vessel and its endothelial lining. For example, undesirable results such as denudation (removal) of the endothelial cell layer in the region of the angioplasty, dissection of part of the inner vessel wall from the remainder of the vessel wall with the accompanying occlusion of the vessel, or rupture of the tunica intima layer of the vessel. A functioning endothelial reduces or mitigates thrombogenicity, inflammatory response, and neointimal proliferation.
According to one embodiment of the invention that may be used to reduce the risk of intravascular thrombosis formation, and/or it may be used to inhibit vascular smooth muscle cell proliferation or restenosis following, for example, vascular intervention or injury, or in denuded or incompletely endothelialized areas of vasculature. One way the method achieves this is by accelerating recovery of endothelial coverage by delivering to a treatment site within a lumen of a blood vessel, a cellular component including either or both of endothelial cells and endothelial progenitor cells. The cellular component may be modified (e.g., genetically modified) to increase expression of molecules capable of attaching to a wall of a blood vessel. Alternatively, it may be encapsulated in a lipid or biodegradable polymer membrane capable of lodging in openings or fissures at the injury site, or modified at its surface to attach to a wall of a blood vessel. Still further, the cellular component may be modified to express or release a treatment agent such as a growth factor or a cytokine. In still another embodiment, the cellular component may be modified, for example, at its surface, to include a molecule or molecular moiety that either or in conjunction with a compatible molecule is capable of attaching the cellular component to a wall of a blood vessel.
In addition to accelerating endothelial coverage area, the functionality of the endothelial cells may also be facilitated. As endothelial density up to confluence and inter-cellular communication influences endothelial function, improved or accelerated recovery of endothelial function may also be achieved by increasing the rate of recovering endothelial coverage. While a confluent coverage of a functionally competent endothelium is a desired outcome, the method may be deemed successful in any instance where vascular healing mediated by facilitation of re-endothelialization is improved.
According to another embodiment, the method includes delivering to an injury site within a lumen or a blood vessel, a treatment agent having a first site capable of adhering with a wall of a blood vessel and a second site capable of bonding or conjugating with a cellular component. By utilizing a treatment agent having a second site having an affinity for endothelial progenitor cells, the conjugates may attract circulating cells (e.g., endothelial progenitor cells) from the blood stream, either those cells naturally present or cells introduced (infused locally or systemically) in or after a procedure.
According to another embodiment, a method is also described. The method includes coating an injury site within a lumen of a blood vessel with a polymeric biomaterial. The biomaterial may contain molecular moieties with affinity to cells and/or a treatment agent. For example, a coating may present molecular moieties at its luminal surface with affinity to the surface of circulating progenitor cells or cells locally infused after coating the blood vessel wall. The coating may be loaded with a treatment agent, such as a cytokine and/or growth factor to stimulate migration of neighboring cells to the injury site or impede proliferation of target cells (e.g., smooth muscle cells). Additionally the coating may also be loaded with cytokines or growth factors such as, for example, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) to stimulate recovery of endothelial coverage and/or function. Alternatively or in addition, the composition from the culture expanded media for endothelial coverage may be added to the coating. This will include an array of cytokines, growth factors to elicit a synergistic effect. In another embodiment, a treatment agent may be embedded in the coating through the use of carriers such as polymer particles, liposomes and polymer vesicles. Alternatively, a coating may incorporate a treatment agent by providing attachment site for the treatment agent. The treatment agent, in such case, may disassociate from the attachment site with a certain dissolution rate or may be chemically conjugated to the biomaterial through a degradable bond, releasing the treatment agent upon degradation.
One property of a polymeric biomaterial coating of a blood vessel is that it may insulate a vessel wall from platelets deposition and monocyte/neutrophil adhesion. In order to increase a thrombo-resistant property of the biomaterial coating, drugs such heparin may be incorporated into the coating.
According to still another embodiment, a composition is described that may include an amount of a cellular component suitable for delivery to a blood vessel. The cellular component may include endothelial cells or progenitor cells (e.g., endothelial progenitor cells) that have been modified to increase the potential for retention at a treatment site within the blood vessel. Modifications include but are not limited to, genetic or molecular modifications to increase the retention of molecules at a treatment site (e.g., affinity for a blood vessel wall), encapsulation in lipid or polymer membranes or shells with affinity to the vessel wall, expressing or releasing agents that stimulate migration of neighboring cells to a treatment site or impede proliferation of target cells. In another embodiment, a composition is disclosed that is suitable for being introduced at a treatment site and has a property capable of capturing or recruiting circulating cells, such as circulating progenitor cells.
In a further embodiment, a composition including a polymeric biomaterial is described. The polymeric biomaterial is suitable for delivery into a blood vessel possibly to form an in situ coating on a wall of the blood vessel. The biomaterial may include moieties with affinity to circulating cells and/or treatment agents such as cytokines, growth factors or drugs. The embodiment includes but is not limited to the following coating configurations: a) Hydrogel materials containing bioactive agent, that are packaged in nanoparticle or nanovesicular form; b) a blend of hydrophilic and hydrophobic polymers such as polyethylene glycol (PEG) and d,l-polylactic acid (d,l-PLA) such that the blend contains and allows the transport of bioactive agents into the tissue and prevents platelet activation by virtue of, for example, a PEG rich surface. The blend ratio may be optimized based on four parameters: transport of bioactive, surface hydrophilicity without any polyion, interfacial adhesion to the tissue, and the kinetics of dissolution or disintegration of the coating.
The features, aspects, and advantages of the invention will become more thoroughly apparent from the following detailed description, appended claims, and accompanying drawings in which:
Referring to
Stenosis or occlusion of a blood vessel such as blood vessel 100 occurs by the build-up of plaque on inner most layer 110. The stenosis or occlusion can result in decreased blood flow through lumen 140. One technique to address this is angioplasty.
Balloon angioplasty and stent deployment may result in injury to blood vessel 100 and its endothelial lining, resulting in a potential formation of thrombus or neointimal proliferation. A functioning endothelial reduces or mitigates thrombogenecity, inflammatory response, neointimal proliferation. Therefore, it is desirable to accelerate re-endothelialization.
One technique for accelerating re-endothelialization at an injury site within a blood vessel is to infuse a cellular component that promotes the growth of endothelial cells or a restoration of an endothelial layer. In one embodiment, the technique includes introducing endothelial cells or progenitor cells (e.g., endothelial progenitor cells) as, for example, a fluid local to the target site to repopulate an injured vessel wall and/or stent (or other blood contacting implant) surface. The cell source may be autologous, meaning perhaps that it was previously harvested from the blood stream of the patient undergoing a procedure. In such case, the endothelial cells or endothelial progenitor cells (EPC) harvested from the blood stream may be concentrated and then fused locally to an injury site. Alternatively, the cell source may be an exogenous cell line, such as an allogenic (human) cell line not from the patient.
Treatment Agents
In one embodiment, a treatment agent may include suitable cellular components such as but not limited to endothelial cells or progenitor cells (e.g., endothelial progenitor cells) or bone marrow derived stem cells or other stem cells that may have a property or function that modifies (e.g., improves) a blood vessel wall following an injury to the vessel wall such as may occur in the context of a treatment of a stenosis or occlusion, or in the context of naturally occurring incompletely endothelialized vasculature. In another embodiment, these cells may be pre-conditioned to increase the expression of attachment molecules, where such attachment molecules have, for example, affinity to a subendothelium. For example, cells may be genetically modified to express integrins or other moieties that have an affinity to binding sites of the subendothelium such as proteins present therein, e.g. laminin, collagen or fibrin, or the arginine-glycine-aspartic acid (RGD) sequence found in these proteins.
In another embodiment, the cells may be packaged or encapsulated. in a liposome or stealth liposome or other outer shell such as, for example, lipid or polymer membranes, or polymer shells, or other lipid-philic shells. This embodiment recognizes that an atheromatous plaque tends to have a number of micro-cracks in its surface. These micro-cracks can act as secondary reservoirs for cell component treatment agents. Accordingly, an embodiment where a cell component treatment agent is packaged or encapsulated in liposomes or other outer shell such as lipid or polymer membranes, or polymer shells, or other lipid-philic shells, allows the treatment agent to be lodged into the micro-cracks of the atheromatous plaque. In order to accommodate endothelial progenitor cells, these cell-loaded capsules are, for example, of a size of 10 to 20 micrometers (μm).
In another embodiment, cells such as endothelial cells or endothelial progenitor cells may be genetically modified to express and/or release a therapeutic in situ. For example, a cell may be modified to express and/or release a cytokine capable of stimulating migration toward a particular site or a growth factor (e.g., VEGF) having a tendency to make cells proliferate. Such cytokines or growth factors may help to induce migration and/or proliferation of neighboring endothelial cells to an injured (e.g., denuded) vessel wall surface or help to recruit circulating endothelial progenitor cells to the target site. A modification of cells to express and/or release a therapeutic may be done in conjunction with a modification to the cell to increase the expression of attachment molecules or the packaging of cells in liposomes or other membrane capsules with a surface having affinity to the subendothelium of a vessel wall.
In another embodiment, cells may be modified, for example, at their surface, by bi- or multifunctional linker molecules where at least one functionality of the linker molecule has affinity to the cell surface of molecular components thereof, and at least one other functionality has affinity to the surface of the target site, e.g., the subendothelium. For example, a molecule having two linked antibodies, where one antibody has affinity to a receptor on a cell surface and the other antibody has affinity to proteins of the subendothelium may be used to modify the cells. Alternatively, antibody fragments, affibodies (a library of proteins with recognition capabilities similar to antibodies), peptides or other molecules with the desired affinity may be used. For example, an anti-CD34 antibody linked to an affibody with affinity to an RGD sequence via a short organic spacer may be used to modify the surface of endothelial progenitor cells. When modifying progenitor cells in this fashion, the CD34 antibody will adhere to CD34 receptors at the cell surface and the cell surface will present molecules (affibodies) with affinity to proteins of the subendothelium (e.g., RGD sequences present in proteins of the subendothelium). In another example, anti-laminin-anti-CD34 may be used to modify the cell surface. Alternatively, suitable linker molecules, having an affinity to the subendothelium, may be chemically conjugated to a cell surface, such as to amine groups using reactive esters, epoxides, aldehydes; to sulfhydryl groups using maleimides, vinyl sulfones; to carboxyl groups using dimethylaminopropylcarbodiimide (EDC) chemistry. A molecular moiety having affinity for a target area such as a lumen surface may be separated from the attachment site on the cell surface by a spacer. Representative spacers include hydrophilic polymers such as polyethylene glycol (PEG) of molecular weight from about, but are not intended to be limited to, 500 to 40,000, preferably from about 2,000 to 10,000, and more preferably, from about 2,000 to 5,000.
In a situation where a stent is deployed at a target site, it may be desirable to deliver a treatment agent including a cellular component to the stent surface. Delivery to a stent surface may be enhanced by using a stent the surface of which is coated with cell adhesion molecules, such as laminin, fibronectin, or an adhesion peptide such as RGD peptide. The treatment agent may be modified in a manner specified above to enhance adhesion or improve the therapeutic activity of the treatment agent. Alternatively, a stent surface may be modified to include morphological features to provide a means of cell adhesion enhancement.
Modification of Blood Vessel
In the above embodiments, compositions and devices for introducing compositions are described, where the compositions may be introduced as a treatment agent into a blood vessel or to a stent in a blood vessel to, for example, promote endothelial cell migration or proliferation at a target site. In another embodiment, a treatment agent may be introduced that has a capability to recruit cells to a target site such as a luminal surface of the blood vessel. These treatment agents may include properties capable of recruiting circulating endothelial progenitor cells, either those naturally present or those cells infused to a target site. One technique to recruit cells to a target site is to modify a vessel wall to retain such cells.
Bi- or multifunctional linkers or molecules have at least one functionality having affinity to a surface of the lumen surface of the target site, such as an affinity for proteins of the subendothelium (e.g., laminin, fibronectin, collagen, tissue factor) and at least one other functionality having affinity to the surface of endothelial cells or progenitor cells, or molecular components present at the respective cell surface. One example of a molecule having affinity to a surface of circulating endothelial cells is a CD34 antibody. An example of a bi-functional molecule is an anti-CD34 -anti-RGD molecule. When infused into a target area, the anti-RGD moiety of this molecule can attach to proteins (e.g., laminin, fibrin) present at a denuded lumen surface, thereby presenting the anti-CD34 moiety to the vessel lumen. When circulating endothelial progenitor cells come in contact with the modified lumen surface, the CD34 receptor of the cell can attach to the CD34 antibody, thereby effectively retaining the cell at the modified target surface. An additional example would be the fab-fragment of an anti-CD133 antibody conjugated to an anti-laminin antibody. Alternatively, a vessel wall may be coated with an anti-laminin-anti-CD34 or an anti-laminin-anti-CD133 molecule by inducing either of these molecules local to a target site.
Molecules or molecular moieties possessing affinity to a surface of endothelial progenitor cells may be chemically conjugated through a luminal surface of a target site. The molecule or molecular moiety may be conjugated to the lumen surface via a spacer molecule, such as a hydrophilic polymer (e.g., PEG) to enhance accessibility. In one embodiment, the molecular moiety may possess more than one molecular moiety with affinity to a cell surface wherein a spacer may be, for example, branched.
Alternatively, attachment molecules may be chemically conjugated to the luminal surface of a blood vessel, through, for example: (i) amine groups using reactive esters, epoxides, aldehydes, or isocyanates (NCO); (ii) sulfhydryl groups using maleimides, vinyl sulfones; (iii) carboxyl groups using dimethylaminopropylcarbodiimide chemistry; (iv) hydroxyl groups using isocyanates (NCO) or epoxides. In this embodiment, one of the functionalities of the bi-functional molecule consists of a chemically reactive group while the other functionality of the molecule has affinity, for example, to the surface of endothelial or endothelial progenitor cells. Alternatively, photo-reactive chemistry may be used for conjugation. An example of a photo-reactive conjugation involves activating a photo-reactive moiety of a molecule by a catheter-based light or ultraviolet (UV) radiation after infusion of the molecular into a target lumen.
One example of modifying a vessel wall with an agent capable of recruiting cells at a target site is modifying a lumen surface of a blood vessel with antibodies to receptors present on endothelial progenitor cells (e.g., CD34, CD133, KDR). This may be done by conjugating a vinyl sulfone(VS)-PEG-antibody molecule to sulfhydryl groups present at a lumen surface. VS-PEG-antibody molecule may be locally infused or circulated in a lumen volume isolated by proximal and distal occlusion balloon (e.g., see
In another example, a maleimide-anti-CD133 molecule may be used to conjugate the CD133 antibody to sulfhydryl groups present in the vessel lumen surface. Alternatively, an NHS-PEG-biotin may be conjugated to the subendothelium at a target site and avidin may be subsequently infused into the target area. In a final step, VEGF-biotin may be bound to the vessel wall by infusing it into the avidin-modified target area. VEGF has affinity to the KDR receptor found on the surface of endothelial progenitor cells. Alternatively, biotinylated anti-CD34 may be used in the last step.
In yet another example, cyclic RGD (cRGD) molecules may be infused to the treatment site, where the cRGD non-specifically adheres to the subendothelial matrix, thereby providing attachment sites for endothelial cells or endothelial progenitor cells.
Modification of Blood Vessel Wall and Cellular Component
In the above embodiments, compositions may, for example, be introduced into a blood vessel as treatment agents to promote endothelial cell migration or proliferation at a target site. For example, treatment agents including cellular components that have been modified to increase affinity for a luminal wall of a blood vessel or treatment agent that has affinity to a cell surface (e.g., endothelial progenitor cells) may be introduced into a blood vessel. In a further embodiment, a treatment agent (first treatment agent) may be introduced into a blood vessel that has affinity for a cell surface without affinity for a luminal surface of the blood vessel at approximately the same time, after or prior to the introduction of a treatment agent (second treatment agent) with no affinity for a cell surface, but with affinity to the luminal surface of the blood vessel. In such case, the first treatment agent, in addition to being modified to have an affinity for a wall surface may be modified to present a conjugate and the second treatment agent may have a corresponding conjugate so that the first treatment agent and the second treatment agent may be conjugated through a bioconjugate of a conjugate on the first treatment agent and the conjugate on the second treatment agent.
Blood Vessel Wall Modification
In another embodiment, a luminal surface of a vessel wall may be modified at a treatment site by forming a coating on the luminal surface of, for example, a hydrogel. In one embodiment, this modification or coating may be formed in situ. Suitable hydrogels include, but are not limited to, cross-linked PEG hydrogels or hydrogels formed from biopolymers. One example of a hydrogel that may be formed in situ (e.g., within a lumen of a blood vessel) is the combination of tri- or more functional PEG-amine with bi- or more functional PEG-reactive ester at a slightly basic pH (e.g., on the order of 7.6 to 9.0). Another example of a suitable hydrogel is a hydrophilic polymer such as PEG or a biopolymer such as chitosan mixed with a photoreactive crosslinker. A suitable photoreactive crosslinker is, for example, is a bi- or multifunctional acrylate where site specific photo-irradiation will locally activate the crosslinker to form a localized hydrogel.
In addition to having molecular moieties to promote the adhesion of the hydrogel to a vessel wall or a hydrogel with an affinity for circulating progenitor cells, a hydrogel may be loaded with a therapeutic agent, such as a cytokine and/or growth factor to stimulate migration of neighboring endothelial cells to the target area, or a therapeutic agent to impede proliferation of target cells, e.g., smooth muscle cells. Drug carriers such as polymer particles, liposomes, or polymer vesicles may be embedded in the hydrogel. Alternatively, the hydrogel may incorporate the therapeutic by providing attachment sites for the therapeutic, for example, where the therapeutic disassociates from these attachment sites with a certain disassociation rate. Or, the therapeutic may be chemically conjugate to the polymers of the hydrogel where the chemical bond is degradable, releasing the therapeutic upon degradation.
In one embodiment, a hydrogel formed in situ on a vessel wall, such as a denuded vessel wall may insulate the vessel wall from platelet deposition and monocyte/neutrophil adhesion. In order to increase a thrombo-resistant property of the hydrogel, an inhibitor such as heparin may be incorporated into the coating. A hydrogel coating may also contain a cocktail of acellular components of culture expansion in order to induce controlled healing.
Cellular components may be delivered as described above after a vessel wall has been modified, such as by a hydrogel coating. Cellular components may include mature endothelial cells or progenitor cells (e.g., endothelial progenitor cells). The affinity of a hydrogel for a particular cell may be modified using techniques described above (e.g., presenting moieties in the hydrogel that have an affinity for a particular cell).
In addition to combining surface modification of a wall coating such as a hydrogel with affinity for cellular components and cell delivery, a vessel coating modification and cell surface modification may be used as a complement. For example, a surface of a wall coating (e.g., a hydrogel) may be modified to present a conjugate and a separate cellular component may be modified at its surface or genetically modified to express surface receptors to present a conjugate or molecular moiety having an affinity for the conjugate presented by the wall coating. The conjugation of a conjugate on the wall coating and a conjugate or other molecular moiety on the surface of the cell will form a bioconjugate. An alternative to a chemical conjugation or binding, these conjugates or conjugate and molecular moieties may be in the form of magnetically responsive materials.
One example of the above description is modifying the surface of endothelial progenitor cells by incubation with NHS-PEG-biotin and subsequent incubation in avidin. At the same time, a surface of a wall coating is modified by NHS-PEG-biotin alone. Thus, avidin is attached to the cell surface, or biotin is presented at the lumen surface. When the avidin-modified cells are infused into a target area and the cell surface bound avidin is brought into contact with the lumen-bound biotin, the avidin will bind the biogen and thereby retain the cells at the lumen surface.
Devices
In the above embodiments, treatment agents including a cellular component and modified treatment agents are described that may be used to modify (e.g., improve) a target site such as luminal surface of a blood vessel. Also described are treatment agents having a capability to recruit cells to a target site or to modify a target site such as by coating a luminal surface of a blood vessel. The following paragraphs describe representative devices that may be used to introduce the contemplated treatment agents.
To increase delivery and engraftment efficiency of a treatment agent including, for example, modified or unmodified cells, blood flow may be temporarily reduced or a stopped through balloon occlusion of the target vessel prior to the introduction.
In one embodiment, catheter assembly 800 includes primary cannula 815 having a length that extends from proximal portion 805 (e.g., located external through a patient during a procedure) to connect with a proximal end or skirt of balloon 825. Primary cannula 815 has a lumen therethrough that includes inflation cannula and delivery cannula 840. Each of inflation cannula 830 and delivery cannula 840 extends from proximal portion 805 of catheter assembly 800 to distal portion 810. Inflation cannula 830 has a distal end that terminates within balloon 825. Delivery cannula 840 extends through balloon 825.
Catheter assembly 800 also includes guidewire cannula 820 extending, in this embodiment, through balloon 825 through a distal end of catheter assembly 800. Guidewire cannula 820 has a lumen sized to accommodate guidewire 822. Catheter assembly 800 may be an over the wire (OTW) configuration where guidewire cannula 820 extends from a proximal end (external to a patient during a procedure) to a distal end of catheter assembly 800. Guidewire cannula 820 may also be used for delivery of a treatment agent such as a cellular component or other vessel wall modifying agent when guidewire 822 is removed with catheter assembly 800 in place. In such case, separate delivery cannula (delivery cannula 840) is unnecessary or a delivery cannula may be used to delivery one treatment agent while guidewire cannula 820 is used to delivery another treatment agent.
In another embodiment, catheter assembly 800 is a rapid exchange (RX) type catheter assembly and only a portion of catheter assembly 800 (a distal portion including balloon 825) is advanced over guidewire 822. In an RX type of catheter assembly, typically, the guidewire cannula/lumen extends from the distal end of the catheter to a proximal guidewire port spaced distally from the proximal end of the catheter assembly. The proximal guidewire port is typically spaced a substantial distance from the proximal end of the catheter assembly.
In one embodiment, catheter assembly 800 is introduced into blood vessel 100 and balloon 825 is inflated (e.g., with a suitable liquid through inflation cannula 830) to occlude the blood vessel. Following occlusion, a solution (fluid) including a cellular component that promotes the growth of endothelial cells or a restoration of an endothelial layer is introduced through delivery cannula 840. A suitable solution of endothelial cells or progenitor cells is a saline solution with a concentration of endothelial cells or progenitor cells on the order of 102 to 105 per milliliter (ml), more specifically 103 to 105 per milliliter. By introducing the cellular component in this manner, the endothelial cells or progenitor cells can re-populate the vessel wall at treatment site 210 or stent 300.
In an effort to improve the target area of a cellular component to a treatment site, such as treatment site 210, the injury site may be isolated prior to delivery.
Catheter assembly 900 also includes guidewire cannula 920 extending, in this embodiment, through each of balloon 925 and balloon 935 through a distal end of catheter assembly. Guidewire cannula 920 has a lumen therethrough sized to accommodate a guidewire. No guidewire is shown within guidewire cannula 920. Catheter assembly 900 may be an over the wire (OTW) configuration or a rapid exchange (RX) type catheter assembly.
Catheter assembly 900 also includes delivery cannula 940. In this embodiment, delivery cannula extends from a proximal end of catheter assembly 900 through a location between balloon 925 and balloon 935. Secondary cannula 945 extends between balloon 925 and balloon 935. A proximal portion or skirt of balloon 935 connects to a distal end of secondary cannula 945. A distal end or skirt of balloon 925 is connected to a proximal end of secondary cannula 945. Delivery cannula 940 terminates at opening 960 through secondary cannula 945. In this manner, a treatment agent may be introduced between balloon 925 and balloon 935 positioned between treatment site 210.
In the above embodiment, separate balloons having separate inflation lumens are described. It is appreciated, however, that a single inflation lumen may be used to inflate each of balloon 925 and balloon 935. Alternatively, in another embodiment, balloon 935 may be a guidewire balloon configuration such as a PERCUSURG™ catheter assembly where catheter assembly 900 including only balloon 925 is inserted over a guidewire including balloon 935.
Primary cannula 1015 is connected in one embodiment to a proximal end (proximal skirt) of balloon 1025. A distal end (distal skirt) of balloon 1025 is connected to secondary cannula 1045. Secondary cannula 1045 has a length dimension, in one embodiment, suitable to extend from a distal end of a balloon located proximal to a treatment site beyond a treatment site. In this embodiment, secondary cannula 1045 has a property such that it may be inflated to a greater than outside diameter than its outside diameter when it is introduced (in other words, secondary cannula 1045 is made of an expandable material). A distal end of secondary cannula 1045 is connected to a proximal end (proximal skirt of balloon 1035). In one embodiment, each of balloon 1025, balloon 1035, and secondary cannula 1045 are inflatable. Thus, in one embodiment, each of balloon 1025, balloon 1035, and secondary cannula 1045 are inflated with a separate inflation cannula.
By using an expandable structure such as secondary cannula 1045 adjacent a treatment site, the expandable structure may be expanded to a point such that a treatment agent may be dispensed very near or at the treatment site.
Catheter assembly 1100 also includes guidewire cannula 1120 extending, in this embodiment, through balloon 1125. Guidewire cannula 1120 has a lumen therethrough sized to accommodate a guidewire. No guidewire is shown within guidewire cannula 1120. Catheter assembly 1100 may be an over-the-wire (OTW) configuration or rapid exchange (RX) type catheter assembly.
Catheter assembly 1100 also includes delivery cannula 1140. In this embodiment, delivery cannula 1140 extends from a proximal end of catheter assembly 1100 to proximal end or skirt of balloon 1125. Balloon 1125 is a double layer balloon. Balloon 1125 includes inner layer 11250 that is a non-porous material, such as PEBAX, Nylon or PET. Balloon 1125 also includes outer layer 11255. Outer layer 11255 is a porous material, such as extended polytetrafluoroethylene (ePTFE). In one embodiment, delivery cannula 1140 is connected to between inner layer 11250 and outer layer 11255 so that a treatment agent can be introduced between the layers and permeate through pores in balloon 1125 into a lumen of blood vessel 100.
As illustrated in
Disposed within primary cannula 1215 is guidewire cannula 1220 and inflation cannula 1230. Guidewire cannula 1220 extends from a proximal end of catheter assembly 1200 through balloon 1225. A distal end or skirt of balloon 1225 is connected to a distal portion of guidewire cannula 1220.
Inflation cannula 1230 extends from a proximal end of catheter assembly 1200 to a point within balloon 1225. In one embodiment, balloon 1225 is made of a porous material such as ePTFE. A suitable pore size for an ePTFE balloon material is on the order of one micron (μm) to 60 μms. The porosity of ePTFE material can be controlled to accommodate a treatment agent flow rate or particle size by changing a microstructure of an ePTFE tape used to form a balloon, for example, by wrapping around a mandrel. Alternatively, pore size may be controlled by controlling the compaction process of the balloon, or by creating pores (e.g., micropores) using a laser.
ePTFE as a balloon material is a relatively soft material and tends to be more flexible and conformable with tortuous coronary vessels than conventional balloons. ePTFE also does not need to be folded which will lower its profile and allow for smooth deliverability to distal lesions and the ability to provide therapy to targeted or regional sites post angioplasty and/or stent deployment.
A size of balloon 1225 can also vary. A suitable balloon diameter is, for example, in the range of two to five millimeters (mm). A balloon length may be on the order of eight to 60 mm. A suitable balloon profile range is, for example, approximately 0.030 inches to 0.040 inches.
In one embodiment, a porous balloon may be masked in certain areas along its working length to enable more targeted delivery of a treatment agent.
In another embodiment, a sheath may be advanced over a porous balloon (or the balloon withdrawn into a sheath) to allow tailoring of a treatment agent distribution.
In another embodiment, a sheath may have a window for targeting delivery of the treatment agent through a porous balloon.
In another embodiment, a liner inside a porous balloon may be used to target preferential treatment agent delivery. For example, the liner may have a window through which a treatment agent is delivered, e.g., on one side of a liner for delivery to one side of a vessel wall. This type of configuration may be used to address eccentric lesions.
In an alternative embodiment, rather than using a porous material like ePTFE for forming a porous balloon (e.g., balloon 1225 in
According to any of the embodiments described with reference to
In one embodiment, catheter assembly 1800 includes guidewire cannula 1820 extending from a proximal end of catheter assembly 1800 (e.g., external to a patient during a procedure) to a point in blood vessel 100 beyond treatment site 210. Overlying guidewire cannula 1820 is primary cannula 1840. In one embodiment, primary cannula 1840 has a lumen therethrough of a diameter sufficient to accommodate guidewire cannula 1820 and to allow a treatment agent to be introduced through primary cannula 1840 from a proximal end to a treatment site. In one embodiment, catheter assembly 1800 includes a brush or sponge material connected at a distal portion of primary cannula 1840. A sponge is representatively shown. Sponge 1890 has an exterior diameter that, when connected to an exterior surface of primary cannula 1840 will fit within a lumen of blood vessel 100. Catheter assembly 1800 also includes retractable sheath 1818 overlying primary cannula 1840. During insertion of catheter assembly 1800 into a blood vessel to a treatment site, sponge 1890 may be disposed within sheath 1818. Once catheter assembly 1800 at a distal portion disposed at a treatment site, sheath 1818 may be retracted to expose sponge 1890.
In one embodiment, prior to insertion of catheter assembly 1800, sponge 1890 may be loaded with a treatment agent. Representatively, sponge 1890 may be loaded with a cellular component including endothelial cells and progenitor cells (e.g., endothelial progenitor cells).
In one embodiment, catheter assembly 1800 may provide for additional introduction of a treatment agent through primary cannula 1840.
In one embodiment, catheter assembly 1900 has a configuration similar to a dilation catheter, including guidewire cannula 1920 and inflation cannula 1940 disposed within primary cannula 1915. Guidewire cannula 1920 extends through balloon 1925 and balloon 1925 is connected to a distal end or skirt of guidewire cannula 1920. Inflation cannula 1940 extends to a point within balloon 1925.
In one embodiment, catheter assembly 1900 includes sleeve 1990 around a medial working length of balloon 1925. Balloon 1925, including a medial working length of balloon 1925, may be made of a non-porous material (e.g., a non-porous polymer). In one embodiment, sleeve 1990 is a porous material that may contain a treatment agent such as a cellular component as described above. A representative material for sleeve 1990 is a silastic material. Sleeve 1990 may be loaded with or soaked (e.g., saturated) in a treatment agent before inserting catheter assembly 1900 into a blood vessel. Representatively, the pores of the porous sleeve may be filled with agent beforehand. The pores can also expand upon balloon inflation to deliver payload.
At a distal portion of coil 2090 (e.g., the coiled portion), a number (e.g., hundreds) of perfusion holes or micropores 2095 are formed to release a treatment agent therethrough. A suitable hole or micropore diameter is on the order of five to 100 microns formed, for example, around a circumference of a distal portion of coil 2090 using a laser. A proximal end of coil 2090 is connected to delivery hub 2098. A treatment agent, such as a treatment agent including a cellular component, can be injected through delivery hub 2098 and exit through holes or micropores 2095.
Catheter assembly 2000 includes sheath 2035. Sheath 2035 may be used to deliver coil 2090 to a treatment site and then retracted to expose at least a portion of the distal portion of coil 2090 including holes or micropores 2095. For delivery to a treatment site, a distal end of coil 2090 is tightly wound in either a clockwise or counterclockwise configuration. For delivery of a treatment agent, a distal portion of coil 2090 may be unwound, either by inflation through pressurization or through re-expansion into a previously memorized shape (e.g., where coil is a shape-memory material such as a nickel-titanium alloy). After a treatment agent has been introduced through pores 2095, a distal portion of coil 2090 may be withdrawn, either by deflation or by withdrawal into sheath 2035.
To minimize potential trauma to a vessel wall by shearing of the coil and against the vessel wall, a distal end of coil 2090 may be rounded or have a small sphere. Alternatively, two coils of opposite helisity may be joined at their distal end but not at overlaps in between. In another embodiment, the delivery system may consist of joined “Vs” which are rolled into a cylindrical configuration around an axis orthogonal to a plane of the Vs. Tightly wound in this configuration, a catheter assembly may be delivered to a treatment site where it is unwound to deliver a treatment agent through pores incorporated into the system.
In any of the embodiments of utilizing a coil to deliver a treatment agent, a pore distribution along a distal portion of the coil may be non-uniform to deliver the treatment agent preferentially to specific sites within a treatment area (e.g., to one side of a blood vessel). Techniques for forming coil 2090 include extruding tubing where certain treatment agents such as drugs can be mixed with extrusion resin and then herically slitting the tubing to form a coil. Alternatively, coil 2090 may be made from a hollow ripen.
A flexibility and profile of coil 2090 allows for regional treatment agent delivery in one embodiment up to approximately 15 centimeters long in a coronary vessel. An outer diameter of a hollow coil can range from 0.005 inches to 0.010 inches, and a wall thickness may range from 0.0005 inches to 0.003 inches. Treatment agent distribution may be controlled by pitch length of coil 2090.
The above delivery devices and systems are representation of devices that may be used to deliver a treatment agent including, but not limited to, a modified or unmodified cellular component or treatment agents to modify a luminal surface of a blood vessel. For example, treatment agents suitable to form an in situ layer for wall modification described above with reference to
In the preceding detailed description, reference is made to specific embodiments thereof. It will, however, be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the following claims. The specification and drawings are, accordingly, to be regarded, in an illustrative rather than a restrictive sense.
