Patent Grant
9539410
Post-myocardial infarction treatments and compositions.
Ischemic heart disease typically results from an imbalance between the myocardial blood flow and the metabolic demand of the myocardium. Progressive atherosclerosis with increasing occlusion of coronary arteries leads to a reduction in coronary blood flow. “Atherosclerosis” is a type of arteriosclerosis in which cells including smooth muscle cells and macrophages, fatty substances, cholesterol, cellular waste product, calcium and fibrin build up in the inner lining of a body vessel. “Arteriosclerosis” refers to the thickening and hardening of arteries. Blood flow can be further decreased by additional events such as changes in circulation that lead to hypoperfusion, vasospasm or thrombosis.
Myocardial infarction (MI) is one form of heart disease that often results from the sudden lack of supply of oxygen and other nutrients. The lack of blood supply is a result of a closure of the coronary artery (or any other artery feeding the heart) which nourishes a particular part of the heart muscle. The cause of this event is generally attributed to arteriosclerosis in coronary vessels.
Formerly, it was believed that an MI was caused from a slow progression of closure from, for example, 95% then to 100%. However, an MI can also be a result of minor blockages where, for example, there is a rupture of the cholesterol plaque resulting in blood clotting within the artery. Thus, the flow of blood is blocked and downstream cellular damage occurs. This damage can cause irregular rhythms that can be fatal, even though the remaining muscle is strong enough to pump a sufficient amount of blood. As a result of this insult to the heart tissue, scar tissue tends to naturally form.
Various procedures, including mechanical and therapeutic agent application procedures, are known for reopening blocked arteries. An example of a mechanical procedure includes balloon angioplasty with stenting, while an example of a therapeutic agent application includes the administration of a thrombolytic agent, such as urokinase. Such procedures do not, however, treat actual tissue damage to the heart. Other systemic drugs, such as ACE-inhibitors and Beta-blockers, may be effective in reducing cardiac load post-MI, although a significant portion of the population that experiences a major MI ultimately develop heart failure.
An important component in the progression to heart failure is remodeling of the heart due to mismatched mechanical forces between the infarcted region and the healthy tissue resulting in uneven stress and strain distribution in the left ventricle. Once an MI occurs, remodeling of the heart begins. The principle components of the remodeling event include myocyte death, edema, and inflammation, followed by fibroblast infiltration and collagen deposition, and finally scar formation. The principle component of the scar is collagen. Since mature myocytes of an adult are not regenerated, the infarct region experiences significant thinning. Myocyte loss is the major etiologic factor of wall thinning and chamber dilation that may ultimately lead to progression of cardiac myopathy. In other areas, remote regions experience hypertrophy (thickening) resulting in an overall enlargement of the left ventricle. This is the end result of the remodeling cascade. These changes in the heart result in changes in the patient's lifestyle and their ability to walk and to exercise. These changes also correlate with physiological changes that result in increased in blood pressure and worsening systolic and diastolic performance.
A device comprising: a first delivery needle, and a second delivery needle, a biasing element associated with the first delivery needle and the second delivery needle, wherein the first delivery needle and the second delivery needle are arranged in a side-by-side configuration, whereby a first gel component can be delivered through the first delivery needle without contacting a second gel component that may be disposed in the second delivery needle.
In an embodiment, the device includes a biasing element associated with the laterally offset first delivery needle and second delivery needle. The biasing element may urge the device toward a first configuration in which a distal end of the first delivery needle is longitudinally offset from a distal end of the second delivery needle. The first delivery needle may be moved relative to the second delivery needle to decrease the longitudinal offset, and in doing so, potential energy stored in the biasing element may increase. The device may include a first adaptor for delivering a first gel component through the first delivery needle and a second adaptor for delivering a second gel component through the second delivery needle. The lateral offset between the first delivery needle and second delivery needle may prevent the gel components from contacting the opposite needle during delivery. Furthermore, the longitudinal offset between the needle distal ends may prevent the gel components from admixing into a two-component gel matrix until the longitudinal offset is decreased, such as after puncturing a target tissue.
Methods and compositions for treating post-myocardial infarction damage are herein disclosed. In some embodiments, a carrier with a treatment agent may be fabricated. The carrier can be formulated from a bioerodable, sustained-release substance. The resultant loaded carrier may then be suspended in at least one component of a two-component matrix system for simultaneous delivery to a post-myocardial infarction treatment area.
Treatment Agents
Treatment agents to treat post-myocardial infarction treatment areas may include: (i) agents that promote angiogenesis (angiogenesis promoting factors); (ii) agents that promote cell survival (cell survival promoting factors); and (iii) agents that recruit endogenous progenitor and/or stem cells (endogenous recruiting factors). Various forms of treatment agents are intended to include, but are not intended to be limited to, drugs, biologically active agents, chemically active agents, therapeutic agents, and the like, and pharmaceutical compositions thereof, which can be used in the delivery of a treatment agent to a treatment site as described herein.
“Angiogenesis” is the promotion or causation of the formation of new blood vessels. After an MI, the infarct tissue as well as the border zone and the remote zone around the infarct tissue begin to remodel. Scar tissue forms in the infarct region as the granulation is replaced with collagen. Stress from blood pressure cause the scar to thin out and stretch. The perfusion in this region is typically 10% of the healthy zone, decreasing the number of active capillaries. Increasing the number of capillaries may lead to an increase in compliance of the ventricle due to filling up with blood. Other benefits of increasing blood flow to the infarcted region include providing a route for circulating stem cells to seed and proliferate in the infarct region. Angiogenesis may also lead to increased oxygenation for the surviving cellular islets within the infarct region, or to prime the infarct region for subsequent cell transplantation for myocardial regeneration. In the border zone, surviving cells would also benefit from an increase in blood supply through an angiogenesis process. In the remote zone, where cardiac cells tend to hypertrophy and become surrounded with some interstitial fibrosis, the ability of cells to receive oxygen and therefore function to full capacity are also compromised; thus, angiogenesis would be beneficial in these regions as well.
In some embodiments, angiogenesis promoting factors include, but are not intended to be limited to, growth factors such as isoforms of vasoendothelial growth factor (VEGF), fibroblast growth factor (FGF, e.g. beta-FGF), Del 1, hypoxia inducing factor (HIF 1-alpha), monocyte chemoattractant protein (MCP-1), nicotine, platelet derived growth factor (PDGF), insulin-like growth factor 1 (IGF-1), transforming growth factor (TGF alpha), hepatocyte growth factor (HGF), estrogens, follistatin, proliferin, prostaglandin E1 and E2, tumor necrosis factor (TNF-alpha), interleukin 8 (I1-8), hematopoietic growth factors, erythropoietin, granulocyte-colony stimulating factors (G-CSF) and platelet-derived endothelial growth factor (PD-ECGF). In some embodiments, angiogenesis promoting factors include, but are not intended to be limited to, peptides, such as PR39, PR11 and angiogenin, small molecules, such as PHD inhibitors, or other agents, such as eNOS enhancers.
Endogenous cardiomyocyte (myocytes) apoptosis is the major etiological factor of wall thinning and chamber dilation and may ultimately lead to progression of cardiac myopathy. After an infarction, mature myocytes of an adult are not regenerated which can lead to significant thinning in the infarct region. Thus, factors which promote cell survival applied to the infarct region are believed to be beneficial. In some embodiments, cell survival promoting factors include, but are not intended to be limited to, growth factors such as insulin-like growth factor (IGF-1) and human growth factor (HGF), which are known to mediate cell growth, differentiation and survival of a variety of cell types. In addition, small molecules such as, for example, HMG-CoA reductase inhibitors (statins) and capsase inhibitors can also promote cell survival and inhibit apoptosis.
To assist in the generation of new cells at the infarct region, autologous or allogeneic stem cells may be delivered to a patient. “Autologous” means the donor and recipient of the stem cells are the same. “Allogeneic” means the donor and recipient of the stem cells are different. Cell survival promoting factors can also be used to increase the survivability of autologous and allogeneic implanted stem cells at the infarct region.
Cardiac progenitor cells are highly specialized stem cells which have shown the ability to differentiate into certain types of fully mature cardiac tissue. Examples of cardiac progenitor cells include, but are not limited to, c-Kit(+), Sca-1(+) and Isl-1(+). Thus, factors which recruit endogenous factors when applied to the infarct region are believed to be beneficial. In some embodiments, an endogenous recruiting factor can include, for example, HGF. HGF has been shown to control cell motility and promote cell migration. If applied post-infarction, HGF can assist in mobilizing and recruiting resident cardiac progenitor cells to the infarct region. In some embodiments, an endogenous recruiting factor can include, but is not intended to be limited to, stromal cell-derived factor 1 (SDF-1). SDF-1 is the ligand for the CXCR4 receptor, which is a surface receptor on circulating endothelial progenitor cells. Thus, when applied in or around the infarct region, SDF-1 may facilitate the homing of circulating endothelial progenitor cells to induce neovascularization.
It is contemplated that any of the above-described treatment agents can be used singularly or in combination thereof. In addition, other treatment agents, including but not limited to, anti-inflammatory, anti-platelet, anti-coagulant, anti-fibrin, anti-thrombotic, anti-mitotic, anti-biotic, anti-allergic, anti-oxidant, anti-proliferative, or anti-migratory agents, may be optionally used singularly or in combination thereof.
Sustained-Release Carriers
Bioerodable carriers (hereinafter interchangeably referred to as sustained-release carriers) infused with (or without) a treatment agent can be used for the sustained or controlled release of treatment agent for maximum benefit to the infarct region. It is believed that a large percentage of treatment agent delivered directly to the infarct region, or even diffused within a gel-like matrix, will be substantially washed away by the body's natural mechanisms, thus lessening the benefit of the treatment agent that may otherwise be obtained. Thus, sustained-release carriers infused with treatment agent that release the treatment agent over an extended time period can be beneficial by increasing the amount of time in which the infarct region is exposed to the treatment agent. Sustained-release carriers include, but are not limited to, (i) microparticles or nanoparticles (hereinafter interchangeably referred to as microparticles), (ii) microfibers or nanofibers (hereinafter interchangeably referred to as microfibers) and (iii) liposomes and polymerosomes.
In addition, in some embodiments, a bioerodable carrier may be infused with (or without) a treatment agent and delivered to a treatment site to act as a “docking site” for endogenous myocardial stem cells and encourage their differentiation into cardiomyocytes. A.
In some embodiments, the sustained-release carrier is a microparticle. Various methods can be employed to formulate and infuse or load the microparticles with treatment agent. In some embodiments, the microparticles are prepared by a water/oil/water (W/O/W) double emulsion method. In the W1 phase, an aqueous phase containing treatment agent, is dispersed into the oil phase consisting of polymer dissolved in organic solvent (e.g., dichloromethane) using a high-speed homogenizer. Examples of sustained-release polymers include, but are not limited to, poly(D,L-lactide-co-glycolide) (PLGA), poly(D,L-lactide) (PLA) or PLA-PEEP co-polymers, poly-ester-amide co-polymers (PEA) and polyphophazines. The primary water-in-oil (W/O) emulsion is then dispersed to an aqueous solution containing a polymeric surfactant, e.g., poly(vinyl alcohol) (PVA), and further homogenized to produce a W/O/W emulsion. After stirring for several hours, the microparticles are collected by filtration.
B.
In some embodiments, the sustained-release carrier is a microfiber or nanofiber. For example, the treatment agent (or no treatment agent) infused microfiber can be formulated by electrospinning. “Electrospinning” is a process by which microfibers are formed by using an electric field to draw a polymer solution from the tip of a capillary to a collector. A voltage is applied to the polymer solution which causes a stream of solution to be drawn toward a grounded collector. Electrospinning generates a web of fibers which can be subsequently processed into smaller lengths.
Examples of sustained-release polymers which can be used in electrospinning include, but are not limited to, PLGA, PLA or PLA-PEEP co-polymers, PEA, polyphosphazines and collagen. In one method, the treatment agent is mixed with a bioerodable polymer solution, a solvent and a surfactant. Examples of surfactants can include, but are not limited to, anionic or cationic surfactants. Useful anionic surfactants include, but are not intended to be limited to, bis(2-ethylhexyl) sodium sulfosuccinate (AOT), bis(2-ethylhexyl)phosphate (NaDEHP), tauroglycocholate, and sodium lauryl sulfate. A useful cationic surfactant is tetradecyltrimethyl-ammonium bromide (TTAB). An example of a solvent includes, but is not limited to, hexafluoro isopropanol. The treatment agent-infused polymer solution is then subjected to electrospinning. As the solvent evaporates during electrospinning, the treatment agent incorporates and distributes within the polymer by non-covalent interactions. The resultant microfibers which can be from about 0.5 μm to about 3 μm in diameter form a web which may then be processed into smaller lengths of about 0.5 μm to about 500 μm. Based on the treatment agent, in some applications, microfibers may be a preferred sustained-release carrier due to the non-aqueous process by which they are formed. In some applications, microspheres may be preferable when the treatment agent is hydrophilic. In some applications, a microfiber is a preferred sustained-release carrier due to its release pharmacokinetic profile when compared to the release pharmacokinetic profile of a microsphere. In some cases, microspheres as well as microfibers can be used as a carrier of one or more than one treatment agent as the two types of carriers will provide different pharmacokinetic release profiles which may be advantageous for therapy.
In one embodiment, fibers can be electrospun from collagen and elastin dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (HFP), forming a polymer solution. A treatment agent can be added to the polymer solution. A surfactant and a stabilizer can be used to evenly disperse the treatment agent in the solvent. The polymer solution can then be loaded into a syringe and placed in a syringe pump for metered dispensing at a predetermined rate. A positive output lead of a high voltage supply can be attached to a needle on the syringe. The needle can be directed to a stainless steel grounded target placed approximately 10 cm from the needle tip, which can be rotated at a predetermined speed to ensure an even coating. The distance of the needle from the target can be varied depending upon the diameter of the fibers needed. The resultant microfibers are from about 0.5 μm to about 3 μm in diameter and the resulting non-woven mat of fibers can then be processed into smaller lengths of about 0.5 μm to about 500 μm.
C.
In some embodiments, the sustained-release carrier is a liposome or a polymerosome. “Liposomes” are artificial vesicles that are approximately spherical in shape and can be produced from natural phospholipids and cholesterol. In one method, phospholipids are mixed with cholesterol in chloroform. Suitable phospholipids include, but are not limited to, dimyristoyl phosphatidyl choline or dipalmitoyl ethanolamine. In some embodiments, hydrophobic treatment agent can be added with an optional co-solvent, such as heptane or toluene. The liposomes may also be hydrophilically modified with an agent such as polyethylene glycol or dextran. After mixing, the solvent (and optional co-solvent) can be evaporated with heat or ambient temperature in a round bottom flask. Resultant lipids will be deposited on the glass surface. In some embodiments, hydrophilic treatment agent and water can be added to the flask and sonicated to form liposomes. The resultant suspension can be pressure filtered through ceramic pore size controlled filters to reduce liposome particle size. In the case of a polymerosome, a similar manufacturing technique can be used as that of a liposome. Polymerosomes can be formed from di-block co-polymers of differing solubility. For example, one block can be hydrophobic, e.g., poly lactic acid, polycaprolactone, n-butyl acrylate, and the other block can be hydrophilic, e.g., poly(ethylene glycol), poly(acrylic acid).
Matrix Systems
A biocompatible matrix system can be used to suspend the treatment agent or the treatment agent-infused sustained-release carrier for delivery to the infarct region. In some embodiments, the matrix system can be a one-component or a two-component gel. In some embodiments, the matrix system is a two-component gel. Two-component gels can include, for example, fibrin glues (e.g., two components comprising fibrinogen and thrombin), self-assembled peptides or alginate constructs.
In some embodiments, the matrix system is a one-component gel. An example of a one-component gel includes an acrylate agent that is biocompatible. The one-component gel serves in one aspect to disperse the sustained-release carrier in order to form a more uniform scaffold over the entire infarct zone and may include border zone as well. For example, the one-component gel may be sodium hyaluronate. The gel disperses the sustained-release carrier acting as a suspending media.
A.
In some applications, the two-component gelation system includes a fibrin glue. Fibrin glue consists of two main components, fibrinogen and thrombin. Fibrinogen is a plasma glycoprotein of about 340 kiloDaltons (kDa) in its endogenous state. Fibrinogen is a symmetrical dimer comprised of six paired polypeptide chains, alpha, beta and gamma chains. On the alpha and beta chains, there is a small peptide sequence called a fibrinopeptide which prevent fibrinogen from spontaneously forming polymers with itself. In some embodiments, fibrinogen is modified with proteins. Thrombin is a coagulation protein. When combined in equal volumes, thrombin converts the fibrinogen to fibrin by enzymatic action at a rate determined by the concentration of thrombin. The result is a biocompatible gel which gelates when combined at the infarct region. Fibrin glue can undergo gelation at about 10 to about 60 seconds. Examples of other fibrin glue-like systems include, but are not limited to, Tisseel™ (Baxter), CoSeal™ (Baxter), Crosseal™ (Omrix Biopharmaceuticals, Ltd.), Hemaseel® (Haemacure Corp.) and CoStasis® (Angiotech Pharmaceuticals).
B.
In some embodiments, the two-component gel comprises self-assembled peptides. Self-assembled peptides generally include repeat sequences of alternating hydrophobic and hydrophilic amino acid chains. The hydrophilic amino acids are generally charge-bearing and can be anionic, cationic or both. Examples of cationic amino acids are lysine and arginine. Examples of anionic amino acids are aspartic acid and glutamic acid. Examples of hydrophobic amino acids are alanine, valine, leucine, isoleucine, or phenylalanine. Self-assembled peptides can range from 8 to about 40 amino acids in length and can assemble into nanoscale fibers under conditions of physiological pH and osmolarity. In sufficient concentration and over time, the fibers can assemble into an interconnected structure that appears macroscopically as a gel. Self-assembled peptides typically undergo gelation between several minutes to several hours. Examples of self-assembled peptides include, but are not limited to: AcN-RARADADARARADADA-CNH.sub.2 (RAD 16-II) wherein R is arginine, A is alanine, D is aspartic acid, and Ac indicates acetylation; VKVKVKVKV-PP-TKVKVKVKV-NH.sub.2 (MAX-1) wherein V is valine, K is lysine and P is proline; and AcN-AEAEAKAKAEAEAKAK-CNH.sub.2 wherein A is alanine, K is lysine and E is glutamic acid (EAK16-II).
Example
In one example, the self-assembled peptide is RAD 16-II. At low pH and osmolarity, RAD 16-II forms a solution. At physiological pH and osmolarity, RAD 16-II forms a gel although gel formation can be slow. In some embodiments, RAD 16-II is mixed with phosphate buffer saline (PBS) to form a first component solution. In some embodiments, the first component solution can be co-injected with a second component comprising sodium chloride, sucrose or other osmolarity modifying substance using, for example, a dual-injection delivery assembly. In some embodiments, the components can be co-injected with carriers such as angiogenesis promoting factors, cell survival promoting factors and/or endogenous recruiting factors. These factors bind non-specifically to the self-assembled peptides by electrostatic interactions, and this binding can control or retard the release of the factors.
C.
In some embodiments, the two-component gel is an alginate construct. For example, the alginate construct may be collagen or gelatin grafted alginate. In one example, a first component can be a solution of about 0.5 percent to about 1.0 percent alginate while a second component can be a solution of about 40 mM to about 180 mM calcium chloride. One example of a suitable amount of components is about 200 microliters of alginate solution and about 200 microliters of calcium chloride. In one embodiment, a desired amount of a treatment agent may be introduced with the alginate solution.
Methods of Manufacture
Example
In one embodiment, collagen electrospun fibers can be processed to a range from about 200 nm and about 1300 nm. The range of electrospun fibers is approximately the range of naturally occurring type 1 and type 3 fibers which make up the heart matrix. Thus, the electrospun fibers may mimic endogenous fibers and accelerate growth of repair tissue to the infarct region, in particular, on the heart. The fibers can be dispersed throughout one component of a two-component gel. The two components can then be delivered to myocardial infarct region. The fibers can provide “docking sites” for endogenous myocardial stem cells and encourage their differentiation into cardiomyocytes. The gel can provide temporary containment of the fibers and prevent premature removal by macrophage cells.
The fibers can be fabricated such that they include an agent or no agent. Examples of agents can include a chemoattractant, such as SDF-1, or a cell survival promoting factor, such as IGF-1. In one embodiment, SDF-1 may be incorporated within the electrospun fibers and the resultant agent infused electrospun fibers may be dispersed throughout one component of a two-component gel. When delivered, the release of SDF-1 may recruit endogenous stem cells to the infarct region where they will adhere to the electrospun fibers and differentiate into stem cells.
In another embodiment, IGF-1 may be incorporated within the electrospun fibers and the resultant agent infused electrospun fibers may be dispersed throughout one component of a two-component gel. Stem cells may be incorporated within the other component of the two-component gel. When delivered, the stem cells may be temporally immobilized in the gel and adhere to the electrospun fibers. IGF-1 may enhance stem cell survival.
It should be appreciated that any of the above-described methods may be combined to treat an infarct region.
Methods of Treatment
Devices which can be used to deliver each component of the gel include, but are not limited to, dual-needle left-ventricle injection devices and dual-needle transvascular wall injection. Methods of access to use the injection devices include access via the femoral artery or the sub-xiphoid. “Xiphoid” or “xiphoid process” is a pointed cartilage attached to the lower end of the breastbone or sternum, the smallest and lowest division of the sternum. Both methods are known by those skilled in the art.
In one embodiment, delivery assembly 400 includes main needle 420 disposed within delivery lumen 430. Main needle 420 is movably disposed within delivery lumen 430. Main needle 420 is, for example, a stainless steel hypotube that extends a length of the delivery assembly. Main needle 420 includes a lumen with an inside diameter of, for example, 0.08 inches (0.20 centimeters). In one example for a retractable needle catheter, main needle 420 has a needle length on the order of 40 inches (1.6 meters) from distal portion 405 to proximal portion 415. Lumen 410 also includes separate, possibly smaller diameter, auxiliary lumen 440 extending, in this example, co-linearly along the length of the catheter (from a distal portion 405 to proximal portion 415). Auxiliary lumen 440 is, for example, a polymer tubing of a suitable material (e.g., polyamides, polyolefins, polyurethanes, etc.). At distal portion 405, auxiliary lumen 440 is terminated to auxiliary needle end 450 co-linearly aligned with a delivery end of needle 420. Auxiliary lumen 440 may be terminated to auxiliary needle end 450 with a radiation-curable adhesive, such as an ultraviolet curable adhesive. Auxiliary needle end 450 is, for example, a stainless steel hypotube that is joined co-linearly to the end of main needle 420 by, for example, solder (illustrated as joint 455). Auxiliary needle end 450 has a length on the order of about 0.08 inches (0.20 centimeters).
Referring to
The proximal end of main needle 420 includes adaptor 470 for accommodating a substance delivery device (e.g., a component of a two-component bioerodable gel material). Adaptor 470 is, for example, a molded female luer housing. Similarly, a proximal end of auxiliary side arm 460 includes adaptor 480 to accommodate a substance delivery device (e.g., a female luer housing).
The design configuration described above with respect to
In one embodiment, catheter assembly 500 is defined by elongated catheter body 550 having proximal portion 520 and distal portion 510.
Guidewire cannula 570 is formed within catheter body (from proximal portion 510 to distal portion 520) for allowing catheter assembly 500 to be fed and maneuvered over guidewire 580. Balloon 530 is incorporated at distal portion 510 of catheter assembly 500 and is in fluid communication with inflation cannula 560 of catheter assembly 500.
Balloon 530 can be formed from balloon wall or membrane 535 which is selectively inflatable to dilate from a collapsed configuration to a desired and controlled expanded configuration. Balloon 530 can be selectively dilated (inflated) by supplying a fluid into inflation cannula 560 at a predetermined rate of pressure through inflation port 565. Balloon wall 535 is selectively deflatable, after inflation, to return to the collapsed configuration or a deflated profile. Balloon 530 may be dilated (inflated) by the introduction of a liquid into inflation cannula 560. Liquids containing treatment and/or diagnostic agents may also be used to inflate balloon 530. In one embodiment, balloon 530 may be made of a material that is permeable to such treatment and/or diagnostic liquids. To inflate balloon 530, the fluid can be supplied into inflation cannula 560 at a predetermined pressure, for example, between about one and 20 atmospheres. The specific pressure depends on various factors, such as the thickness of balloon wall 535, the material from which balloon wall 535 is made, the type of substance employed and the flow-rate that is desired.
Catheter assembly 500 also includes substance delivery assembly 505 for injecting a substance into a myocardial infarct region. In one embodiment, substance delivery assembly 505 includes needle 515a movably disposed within hollow delivery lumen 525a. Delivery assembly 505 includes needle 515b movably disposed within hollow delivery lumen 525b. Delivery lumen 525a and delivery lumen 525b each extend between distal portion 510 and proximal portion 520. Delivery lumen 525a and delivery lumen 525b can be made from any suitable material, such as polymers and copolymers of polyamides, polyolefins, polyurethanes, and the like. Access to the proximal end of delivery lumen 525a or delivery lumen 525b for insertion of needle 515a or 515b, respectively, is provided through hub 540. Delivery lumens 525a and 525b may be used to deliver first and second components of a two-component gel composition to a myocardial infarct region.
Referring now to
It is an object of this invention to prevent the inadvertent mixture of the two gel components of the present invention prior to their delivery into the target tissue. Controlling the flow direction of injectate moved through the distal end of each needle will accomplish this. For example, by providing divergent flow paths for each gel component, when the gel components are injected while the distal needle portion is positioned within the turbulent blood flow of a heart chamber, the gel components will be quickly dispersed by the circulating blood before they are able to interact with each other. In contrast, when the distal needle portion 405 is inserted within the heart tissue and the gel components are injected through the divergent flow paths, the resistance of the heart tissue will moderate the dispersal of the gel components, allowing them to admix and form a two-component gel composition.
In accordance with this invention, the distal needle portion 405 may be configured as shown in
As shown in
An alternative configuration for a distal needle portion 405 that prevents the inadvertent mixture of injectate is shown in
It will be appreciated that the main needle 420 and auxiliary needle 450 of the embodiments shown in
Another method of ensuring that injectate is not inadvertently mixed is to longitudinally space the distal ends of the needles while they are positioned outside of the target tissue.
Referring now to
Referring now to
In the embodiments that include an offset distance between needle tips such as those described in
Alternatively, the leading needle may have a blunted distal tip to prevent it from puncturing the tissue before the lagging needle has contacted the tissue also. A blunted needle tip may be incorporated in any of the needles described throughout this description at least for this purpose.
Referring now to
Referring now to
As discussed in several of the embodiments above, the needle assembly may advantageously comprise a leading needle that is offset from another needle in a first configuration. This prevents mixing of gel components when they are released from the needle assembly outside of the presence of tissue, and therefore mitigates the risk of a thromboembolic event. A suitable offset distance for preventing inadvertent mixture of gel components outside of the target tissue is contemplated to be about 1-5 mm. In a second configuration, the leading needle is moved relative to the lagging needle by a reactive load applied by the target tissue until both needles contact and puncture the tissue. Following tissue puncture, gel components may be delivered through each needle lumen to admix within the target tissue and form a two-component gel composition in accordance with this invention. The two needles may be configured to slide over one another. This can be enabled, for example, by housing the needles within a sheath over at least a portion of their length. Alternatively, the needle components may be constrained within bands placed at predetermined positions along the length of the catheter device.
Referring now to
Referring now to
Upon retraction of the needle assembly 600 from the tissue, the biasing element 650 will release potential energy and again force the separation of the distal ends of needle 640 and 642, thereby preventing gelation of the two gel components within the heart chamber and mitigating the risk of a thromboembolic event.
In this embodiment, the stops 644 and 646 may be formed from collars that are bonded to the surface of the needles as described. Bonding may be facilitated through the use of adhesive or thermal welding. Alternatively, the collars may be press fit with the corresponding needle components. The collars are sized and configured to provide adequate seating for the biasing element 650 without excessively impeding the flow of fluid within the needle components.
It may be desirable to vary the distance of the offset between the first and second needle. In this case, an adjustable stop may be provided on one or both needles to affect this offset distance. The stop may be threaded, for example, and be engaged with a screw thread on the corresponding needle surface. Rotation of the needle via an association with a proximal handle component of the delivery device (not shown) would cause movement of the stop, which would in turn adjust the offset distance between the distal ends of the needle components.
Biasing element 650 is preferably formed from a compression spring that applies a separation load to first needle 640 and second needle 642. However, alternative embodiments are possible, such as the use of a volute, Belleville, tension, v-spring and leaf-type spring, or other configurations that may be contemplated by one skilled in the art.
Referring to
In an embodiment, biasing element 650 may be a compression spring having a generally cylindrical profile and thus may be placed concentrically with first delivery needle 640 between first stop 644 and second stop 646. Thus, as first stop 644 moves toward second stop 646, and more particularly toward the extended portion of second stop 646 that contains bore 1504, biasing element 650 may compress and shorten in length. Accordingly, as the needle catheter device transitions from the first configuration shown in
The side-by-side needle configuration of
Ideally, a needle assembly for delivering injectate into tissue will have a minimized cutting profile to reduce tissue damage caused by needle puncture. The ideal needle assembly will also prevent excessive back pressure in order to ease delivery of the injectate. These are competing goals since needle profile can be decreased to minimize puncture size while lumen profile can be increased to reduce back pressure.
Referring now to
Referring now to
Referring now to
An alternative embodiment of a needle assembly 800 in accordance with this invention is shown in
Referring now to
Notwithstanding the description above, the needle components of this invention may be formed from any material that is suitable for the intended purpose. Needle components may therefore be formed from an appropriate metal, such as stainless steel, Nitinol, or cobalt-chromium alloys such as L605 or MP35N, any equivalents thereof, alloys thereof, and combinations thereof. Further, the one or both needle components may be formed from a suitable polymeric compound such as nylon, urethane, polyurethane, polyvinylchloride, polyester, PEEK, PTFE, PVDF, Kyner, polyimide, or polyethylene of various suitable densities. Further, one or both needle components may be a combination of metal and polymer materials, such as a polymer tube reinforced by a metal braid or coil, as are well known in the art.
The needle components described above are sized and configured to puncture the target tissue and effectively deliver the intended gel components therein. Accordingly, a wide range of needle sizes exist for achieving the goal of the invention. Nonetheless, it is contemplated that needle components in accordance with this invention may have an outer dimension at the distal end of between 23 and 33 Gauge.
In accordance with this invention, the bevel angle of the needles may be varied to facilitate tissue puncture. Therefore, the bevel angle could be in the range of 5 to 80 degrees. More preferably, the bevel angle could be in the range of 10 to 65 degrees, and even more preferably, the bevel angle could be in the range of 15 to 45 degrees. Further, it may only be necessary for one of the needle components to include a beveled tip. The beveled tip needle would facilitate tissue puncture, while the second needle may have a blunted or flat tip that is inserted within the punctured tissue.
Referring to
Referring to
Referring to
Referring to
In an embodiment, biasing element 650 may be a contiguous body formed from a resilient material, which may be axially compressed. For example, biasing element 650 may be an elastomer of a sufficiently low durometer to be compressed by first stop 644 and second stop 646 when first delivery needle 640 and second delivery needle 642 move axially relative to each other. In a particular embodiment, biasing element 650 may be formed from a continuous elastic material formed in a solid or foam structure with high resilience and a Shore A durometer of less than about 30. For example, biasing element 650 may be formed from an elastomer, such as latex, silicone, or polyurethane. Numerous alternative materials and structures may be substituted to provide a biasing element 650 that stores potential energy as it is compressed under a load, and resiliently expands back to an original configuration when the load is removed or decreased.
Referring to
First delivery needle 640 may be coupled with first stop 644, which in an embodiment includes a cylindrical collar bonded to an outer diameter of first delivery needle 640. Similarly, second stop 646 may be coupled with second delivery needle 642 through a bond and be positionally associated with first delivery needle 640 by receiving first delivery needle 640 within second bore 2101, as described above. Therefore, in an embodiment, biasing element 650 may be sandwiched between first stop 644 and second stop 646 while being associated only with one needle. For example, biasing element 650 may be a cylindrical form concentrically located about first delivery needle 640.
Referring to
Referring to
In addition to being any of a number of spring configurations, such as those described above, biasing element 650 may be configured to exert a separation force to the delivery needles that varies according to offset distance 1501. For example, in an embodiment biasing element 650 may be a compression spring that becomes completely stacked, i.e., in which the pitch distance becomes zero, once the desired offset distance 1501 is reached before puncturing tissue. For example, an offset distance 1501 of zero may facilitate gel component admixture within a punctured tissue, and thus, biasing element may be designed to reach a stacked coil configuration when offset distance 1501 reaches zero, thereby producing a spike in system stiffness and facilitating tissue puncture. Alternatively, biasing element 650 may include a variable stiffness spring with a spring constant that depends on the deflection of biasing element 650. For example, the spring constant, and thus the system stiffness, may increase significantly after basing element 650 deforms a certain amount. Such springs are known and may be designed using variable pitches or diameters over the spring length to result in the variable spring constant.
Referring to
Referring to
Referring to
Referring to
Referring to
Referring to
Referring to
As in the embodiments described above, first delivery needle 640 may be in fluid communication with first adaptor 470 and second delivery needle 642 may be in fluid communication with second adaptor 480. More particularly, the needle catheter device may include a distal portion having distal ends, e.g., first distal tip 2301 and second distal tip 2303, of first delivery needle 640 and second delivery needle 642. Furthermore, the needle catheter device may include a proximal portion having first adaptor 470 and second adaptor 480. First adaptor 470 may receive a first gel component and deliver it through first lumen 1502 to first distal tip 2301 and second adaptor 480 may receive a second gel component and deliver it through second lumen 1503 to second distal tip 2303. An elongated catheter body, such as lumen 410 or elongated catheter body 550, may retain lumens 1502, 1503 over the needle catheter device length between the proximal and distal portions.
A method of using a needle catheter device having a side-by-side needle configuration includes advancing the needle catheter device within a patient toward a target tissue 700. Advancement may be controlled by manually advancing the elongated catheter body of the needle catheter device via femoral or sub-xiphoid access until first distal tip 2301 of first delivery needle 640, which is longitudinally offset from second distal tip 2303 of second delivery needle 642, contacts tissue 700. After contacting tissue 700 with first delivery needle 640, the needle catheter device may be advanced further to transition the needle catheter device from the first configuration to a second configuration. During this transition, first delivery needle 640 in contact with 700 may remain stationary, while second delivery needle 642 advances. This relative movement between needles may be accompanied by compression of biasing element 650 under the reactive load applied by tissue 700 on first delivery needle 640. As resilient biasing element 650 is compressed, it stores more potential energy.
Once second distal tip 2303 contacts tissue 700, the needle catheter device is in a second configuration in which biasing element 650 stores more potential energy than in the first configuration, and in which the needle catheter device system has sufficient stiffness to facilitate for the puncture of tissue 700. Thus, the needle catheter device may be advanced further until distal tips 2301, 2303 puncture tissue 700 while they are approximately longitudinally aligned, e.g., while an offset distance 1501 is less than offset distance 1501 in the first configuration.
Following puncture of tissue 700, a first gel component may be delivered through first lumen 1502 and a second gel component may be delivered through second lumen 1503. Consistent with the side-by-side configuration, the gel components are isolated during delivery and will not contact each other or the other needle from which they are delivered. However, upon exiting the distal tips, the gel components may admix to form a two-component gel composition.
Following injection of the gel components, the needle catheter device may be removed from tissue 700. Removal eliminates the reactive load applied to the needles by tissue 700, and thus, biasing element 650 may again urge the needles to the first configuration in which first distal tip 2301 is longitudinally spaced apart from second distal tip 2303 by a greater offset distance 1501 than in the second configuration. Movement of the needles in this way is accompanied by biasing element 650 releasing potential energy to transition toward a less compressed state. Therefore, the needle catheter device returns to the first configuration and may be removed from the patient, or may be advanced again toward a different target location of tissue 700 for further injection treatments.
From the foregoing detailed description, it will be evident that there are a number of changes, adaptations and modifications of the present invention which come within the province of those skilled in the art. The scope of the invention includes any combination of the elements from the different species and embodiments disclosed herein, as well as subassemblies, assemblies, and methods thereof. However, it is intended that all such variations not departing from the spirit of the invention be considered as within the scope thereof.
This is a continuation-in-part of U.S. application Ser. No. 12/963,397, filed Dec. 8, 2010, now abandoned, which is a divisional of U.S. application Ser. No. 11/978,986, filed Oct. 29, 2007, now abandoned, which is a continuation-in-part of U.S. application Ser. No. 11/447,340, filed Jun. 5, 2006, now U.S. Pat. No. 8,187,621, which is a continuation-in-part of U.S. application Ser. No. 11/361,920, filed Feb. 23, 2006, now U.S. Pat. No. 8,303,972, which is a continuation-in-part of U.S. application Ser. No. 11/110,223, filed Apr. 19, 2005, now U.S. Pat. No. 8,828,433, all of which are incorporated by reference herein.
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