WO2001010315A1

WO2001010315A1 - Gene therapy platformed needle and method of administering a therapeutic solution to a heart

Info

Publication number: WO2001010315A1
Application number: PCT/US2000/021399
Authority: WO
Inventors: Todd K. Rosengart; Ronald G. Crystal
Original assignee: Cornell Research Foundation, Inc.
Priority date: 1999-08-05
Filing date: 2000-08-04
Publication date: 2001-02-15
Also published as: EP1199992A1; CA2378250A1; AU6521500A; WO2001010315A9

Abstract

The invention provides a device for the delivery of a therapeutic solution, in particular, an angiogenesis-promoting substance into a heart. The device includes an elongated needle (10) having a stop, or platform (44), spaced from the distal needle tip (42) to limit the depth of penetration and stabilize the needle in the cardiac tissue. The elongated needle body (30) is flexible enough to maneuver around thoracic and cardiac geometry, yet sufficiently rigid to facilitate such maneuvering. This minimally invasive procedure allows for delivery of the solution 'at a distance' through small incisions.

Description

GENE THERAPY PLATFORMED NEEDLE AND

METHOD OF ADMINISTERING A

THERAPEUTIC SOLUTION TO A HEART

FIELD OF THE INVENTION

The invention relates to devices and methods for delivering a therapeutic solution to the heart, and more specifically to a needle and a method for delivering an angiogenic substance into a beating heart.

BACKGROUND OF THE INVENTION

There have been numerous recent advances in therapies such as angioplasty and coronary bypass surgery, which are now commonly used in the treatment of ischemic heart disease. There still exist a significant number of patients for whom these conventional therapies are not feasible options in a number of circumstances. For example, conventional coronary bypass surgery is not a treatment option in patients with diffuse small vessel coronary artery disease due to the small size and large number of diseased vessel segments. Further, re-occlusion of a diseased vessel may occur despite multiple angioplastic procedures or bypass surgeries.

One promising alternative treatment for ischemic heart disease is the delivery of angiogenesis-promoting substances to the heart tissue to induce angiogenesis.

Angiogenesis is a complex biological process that results in the growth of new blood vessels within tissue. Angiogenesis is an essential process common to several normal and pathologic conditions including embryologic development, wound healing, development of neoplasms, and the like. Angiogenesis involves the disruption of vascular basement membranes, migration and proliferation of endothelial cells, and subsequent blood vessel formation and maturation.

Angiogenesis has also been induced in heart tissue for reperfusion of tissue compromised by myocardial ischemia. Several growth factors or mediators are known to elicit angiogenic responses, and administration of these mediators promotes revascularization of ischemic tissues. These growth factors are typically proteins which stimulate endothelial cell reproduction in the target tissue. Vascular endothelial growth factor (VEGF) is one of the most specific of the known angiogenic mediators due to localization of its receptors almost exclusively on endothelial cells. Receptors for VEGF are upregulated under ischemic conditions. Accordingly, the administration of VEGF augments the development of collateral vessels and improves function in peripheral and myocardial ischemic tissue. Delivery of VEGF remains a significant challenge. The half-life of VEGF is very short. Accordingly, the tissue must be exposed to the growth factor for a period of days. The administration of high doses of VEGF, however, is associated with hypotension. The growth factor should be limited to the target tissue inasmuch as the systemic administration of VEGF can induce angiogenesis in tissues other than that which has been targeted, such as occult tumors, or sensitive non-diseased organs, such as the retina. This promiscuous induction of angiogenesis can cause blindness, increase the aggressiveness of tumor cells, and lead to a multitude of other negative side-effects.

The growth factor can be delivered to the target tissue through the use of indwelling catheters over a period of time. A preferred method of delivering the growth factor, however, is in the form of gene transfer, for example, by a replication deficient adenoviral vector containing the transgene coding for the growth factor. Under this method, a quantity of the adenoviral vector having the desired genetic component is delivered to the treatment area by injection in solution.

In the past, an open-chest procedure has been used to deliver the treatment solution. According to this procedure, the patient's chest is opened surgically to expose the heart. The solution containing the adenoviral vector is then delivered to the heart tissue by using a syringe to make a number of injections in a grid-like pattern, with the surgeon keeping track of the location of each injection. U.S. Patent Application Serial No. 09/357,010, filed July 19, 1999, which is a continuation of PCT/US98/01638, filed January 29, 1998, and published on July 30, 1998, as WO 98/32859, which is assigned to the assignee of the present invention, discloses a method of enhancing the level of perfusion of blood to a target tissue during such a procedure.

Once injected, the adenoviral vector causes the cells in the target tissue to produce the desired growth factor, and this growth factor production of the treated cells will continue for a period of time. Previous studies have shown the feasibility and efficacy of safe, sustained, and localized expression of angiogenesis-promoting growth factors utilizing adenoviral-mediated gene transfer therapy.

It is desirable to be able to provide the above described therapy without the necessity of performing open-chest surgery on the patient. U.S. Patent

Application Serial No. 09/035,892 filed March 6, 1998, discloses an injection apparatus and method for providing gene therapy treatment to the heart or other internal organs without necessitating such open heart surgery. The device includes an elongate flexible tubular body having a hollow needle mounted at the distal end for delivery of the therapeutic substance to the tissue. This and other currently available devices have relatively complex designs and, accordingly, are extremely expensive to manufacture. Further, they may be difficult to manipulate around the contours of the heart and ensure stability of the needle against the target tissue.

OBJECTS OF THE INVENTION It is a primary object of the invention to provide a device and method of delivering a therapeutic solution into a beating heart that may be utilized in various procedures, and a more specific object of the invention to provide a minimally invasive device and method of delivering angiogenesis-promoting substances from a remote location to an area of ischemic heart tissue without necessitating open-chest surgery.

It is a related object of the invention to provide a device and method of delivering angiogenesis-promoting substances to an area of diseased tissue with ease and efficiency.

Another object of the invention to provide such a device that may be manipulated to contour to cardiac and thoracic geometry.

An additional object of the invention is to provide such a device and method that facilitates injection by providing stable positioning of the needle to ensure injection intramyocardially, as opposed to injecting into the ventricle or the pericardium. A further object of the invention is to provide a device and method that may be utilized in areas behind or around the heart where positioning can not be readily visually confirmed. A related object is to provide such a device and method that may provide non- visual confirmation of epicardial contact to facilitate such appropriate positioning of the needle tip. Another object of the invention is to provide such a device and method with reduced trauma and reduced recovery time for the patient.

A further object of the invention is to provide such a device and method that minimizes extravasation of the injectate.

Yet another object of the invention is to provide a single-use disposable device that may be relatively economically manufactured such that its usage is not cost prohibitive. BRIEF SUMMARY OF THE INVENTION

In accomplishing these and other objects of the invention, there is provided a flexible elongated needle having a stabilizing platform spaced from the distal tip. The needle is preferably approximately 100-200 mm (approximately 4-8 inches) long with the platform disposed obliquely, approximately 5-10 mm (approximately 0.20 to 0.80 inch) from the tip of the needle. The elongated needle is preferably on the order of 20-25 Ga (e.g., 22 Ga) and the needle tip on the order of 25-30 Ga (e.g., 27 Ga) with a bevel sharp tip. The platform is preferably approximately 5-6 mm (approximately 0.20 to 0.25 inch) in diameter and is disposed obliquely relative to the needle tip. The proximal end of the needle comprises a standard hub sized to receive the distal end of a syringe or other device for containing and delivering a therapeutic solution. An appropriate metering device may also be provided to control the amount of therapeutic substance injected at the injection site. The device and method may be utilized in administration of a therapeutic solution by injection along an outer surface of the heart or along an inner surface of the heart by any appropriate method. In particular, an angiogenesis-promoting substance, or, more specifically, an adenoviral vector containing a transgene encoding a vascular endothelial growth factor (VEGF), can be introduced into myocardial territories in predetermined quantities at a plurality of points to induce the growth of bypass vessels which allow the bridging of narrowed or occluded coronary vessels. The treatment also can be used to induce the growth of new vessels in myocardial territories poorly supplied by the native coronary vasculature. During use, the needle is advanced into position, and the needle tip penetrates the heart tissue. The flexibility of the elongated needle body permits the needle to contour the path of delivery to the cardiac and thoracic geometry, providing the cardiologist great latitude in placement of the needle. The platform, as well as its oblique positioning relative to the needle tip limits the depth of penetration and allows stabilization of the needle against the epicardial surface of the heart. The solution then can be injected into the tissue by actuating the syringe. The long elongated, small diameter needle device allows for precise delivery of the injectant from a remote distance through a relatively small incision.

The device may be utilized during open-heart surgery, or advanced into the heart through any artery, including, for example, the femoral artery. The device may also be utilized in the manner disclosed in PCT Application No. PCT/US99/03731 filed March 5, 1999 and designating the United States, which is hereby incorporated by reference. More specifically, the patient's lung may be partially collapsed by the introduction of gas into the patient's thoracic cavity. This enlarges the working area for injection of the therapeutic substance and increases access to heart tissue. The delivery of the therapeutic substance to the myocardium can be by way of any suitable route, transpericardially, as well as endocardially. An electrode may be located on the on the platform section needle, and connected to an ECG, for determining when the needle has penetrated the patient's myocardium and is properly positioned. Penetration of the myocardium by the needle will show as a current injury on the ECG. Thus, this arrangement facilitates appropriate positioning of the needle tip in locations behind or around the heart beyond the line of sight provided by the surface incision.

These and other features and advantages of the invention will be more readily apparent upon reading the following description of a preferred exemplified embodiment of the invention and upon reference to the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGURE 1 is a perspective view of a needle constructed in accordance with teachings of the invention and a delivery syringe.

FIG. 2 is an enlarged fragmentary view of the distal end of the needle of FIG. 1 , partially broken away.

FIG. 3 is a cross-section of the needle taken along line 3-3 in FIG. 2.

FIG. 4 is a cross-section of the needle taken along line 4-4 in FIG. 2.

FIG. 5 is a view of the needle of FIG. 1 extending into the heart tissue.

While the invention will be described in connection with certain preferred embodiments, there is no intent to limit it to those embodiments. On the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of the invention as defined by the appended claims.

DESCRIPTION OF THE PREFERRED EMBODIMENT Turning now to the drawings, there is shown in FIG. 1 a delivery device 6 constructed in accordance with teachings of the invention for use in delivering a therapeutic solution to the tissue of a heart, especially a beating heart. The device 6 includes a syringe 8 or other solution supply device and a platform needle 10. The distal end of the needle 10 is designated generally as 12 and the proximal end is designated as 14. During use, the device 6 may, for example, be inserted through a thoracoscopic port (not shown), giving thoracoscopic access to the patient's heart. The therapeutic solution my then be injected directly into the cardiac tissue in a predetermined quantity.

In the currently preferred embodiment of the invention, the solution supply device is a conventional syringe 8. The syringe 8 includes a hollow cylindrical body 16 having a distal neck-in end 18. A plunger shaft 20 with a plunger 22 mounted on the distal end thereof and a thumb button 24 mounted to the proximal end thereof is slidably disposed within the cylindrical body, the plunger extending outward from the body. During use, the operator may actuate the plunger 22 by depressing the plunger thumb button 24 to deliver the therapeutic solution. While the solution supply device has been explained with regard to a syringe

8, it will be appreciated by those of skill in the art that the supply device can be of any appropriate design. Additionally, the supply device may include any appropriate metering device to control the amount of therapeutic substance injected at the injection site. For example, and as explained in PCT Application No. PCT/US99/03731 filed March 5, 1999, the syringe 8 may include a shaft having screw threads or include a ratchet mechanism which permits the plunger button to advance within the cylindrical body only a predetermined distance to permit only a predetermined amount of therapeutic solution to be administered at a given injection site. Alternately, the administration of a controlled amount of the therapeutic solution may be facilitated by computer controlled device.

In accordance with the invention, the inventive platformed needle 10 includes an elongated flexible body or cannula 30, as shown in FIGS. 1 and 2, having an elongated bore 32 extending therethrough. In the preferred embodiment of the invention, the needle body 30 is on the order of 100-200 mm (4 to 8 inches) long. According to an important feature of the invention, the needle body 30 desirably is be sufficiently flexible to permit the needle body 30 to contour to cardiac and thoracic geometry. It will be appreciated by those of skill in the art that this flexibility of the needle body 30 provides the cardiologist significant latitude in the maneuvering and proper placement of the needle within the body while minimizing the invasiveness of the procedure. It has been determined that a 22 Ga (or 22 gauge) needle provides a sufficiently rigid, yet adequately flexible structure which may be readily utilized by the cardiologist during a procedure.

To facilitate penetration of the needle 10 into the cardiac tissue, a preferably smaller diameter needle tip 40 is provided at the distal end 12 of the needle body 30. It has been determined that a 27 Ga (or 27 gauge) cannula is particularly appropriate. It will be appreciated by those of skill in the art that this small gauge needle tip 40 minimizes extravasation of injectate. In the illustrated embodiment, the needle tip 40 includes a bevel sharp tip 42. A bore 43 extending through the needle tip 42 is in communication with the elongated bore 32 of the needle body 30 and opens at the bevel tip 42. While a bevel tip is illustrated, it will be appreciated that an alternate tip geometry or structure may provided.

According to another important feature of the invention, in order to facilitate proper transfer of the therapeutic solution, penetration of the needle tip 40 into the tissue is structurally limited. To limit the penetration, the needle 10 is provided with a platform 44 which is spaced from the end of needle tip 42 at the distal end 12 of the needle 10. In this way, during use, the depth to which the needle tip 40 may penetrate the tissue is governed by the proximity of the platform to the distal tip 45 of the needle 10. It is presently anticipated that the distal surface of the platform 44 will be disposed on the order of 5-10 mm from the distal tip 45, although alternate spacing may be dictated by factors such as the particular therapeutic solution utilized, or the physical characteristics of the tissue upon which the procedure is to be performed.

In the preferred design, the platform 44 is in the form of a substantially round, flat disc, minimizing the likelihood of any irritation to tissue due to sharp corners. Preferably, the platform is on the order of 4 to 6 mm in diameter. It has been determined that a 0.5 mm (0.020 inch) thick, 3.5 mm (0.125) inch diameter 304 stainless steel disc is appropriate.

Although the needle tip 40 and the platform 44 may be disposed at a right angle, to further stabilize the needle 10 during delivery of the therapeutic solution, the platform 44 is preferably disposed obliquely the needle tip 40, as shown in FIGS. 1, 2 and 5. In this way, the opportunity for further twisting or rotation of the needle 10 once properly positioned is minimized. Preferably, the platform 44 disposed at an angle on the order of a few degrees from the needle tip 40, although an alternate angle may be provided.

In order to couple the needle 10 to the solution supply device, an appropriate coupling 50 is provided at the proximal 14 end of the body 30. In the currently preferred embodiment, the coupling is in the form of a metal hub 50 having a large bore 52 extending therethrough for receiving the distal neck-in end 18 of the syringe. The metal hub 50 further includes a smaller size bore, which communicates with the large bore 52 and the elongated bore 32 of the needle body 30 such that fluid communication is established between the hollow cylindrical body 16 of the syringe 8 and the elongated bore 32 of the needle body 30. While in the currently preferred embodiment, the hub is a "Luer Lock," it will be appreciated that an alternate structure may be utilized, or the needle body 30 may be directly coupled to the syringe 8 or other supply device.

During assembly of the needle 10, the needle body 30, the needle tip 40 and the platform 44 may be laser welded at one common junction. The smaller diameter needle tip 40 may be slip fit into the larger diameter needle body 30, and the platform 44 fit to the needle tip 40. Similarly, the hub 50 may be laser welded to the proximal end of 14 of the needle body 30.

According to another feature of the invention, the cardiologist may utilize the needle 10 in positions that are typically beyond the line of sight provided by way of a surface incision. An electrode 60 similar to that disclosed in PCT Application No. PCT/US99/03731, filed March 5, 1999, may be provided on the platform 44 (as illustrated) or at the tip of the needle 42, as shown in FIG. 4, and insulated therefrom. Alternately, the needle itself may serve as an electrode if the needle tip 40 or the platform 44 are made from a conductive material. Electrical connection of this electrode 60 to an electrocardiograph ("ECG") (not shown) may be made by running an electrical conductor along the needle 10 to the ECG located outside the patient's body. Standard surface ECG leads are likewise applied to the patient. When the electrode 60 enters the patient's myocardium 62 (see FIG. 5), the event shows as a current injury. In this way, the cardiologist may ensure that the desired positioning and contact is made with the myocardium prior to actuation of the solution supply device 8.

Consequently, the invention provides a device for the delivery of a therapeutic solution, in particular, an angiogenesis-promoting substance (particularly an adenoviral vector containing a transgene encoding a vascular endothelial growth factor (VEGF)) into a heart, especially a beating heart. The device includes an elongated needle 10 having a stop, or platform 44 spaced from the distal needle tip 42. In use, the cardiologist accesses the thoracic cavity and heart tissue by any appropriate method. The needle tip 40 is then maneuvered into a desired position for delivery of the solution. Significantly, the elongated needle body 30 is flexible enough to maneuver around thoracic and cardiac geometry, yet sufficiently rigid to facilitate such maneuvering. When the needle tip 40 is a desired position, the needle 10 is advanced to penetrate the cardiac tissue. In doing so, the platform 44 limits the depth to which the needle tip 40 may penetrate the tissue and stabilizes the needle. The solution is then delivered to the site by actuation of the supply device, preferably, in this case, a syringe. In the minimally invasive procedure, the elongated, small diameter needle device allow delivery of the solution "at a distance" through small incisions, possibly without the use of endotracheal intubation. Moreover, the simple design of the needle 10 may be economically manufactured, facilitating disposability. It is currently anticipated that approximately 10-30 needles will be utilized per patient in a typical administrative procedure of a therapeutic solution.

Claims

WHAT IS CLAIMED IS:

1. A device for delivering a therapeutic solution from a solution supply into cardiac tissue, the device comprising: a hollow needle having a proximal and a distal end, said proximal end being adapted for fluid attachment to said solution supply, said needle comprising an elongated flexible body, shaφened tip disposed at said distal end for penetration of cardiac tissue, and a platform spaced from the distal end, said platform acting as a stop to limit penetration of the shaφened tip into cardiac tissue and whereby the platform stabilizes the needle during delivery of the therapeutic solution.

2. The device of claim 1 wherein the platform is disposed obliquely relative to the shaφened tip.

3. The device of claim 1 wherein the platform is spaced about 5-10 mm from the distal end.

4. The device of claim 1 wherein the platform is a substantially round disc.

5. The device of either of claims 1 or 3 wherein the elongated body is about 100-200 mm long.

6. The device of any of claims 1 , 3, or 5 wherein the needle body is a cannula of about 22 Ga.

7. The device of any of claims 1, 3, or 5 wherein the shaφened tip is a cannula of about 27 Ga.

8. The device of claim 1 comprising a solution supply device, said needle being coupled to said solution supply device.

9. The device of claim 8 wherein the solution supply device is a syringe.

10. The device of claim 9 wherein the needle further comprises a hub adapted for coupling to the syringe.

11. The device of claim 1 further comprising an electrode coupled to the needle and adapted for connection to an ECG to provide an electrical indication of when said shaφened tip has penetrated the cardiac tissue.

12. The device of claim 11 wherein the electrode is coupled to the platform.

13. The device of claim 11 wherein the electrode is coupled to the shaφened tip.

14. The device of claim 1 wherein the therapeutic solution comprises an angiogenesis-promoting substance.

15. A method of delivering a therapeutic solution into cardiac tissue, the method comprising the steps of providing a hollow needle having a proximal end and a distal end in fluid attachment with a solution supply, providing access to the thoracic cavity, advancing an elongated flexible body of the needle into the thoracic cavity, positioning a shaφened tip disposed at said distal end of the needle adjacent the target cardiac tissue, advancing the shaφened tip into the tissue until a platform of the needle which is spaced from the distal tip of the needle comes into contact with the cardiac tissue to stabilize the needle relative to the tissue, delivering the therapeutic solution through the needle to the tissue, removing the needle.

16. The method of claim 15 wherein the solution comprises an angiogenesis-promoting substance.

17. The method of claim 15 wherein the platform is obliquely disposed relative to the shaφened tip, and the method further comprises the step of advancing the needle into the tissue at an angle to the surface of the target cardiac tissue.

18. The method of claim 15 further comprising the step of flexing the needle body to conform to thoracic and/or cardiac geometry.

19. The method of claim 15 further comprising the step of inserting the needle body into the patient through a port inserted into an incision in the patient's body.

20. The method of claim 15 further comprising the step of at least partially collapsing the patient's lung.

21. The method of claim 15 further comprising the step of advancing the needle into the heart through a ventricle.

22. The method of claim 15 further comprising the step of advancing the needle toward the heart through the femoral artery.

23. The method of claim 15 further comprising the step of providing an electrical signal from the distal end of the needle to an ECG.