WO1999049926A2 - Delivery of an angiogenic substance - Google Patents

Abstract

Using either a percutaneous, intraoperative or minimally invasive approach, an elongated member containing an angiogenic agent is guided to a heart wall and the agent is dispensed into heart tissue. The administration of the angiogenic agent can be automated and controlled so as to be synchronized with respect the cardiac cycle. The device has a distal end configured to dissect heart tissue and penetrate into the myocardium. Additional fluids or substances can be dispensed in combination with the angiogenic agent to provide visualization and site mapping. In certain embodiments, the angiogenic agent is delivered adjunctively with the administration of energy, such as laser energy of RF energy which disturbs the heart tissue sufficiently to enhance the effects of the agent. There is also disclosed a device for administering an angiogenic agent that contains the angiogenic agent and additional fluids such as a marker within a single conduit.

Description

DELIVERY OF AN ANGIOGENIC SUBSTANCE

FIELD OF THE INVENTION

The present invention relates to methods and apparatus for the delivery

of substances to tissue, and in particular to ischemic myocardial tissue of a

patient's heart, either percutaneously or intraoperatively. The delivery of the

substances may either be adjunct to transmyocardial revascularization (TMR)

or another procedure, or may constitute a procedure in and of itself.

BACKGROUND OF THE INVENTION

Coronary artery disease affects the lives of millions of patients

worldwide. Many therapies are available for atherosclerosis, including

coronary artery by-pass graft surgery (CABG) to bypass blocked arteries,

percutaneous transluminal coronary angioplasty (PTCA) interventions to

attempt to restore patency, the implantation of stents that attempt to

maintain patency, the use of atherectomy to remove collected plaque, and a

number of pharmacological approaches that attempt to reduce the effects of

narrowing of blood vessel lumens by the stenosis by reducing the amount of

plaque or by altering the hemodynamic characteristics of the patient's blood.

While the aforesaid procedures provide well known clinical improvements,

none provide a fully satisfactory long term therapy., The presently available

pharmacological therapies are of limited value. Ideally, a non-invasive

pharmacological or genetic therapy would facilitate reperfusion of ischemic

myocardium, either by restoring patency or by creating new blood vessels in

the ischemic region. A number of different substances and techniques are known for

attempting to treat coronary artery disease by the administration of a

therapeutic substance to a patient. One common method of administration is

systemic administration. For example, EPO Application EP 31 4105 discloses

the oral administration or intramuscular injection of an "angiogenesis

enhancer". U.S. Patent No. 5,480,975 discloses treating hypoxic tissue

damage by local or topical administration of a transition metal compound to

induce VEGF expression. The indirect nature of these routs of administration,

however, are generally less desirable and not universally applicable to all

forms of substances that might be used to treat ischemic myocardium.

Using a catheterization procedure to deliver a substance to the vessels

in the vicinity of the stenosis is also known. For example, PCT Application

WO 9723256 discloses the percutaneous delivery of an angiogenic factor to a

vessel wall through the lumen of a catheter. The distal end of the catheter is

provided with infusion ports that engage the vessel wall when the catheter is

expanded, and infusion may be enhanced by providing needles or other

penetrating elements. U.S. Patent 5,681 ,278 discloses treating vascular

thrombosis and angioplasty restenosis by administering a bioactive agent to

an extravascular treatment site, particularly introducing such an agent

proximally adjacent to the exterior of a coronary artery. U.S. Patent No.

5,698,531 discloses the site specific installation of cells or the transformation

of cells by delivering proteins by catheterization to discrete blood vessel

segments, wherein the agent is situated on the walls of the blood vessel or perfused in the tissue of the vessel. U.S. Patent No. 5,523,092 discloses an

indwelling catheter for localized delivery of a substance into a "tissue conduit"

without disrupting the fluid flow. U.S. Patent No. 5,244,460 discloses the

intracoronary arterial delivery of a blood vessel growth promoting peptide

periodically over several days.

Recent advances in biotechnology have shown promise for treating

coronary artery disease. In Circulation 1 998;97:645-650, Schumacher et al.

report treating coronary heart disease using human growth factor FGF-I (basic

fibroblast growth factor) to induce neoangiogeneisis in ischemic myocardium.

The FGF-I was administered during a CABG procedure by injection into the

myocardium distal to the IMA/LAD anastamosis and close to the LAD. The

results reported demonstrate the efficiency of FGF-I treatment. However, the

FGF-I administration was made by direct injection during surgery which is less

than optimal because it is as invasive to the patient as a CABG procedure. In

addition, at least one fibroblast growth factor has been delivered by using a

microparticle carrier that is delivered to an artery via a catheter in a non-

ischemic model, as reported in Nature Biotechnology 1 998; 1 6: 1 34 and 1 59-

1 60. The intra-arterial delivery of microparticles produced positive results, but

was chosen so that the surrounding tissue would be undamaged. The article

states that non-invasive techniques to deliver genes into peripheral ischemic

myocardial tissue are presently unavailable.

Thus, there exists a long felt, yet unmet need for methods and

apparatus that permit the localized introduction of a substance into the myocardium directly, either during an intraoperative procedure or

percutaneously.

In addition to these advances in biotechnology, coronary artery disease

is also successfully treated by transmyocardial revascularization (TMR), using

methods and apparatus such as those disclosed in U.S. Patent Nos.

5,380,31 6; 5,389,096 and 5,554, 1 52, all of which are incorporated herein

by reference. During TMR using intraoperative, minimally invasive or

percutaneous approaches, energy is delivered directly to the myocardium,

preferably in or near to the ischemic area, and as a result a focal injury occurs.

This focal injury is often in the form of a "channel" formed by the laser,

although the size of the channel and energy used to create the tissue

disruption can vary. Additionally, the degree of patency of the channel and

the amount of tissue ablated to form the channel may also vary. It has been

found that the focal injury acts to stimulate subsequent neovasculogenesis.

Moreover, in addition to the eventual reperfusion of the ischemic region, there

is evidence that the disruption of certain afferent nerves in the tissue and

other effects provides both acute and chronic reduction in angina pain.

The use of TMR in conjunction with the administration of localized

agents is disclosed in co-pending U.S. patent application Ser. No. 438,51 2,

filed June 7, 1 995 which is assigned to the assignee of the present invention

and the entirety of which is incorporated herein by reference. This application

discloses the administration of therapeutic and diagnostic agents into the

myocardium, and particularly in conjunction with TMR procedures. [Additionally, co-pending U.S. patent application Ser. No. , , filed on

even date herewith, which is assigned to the assignee of the present

invention, the entirety of which is incorporated herein by reference, discloses

a catheter system that is useful for placing a payload within a specified

portion of a patient's heart chambers, and most particularly within the left

ventricle (LV), an area where revascularization is often indicated.]

There still exists, however, a need for improved apparatus and

improved techniques that will permit the adjunctive delivery of substances

into localized regions within the myocardium efficaciously, efficiently and in a

manner that can enjoy widespread adoption by the medical profession, such

as cardiac surgeons and interventional cardiologists.

SUMMARY OF THE INVENTION

The foregoing objects are achieved by the present invention. In

accordance therewith, the apparatus delivers a substance, such as an

angiogenic agent to a desired tissue region. In one presently preferred

embodiment, an elongated device has a handpiece for delivering a metered

dose of a substance via a delivery lumen. The elongated device may be either

a catheter or an intraoperative probe, and in certain preferred embodiments

has a reservoir containing the substance in a deliverable state, such as an

angiogenic agent. Preferably, the device comprises a metered dispensing

apparatus for injecting one or more appropriate doses and includes a

dispensing control system, such as a switch disposed on the handpiece or a

separate foot pedal. In some embodiments, the dispensing control system is

automated, and preferably, a signal generated by the heart is provided to a

circuit synchronizing the activation of the automated dispensing apparatus to

the cardiac cycle. For example, the apparatus may be synchronized to the

patient's ECG by a circuit which inhibits activating the dispensing apparatus

during a pre-determined portion of the cardiac cycle.

In most embodiments, the delivery device has a distal end which is

configured for penetration into the patient's tissue, e.g., has a sharp or

needle-like distal end, and has at least one orifice in fluid communication with

a lumen extending through the distal extremity of the device which is in fluid

communication with the one or more orifices and a source of therapeutic or

diagnostic substance. Additionally, in certain embodiments, the distal end has one or more radially oriented lumens to direct the substance to be delivered

laterally within the patient's tissue. Another aspect of certain embodiments

of the present invention relates to contacting the tissue to be treated with the

distal end. For example, elongated elements such as bristles or barbs may be

provided that deploy from a first position inhibiting tissue contact to a second

position permitting tissue contact are provided in some embodiments.

Preferably, the elongated elements are aligned with a longitudinal axis of the

device and disposed along an outside surface so they deploy from a first

position that inhibits tissue engagement to a second position that permits

tissue engagement. In other embodiments, the distal end can have an

enlarged or bulbous section, which may or may not be expandable.

Other aspects of certain embodiments of the present invention include

providing the device with a radiopaque marker disposed at the distal end to

aid in the fluoroscopic visualization thereof during the procedure and providing

a depth stop to limit device penetration depth. One preferred embodiment of

a depth stop is the construction of a section of the distal end smaller in

diameter than a second section immediately proximal of the distal section and

a shoulder connecting the distal section and the second section that acts as

the depth stop. Alternatively, the depth stop can be one or more mechanical

elements or arms that extend out radially from the distal end. In other

embodiment, visualization of the dose is accomplished by the administration

of a marker substance either along with or in addition to the therapeutic

substance such as an angiogenic agent. In another aspect of the present invention, multiple lumen catheters or probes are provided with one of the

plurality of lumens being used to deliver the substance such as an angiogenic

agent, while other lumens may be utilized to deliver other fluids, substances,

or apparatus.

In certain embodiments, the present invention may also be provided

with a distal tissue contact device for energy delivery to the myocardium to

perform a procedure that dissects, disturbs, disrupts or ablates the tissue

region to which the substance is injected. The distal tissue contact device

may be one of a number of known apparatus whereby energy is delivered to

the myocardium to perform a procedure that dissects, disturbs, disrupts or

ablates the tissue. For example, the distal tissue contact device can be a

mechanical device affixed to the distal end, or it can be a device such as a

laser energy conductor, an RF energy conductor, an ultrasound transducer, or

a current conductor. In another preferred embodiment, the distal tissue

contact device can be a lumen in a device connected to a source of fluid at a

pressure and velocity sufficient to disrupt tissue. In any of these

embodiments, the distal tissue contact device is preferably introduced using a

lumen separate from a lumen carrying the therapeutic or diagnostic substance

to be delivered.

Thus, one preferred embodiment of the present invention broadly

discloses an injector apparatus synchronized to a cardiac cycle signal that has

a conduit with a least one lumen connected on a proximal end to an injection

device and, preferably, a solenoid connected to the injection device. In use, a controlled amount of a substance to be delivered is dispensed when the

solenoid is pulsed by a signal related to the cardiac cycle. Preferably, the

solenoid advances the same amount after each of one or more pulses, so that

more than one injection can be given in each heartbeat if desired. When an

embodiment including a distal tissue contact device is used, an activation

switch is also provided and energy is introduced into the heart tissue by

operation of the activation switch, preferably but not necessarily in

synchronization with the cardiac cycle.

Another additional aspect of the present invention is the provision of an

apparatus for delivering a bolus of substance that has a delivery lumen

extending from a distal end to a proximal point distal to the proximal end, and

wherein at least a first section of the delivery lumen is filled with the

substance to be delivered. In certain embodiments a second section of the

delivery lumen in fluid communication with the first section is provided that

contains a second substance other than the first which may aid in delivery or

visualization of the first substance when it is delivered. In any embodiment, it

is preferred, though not required, that the substance, i.e., an angiogenic

agent, is in a fluidic or thixotropic state to facilitate delivery. In one presently

preferred embodiment, the delivery lumen contains at least an angiogenic

agent and a marker substance.

Although it will be readily understood that the percutaneous and

intraoperative versions of the present invention may differ markedly in

construction, each device may have one or more of a number of features addressed below. The discussion of these features of a substance delivery

system is thus not specific to or limited to either the percutaneous or

intraoperative embodiments.

As used herein, the term "angiogenic agent" includes any material or

substance useful in a procedure that promotes the growth of new vessels,

particularly the growth of new vessels in the myocardium, however, it will be

understood that an angiogenic effect is useful in other organs, such as the

liver and kidneys. The methods and apparatus of the present invention may

employ a wide variety of angiogenic agents, including small molecule drugs,

active compounds and cellular and gene therapy agents. Examples of active

compounds include, by way of non-limiting example, biologically active

carbohydrates, recombinant biopharmaceuticals, agents that are active in the

regulation of vascular physiology, such as nitric oxide agents that effect the

regulation of gene activity by modulating transcription, the turnover of cellular

mRNA, or the efficiency with which specific mRNA is translated into its

protein product, i.e., antisense pharmaceuticals. Other active compounds

include hormones, soluble receptors, receptor ligands, peptides (both

synthetic and naturally occurring), peptidomimetic compounds, specific and

non-specific protease inhibitors, postaglandins, inhibitors of prostaglandin

synthase and/or other enzymes involved in the regulation of prostaglandin

synthesis, growth factors that affect the vascualture such as the fibroblast

growth factors (FGF's), acidic (aFGF, FGF-II) and basic fibroblast growth

factors (bFGF, FGF-1), vascular endothelial growth factors (VEGF), angiogenin, transforming growth factor alpha, and transforming growth factor beta. The

foregoing list is meant to illustrate the breadth of angiogenic agents and other

substances useful with the present invention and is not meant to be

exhaustive or in any way limit the scope of the invention. It is contemplated

that there are classes of angiogenic agents possessing structures significantly

similar to other molecular agents, and that these agents will have specific

biological activities associated with them while being deficient in other

biological activities that are less desirable therapeutically. Any and all of the

angiogenic agents useful with the present invention may comprise

substantially pure compounds, defined or relatively less well defined

admixtures of compounds, such as those that might result from a biological

system such as conditioned serum or conditioned cell culture media.

Finally, any reference to "angiogenic agent" herein will be understood

to include diagnostic agents and markers useful with the present invention.

Such diagnostic agents or markers may be delivered before, after or during

the administration of the angiogenic agent itself, and include any substances

used to ascertain the physical location, configuration or physiologic state of a

tissue or tissues, e.g., dyes, stains, diagnostic challenge agents and agents

such as radiopaque agents used to enhance contrast during diagnostic or

therapeutic procedures such as myogenic compounds, anesthetic agents or

chemical sypathectomy agents. The various features and advantages of the invention will become more

apparent from the following detailed description of the invention when taken

in conjunction with the accompanying exemplary instructions.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of one preferred embodiment of an

intraoperative system for administering a therapeutic substance.

FIG. 2 is a perspective view of one preferred embodiment of a

percutaneous system for administering a therapeutic substance.

FIG. 3 is a diagrammatic illustration of a control system useful with the

embodiments of the present invention illustrated in FIGS. 1 -2;

FIG. 4 is a partial side elevation view of the distal tip of a device

embodying features of the present invention.

FIG. 5 is a partial side elevation view of the an alternative construction

of a distal tip of a device embodying features of the present invention.

FIG. 6 is a partial side elevation view of the an alternative construction

of a distal tip of a device embodying features of the present invention.

FIG. 7 is a partial side elevation view, partially in cross-section,

illustrating the embodiment of FIG. 6 within the lumen of a catheter or guide.

FIG. 8 is a partial side elevation view of the an alternative construction

of a distal tip of a device embodying features of the present invention.

FIG. 9 is a partial side elevation view of the an alternative construction

of a distal tip of a device embodying features of the present invention. FIG. 1 0 is a partial side elevation view of the an alternative

construction of a distal tip of a device embodying features of the present

invention.

FIG. 1 1 is a partial side elevation view of the an alternative

construction of a distal tip of a device embodying features of the present

invention shown after penetration into the myocardium.

FIG. 1 2 is a partial side elevation view, partially in cross-section, of the

an alternative construction of a distal tip of a device embodying features of

the present invention.

FIG. 1 3 is a partial side elevation view of an alternative construction of

a distal tip of a device embodying features of the present invention.

FIGS. 1 4-1 5 are cross-sectional views of alternative multiple lumen

catheters useful with certain embodiments of the present invention;

FIG. 1 6A is a partial side elevation view of the distal tip of a device

embodying features of the present invention shown penetrating the

myocardium;

FIG. 1 6B depicts the apparatus of FIG. 1 6A after deeper penetration

into the myocardium;

FIG. 1 7 is a partial cross-sectional elevation view of a conduit carrying

an angiogenic agent and other substances useful in conjunction with the

present invention.

DETAILED DESCRIPTION OF THE INVENTION Reference is made to FIG 1 which depicts a basic system for the

intraoperative administration of an angiogenic substance. As illustrated, a

distal reservoir 10 for the substance to be delivered is in fluid communication

with a distal administration device 1 2 via a fluid conduit 14. The distal end

1 6 of the administration device 1 2 includes a specialized distal tip

construction that will be described in further detail below. A valve 1 8 is

provided to control the flow of substance from the reservoir 1 0 to the conduit

1 4. The substance to be delivered by the methods and apparatus of the

present invention may be stored either proximally or distally. A number of

different delivery device constructions are useful for each case. In most

embodiments, however, the fluid conduit 14 will comprise a hypodermic tube

formed of suitable metal such as stainless steel or similar material. In certain

embodiments, the conduit 14 may serve as a carrier and reservoir for the

substance. In such embodiments, the conduit 14 will be formed into a coil to

provide for longer "storage length," and thus permit it to serve as a reservoir

of greater capacity. In such embodiments a separate reservoir 1 0 illustrated

may not be required. Additionally, in other embodiments, a reservoir can be

built into the distal end 1 6 of the device 1 0, particularly for those instances

where the volume of substance to be delivered is extremely small.

FIG. 2 illustrates a percutaneous system similar to FIG. 1 which has a

proximal catheter controller 20 and catheter 22. The catheter 22 terminates

in a distal administration tip 24. As explained above, the substance reservoir 10 and connecting fluid conduit 14 may not necessarily be present in each

embodiment of the percutaneous system.

In the case of either FIG. 1 or FIG. 2, the basic function of the present

invention will be to place the distal tip in contact with, or at least in close

proximity to, the surface of the tissue to be treated such as in the patient's

heart tissue. The surface may be the endocardium, epicardium, or the

myocardium, if either the endocardium or epicardium have been pierced. The

placement of the distal tip will permit myocardial delivery of a bolus of

angiogenic agent, preferably by injection, after the distal tip has penetrated

the myocardium.

Another aspect of the present invention is illustrated diagramatically in

FIG. 3. In preferred embodiments, the penetration of tissue of the heart 30

by the distal tip 32 (from either side, the epicardial side being illustrated) will

be followed by substance injection. Preferably, the substance injection is

automated and an automatic administration device 34 (labeled ADMIN) will

dispense a pre-selected amount of substance to the site where the distal tip

32 has penetrated. The activation of the automated administration device 34

may be accomplished via a foot switch (not shown), handpiece switch (not

shown) or via another system. The automated system as shown in FIG. 3 has

a signal line 36 which is connected to an electrocardiograph (ECG) 38 or

similar device for measuring the cardiac cycle. The ECG 38 in turn is

connected to the ADMIN device 34. The dispensing of a dose is initiated upon

a predetermined set of cardiac parameters once an activation signal is received from a foot switch, handpiece switch or other device indicating that

the operator has properly positioned the distal end of the device. As known

in the art, the ECG signal can be coupled to a device controller and can be

used to permit or inhibit an invasive activity, such as the firing of a laser,

during periods of the patient's heart cycle to minimize the possibility of

fibrillation or other arrhythmia. In the use of the present invention, it will also

be preferable in some embodiments when using certain angiogenic agents to

similarly enable administration of the substance during a safe period of systole

or inhibit the administration of an automated dose outside the safe period.

Additionally, by synchronizing substance injection to the ECG, a consistent

value of pre-load force between the distal end 32 and the tissue of heart 30

will be achieved since the spatial relationship between the administration

device and the heart will be similar at a particular point over several cycles.

Thus, in one preferred embodiment, an injector that is synchronized to

the heartbeat is provided by connecting a syringe or similar administration

device 34 to the distal end 32, as described above. A solenoid plunger (not

shown) within the administration device 34 is connected to the syringe so

that when the solenoid is pulsed with electrical energy, the syringe is quickly

advanced a finite distance, resulting in the injection of a controlled amount of

substance. A DC solenoid can be pulsed with a voltage much higher than

the normal DC constant operating voltage, providing the force required to

quickly move a tiny amount of viscous material down a narrow lumen. The

pulse for the solenoid is preferably synchronized to the heartbeat. In certain embodiments, a variable delay circuit can be added to adjust the

synchronization point to the heart cycle. Numerous other timing and control

circuits can be devised to carry out the same function.

As explained above, in certain embodiments, either the handpiece 20 or

the proximal controller 30 may include one or more switches or activation

devices that control the functions of the system, or such functions can be

controlled by a foot switch or other apparatus. An additional function that is

preferably controlled is the advancement of the distal end 34 into the

patient's heart tissue, as well as the discharge of a bolus of the substance

into such tissue. In certain embodiments, the sharp end of the device will be

advanced into the tissue while a catheter or probe remains in place. The

advancement of the sharp end is preferably controlled and linked to the

administration, either mechanically or by control logic, or both.

In those embodiments where a percutaneous system is used and the

injection is at or beneath the endocardial surface, the issue of knowing that

the injector tip is in contact with the endocardial surface arises. In such

embodiments, an indication of tip contact is preferred to ensure that the

substance is administered into the endocardium and underlying myocardium,

and not into ventricular blood. Thus, an additional signal that can be

interconnected with the administration device 34 is a tip contact signal, and

administration is preferably inhibited when there is no tip contact.

In addition to the basic parameters set forth above, those skilled in the

art will appreciate that a number of practical factors may control design details of devices made in accordance with the present invention. For one,

the cost per dose of the substance delivered may be a determinative factor as

to whether wasting the delivered substance is a threshold issue. A related

issue is medical safety and efficacy of the substance delivered. For various

angiogenic agents, the precision of dose needed is likely variable, and the

deleterious effects, if any, of excess delivered substance being deposited or

administered into the blood and carried off without side effects must be

determined for each substance on a case-by-case basis. Additionally, the

ease in which the angiogenic agent is delivered may be related to the viscosity

of the fluid in which the substance is delivered. In some cases, it may not be

possible to alter the viscosity, one reason being that a particular concentration

of substance is necessary for efficacy and as a result the viscosity is higher

than would otherwise be optimal for delivery. Whether it is altered or not, it

is anticipated that the viscosity of angiogenic agents and other fluids that are

delivered in procedures according to the present invention will vary over a

wide range from lower than that of water to significantly higher. Thus, the

term "fluid" as used herein is to be construed in its broadest sense and thus

may be a gas, a colloidal suspension, a gel and further encompasses

embodiments where the angiogenic agent is made into a solid or semi-solid

and carried or moved by the action of another fluid, or by mechanical force at

the end of a column of microspheres or even larger "pellets" or

agglomerations of solids. As known by those skilled in the art, each of these

forms can be delivered, but they may create a unique set of delivery problems which can be readily solved once the fundamental parameters of the delivery

are established.

Similarly, the pharmocokenetics of the angiogenetic agent are also be a

factor in determining how the delivery of the angiogenic agent is to be made.

In other words, even if the identical delivery apparatus is used, a change in

angiogenic agent may require a change in the velocity and pressure by which

the substance travels within the delivery lumen in the device to the distal end

thereof. In some instances, if the velocity and pressure are too great, leakage

of the angiogenic agent around the injection site may occur, or unintended or

excessive tissue damage may occur. If the administration or injection rate is

insufficient the heart may become irritated, position may be lost, or the

procedure may be unnecessarily lengthened. Thus, for each substance,

pharmocokenetic determinations need to be made. For example, when a sub-

endocardial injection is made the contractility of the tissue will cause a certain

amount of a particular angiogenic agent to be expressed from the site of

deposition, depending upon the viscosity and other factors. In some cases,

where a longer residence time is necessary, this effect will be detrimental,

whereas other angiogenic agents possessing a higher affinity and thus

requiring a shorter residence time will be taken up relatively quickly and

efficacy will not be diminished by this phenomenon. These determinations,

however, are easily and effectively made using known techniques that will not

require undue experimentation. Thus, to control the administration of the

angiogenic agent in, for example, embodiments where it is important to reduce or eliminate waste or accidental discharge of excess material into the

bloodstream, a variety of well known solutions such as one-way valves,

metering valves and other apparatus that handle and control the flow of the

fluid from a reservoir to the tissue will be incorporated into the apparatus.

The present invention provides methods and apparatus to localize the

injection of angiogenic agents. For example, the injection site and the growth

of the angiogenic vessels in the direction that will provide the most beneficial

effect is more likely via an injection near the occlusion rather than a

retroperfusion delivery by injection in the coronary sinus. This localization is

difficult if the arterial disease is diffuse. Finally, at least in the case of some

angiogenic agents like VEGF, it is not clear that the administration of growth

factors alone will mediate large vessel growth. Thus, intramyocardial delivery

will be advantageous over the intracoronary delivery described above.

As was the case with the overall system described above with

reference to FIGS. 1 -3, there are a number of useful embodiments for the

distal end of the devices of the present invention. In most embodiments, the

distal end of a device is configured to readily penetrate at least a few layers

of tissue cells.

Referring now to FIG. 4, one preferred embodiment of a distal

end 40 is shown. In the construction of the distal end 40 illustrated it has a

simple sharp tip 42 to permit the flow of angiogenic agent, as illustrated by

the arrows. A radiopaque band 44 is also preferably provided. The distal end

40 preferably perforates the endocardium in the percutaneous embodiment, or the epicardium in the intraoperative embodiment, and then holds its place

while a bolus of substance is directed into the tissue. In one exemplary

embodiment, the dosimetry of the substance is 1 00 μl per injection at 1 0

injection sites, and the inner diameter of the delivery tube is about 0.01 8

inches (0.46 mm). In such an embodiment, the substance doses for the ten

injection sites would take up a significant length of the delivery tube and

would usually require a reservoir. Additionally, in such a case, the retention

of the distal end 40 in place is important. In certain preferred embodiments,

structural elements such as those described in further detail below keep the

distal end properly positioned and engaged during substance delivery.

As shown in FIG. 5, the distal end 50 can be modified by introducing

radial orifices 52. The central lumen may remain open, or may be closed. In

the latter case, the radial orifices 52 will provide the only path for flow into

the myocardium and will thus tend to force the angiogenic agent over a wider

area lateral to the injection site than the bolus delivery as with the distal end

shown in Fig. 4. Additionally, in preferred embodiments, the sharp 54 itself

or other structures associated with the distal end 50 preferably possess shape

memory and/or are comprised of stainless steel, NITINOL, or other materials

known in the art to have such characteristics. Glass and high strength plastic

tubing may also be employed. A radiopaque band 56 may be provided as

with the previously discussed embodiments.

Referring now to FIG. 6, another embodiment of an apparatus made in

accordance with the present invention is shown. In this embodiment the distal end 60 has one or more sharps 62 and 64 in the form of "bristles" or

needles that extend generally radically or along a curved, radially outwardly

extending path or spiral. These sharps 62 and 64 are preferably deployed

when the distal end is located at a specific site and would engage the heart

wall or other portion of the vasculature. In some preferred embodiments, the

bristles may be hollow to provide conduits for the delivery of the angiogenic

substance via those lumens, as shown by the arrows in FIG. 6. Alternatively,

the sharps 62 and 64 are solid and serve as fixation elements for a larger

needle 66 that defines the delivery lumen, as explained above with reference

to FIGS. 4-5. FIG. 7 illustrates a preferred delivery of the distal end 60

shown in FIG. 6. As shown, the bristles 62 and 64 are preferably collapsed

against the body of the distal end 60 by delivering the device within a

catheter or sleeve 68. Delivery in this manner prohibits unwanted dissection

or other damage to tissue that is not being treated. A radiopaque band 69

may be provided as shown for fluoroscopic observation thereof when

disposed within the patient.

Another embodiment of the present invention illustrated in FIG. 8.

includes a distal end 80 with a sharp 82 that is helically shaped. Such a

distal feature will aid in the retention of the distal end 80 in the tissue during

administration of the angiogenesis agent. The construction shown in FIG. 8

includes either diffusion ports 84 along the sharp 82, or diffusion ports 86

along other portions of the distal end structure 80, or both, as illustrated. As

explained with reference to FIG. 5 above, such ports will aid in the lateral diffusion of the angiogenic agent or other substance into the tissue

surrounding the distal end 80 when disposed within the heart tissue. A

radiopaque marker 86 may also be provided.

Referring now to FIG. 9 an additional embodiment of fixation devices

useful in the present invention are illustrated. As shown, the distal end 90

has several moveable barbs 92. As with the radial or spiral extensions

discussed above with reference to FIGS. 6-8, the barbs 92 are preferably

moveable so they will not interfere with the placement of the distal end of the

device within the patient's tissue. After placement, the barbs 92 are

preferably deployed by being pushed outwardly by liquid exiting through one

or more lateral orifices 94 in the distal end 90 as shown by the arrows in FIG.

9. This deployment via fluid pressure may occur just prior to, or simultaneous

with the delivery of angiogenesis substance. The barbs 92 help to keep the

distal end 90 engaged in the myocardium during substance delivery.

Preferably, the barbs 92 are retractable so that they are covered when the

inner catheter or delivery tube is pulled inside a guide catheter or sleeve, as

discussed above with reference to FIG. 7. Alternative constructions to the

barbs 92 include a back cut "sawtooth" or "rasp" structure lying longitudinally

along the sides of the exterior wall of the distal end, which may either be

retractable as shown in FIG. 9, or may be fixed, as were the bristles 62 and

64 shown in FIG. 6.

In addition to deploying structural elements, the movement of the

angiogenic agent or other fluid can additionally be useful to help ensure retention of the sharp and aid in dissection and diffusion. As shown in FIG.

10, in certain embodiments, the distal end 1 00 has angled orifices 1 02 which

are selectively arrayed within the distal end construction so that the

directionality of the substance flow is altered as shown by the arrows. The

resultant force will tend to retain the distal end 1 00 in place, rather than

dislodge it, or in some cases will actually drive the distal end deeper into the

tissue. As shown, it may be necessary to provide an orifice 1 04 at the tip in

order to regulate the effect of the rear facing orifices 1 06.

Another embodiment of a mechanical fixation device useful with the

present invention is shown in FIG. 1 1 . In this embodiment, the distal tip 1 10

comprises a "bulge" 1 1 2 or similar enlarged structure that represents a large

diameter proximal of the distal tip. In certain embodiments, the bulge 1 1 2

may be expandable like a balloon so that it is trapped in place by friction with

the swelled tissue. The expansion and contraction of the bulge can be

controlled by the administration of the angiogenic agent, or by using multiple

lumens, as described above, such that a dedicated lumen provides insufflation

fluid. Alternatively, in some embodiments, a non-expanding distal "bulge"

1 1 2 may be permanently formed near the distal tip will also be effective. The

bulge is pushed sub-endocardially and during systole, the heart muscle 1 14

will "grab" onto the bulge and help to maintain position/placement of the

sharp during substance delivery. A radiopaque marker 1 1 6 may also be

provided. An alternative to the mechanical tissue engagement and dissection

caused by the sharp in the above-described embodiments is to include a

vacuum or suction device to adhere the distal end to the tissue. One of

multiple lumens or the space between multiple catheters or probes will have a

vacuum applied and fix the device in place via suction. In other alternate

embodiments one or more of the above-described features would be

incorporated into a multi-component tip that has mechanically

extendible/retractable elongated elements such as barbs, bristles, teeth or

similar tissue engaging elongated elements. The multi-component tip can also

include irrigation, aspiration, vacuum, heat, coagulation or other

functionalities.

Another aspect of preferred embodiments of the present invention is

the control of the depth of penetration of the distal end structure. As

discussed above, numerous constructions are available to penetrate tissue,

but in many instances, it will be desirable to know with a high degree of

certainty that a maximum depth cannot be exceed. This factor is particularly

important in percutaneous systems where it important that the myocardium

remain unperforated, i.e., that the distal tip not penetrate the epicardium.

One basic type of depth stop is illustrated in FIG. 1 2. In this embodiment the

distal end 1 20 may be of any construction, and a maximum depth of

penetration d is defined from the distal tip back to a depth stop. The depth

stop is a shoulder 1 22 formed by the juncture between the distal end 1 20 and

a larger diameter section 1 24. In addition to serving a depth stop function, the larger diameter section 1 24 will in some embodiments be an outgrowth of

the desire to conduct a particular volume of fluid at a certain pressure and

velocity, with the narrower section serving as a nozzle to change those

characteristics just prior to delivery. In other embodiments, the larger

diameter will serve to permit a larger volume to be stored close to the distal

end as well. The flat shoulder 1 22 connecting the two diameters serves to

preclude the distal tip from exceeding the maximum penetration depth.

Alternatively, other distal end configurations can include mechanical

protuberances or other depth stop structures. As shown in FIG. 1 3, the distal

end 1 30 may be provided with wire loop "petals" 1 32 which provide a depth

stop that is easily placed within a sleeve or outer catheter such as catheter 68

shown as in FIG. 7.

In addition to depth stops that mechanically define a distance between

the distal tip and another portion of the distal structure, other techniques of

limiting the penetration depth are also contemplated in other embodiments.

For example, radiopaque markers can be placed on a catheter or probe, and

additional markers on the distal end of the structure. Such radiopaque

markers are well known in the art. The relative position of the markers will

provide an indication of the depth of penetration. Such an embodiment is

further useful in conjunction with mechanical depth stops. Also, as discussed

above with reference to FIG. 3, if the distal end is advanced in an indexed

fashion, manually or in an automated fashion, the depth of penetration will be

determinable by the control of the distal end advancement precisely. From the foregoing description of various distal end constructions, it

can be seen that in certain embodiments of the present invention the fluid

administered can provide a force useful in the administration procedure. In

these embodiments, a fluid of appropriate viscosity is introduced either

through a single axial lumen or through one or more secondary lumens at a

sufficient velocity and pressure. In some instances, it will be preferable to

use a dissection fluid separate and apart from the angiogenic agent, which

can be accomplished using a multiple lumen device. Multiple lumen delivery

devices are well known in the art, and two typical cross-sections are

illustrated in FIGS. 1 4 and 1 5. In FIG. 14, the catheter 140 has a lumen

which is bisected by a web 1 42 to create two lumens 1 44 and 146 of equal

size. In FIG. 1 5, a catheter 1 50 has a single central lumen 1 52 and additional

lumens 1 54 and 1 56 within the walls of the catheter defining the lumen 1 52.

Variants of these two basic structures are known in the art. In addition to

fluids, certain of the multiple lumens can be selected to carry sensors or

active components such as laser fibers, lead wires to ultrasonic transducers or

RF conductors.

FIGS. 1 6A and 1 6B illustrate another embodiment of the present

invention having a catheter or probe 1 60 in which high pressure fluid is

emitted from the distal end 162 to dissect tissue. The catheter 1 60 may be a

single lumen or multi-lumen catheter are useful. In the embodiments shown in

FIGS. 1 6A-B, the angiogenic substance or another of the fluids that comprise

part of the administered dose is forced out at sufficient velocity and pressure such that an area of disturbance or dissection is created in the myocardium

that is larger than the channel formed by the dissection of a penetrating distal

tip alone. In one embodiment, the substance may be a chemical that ablates

tissue, a chemical denervation agent or a combination of the two with a fluid

to aid delivery. Thus, as seen in FIG. 1 6A, catheter 1 60 emits a jet of fluid

1 62 from the distal end 1 64 which impinges on a tissue section 1 66

disrupting the tissue. As seen in FIG. 1 6B, a combination of this tissue

disruption and mechanical dissection result in the penetration of the distal end

1 64 into the tissue. If a dual lumen delivery device such as that illustrated in

FIG. 1 4 is employed, the fluid stream 1 62 that creates the dissection may be

selectively stopped and an angiogenic agent can be emitted from orifices 1 68

which are in fluid communication with another lumen (not shown) within the

catheter 1 60 as shown by the arrows. This embodiment will be particularly

useful when it is determined that the sharp needs to be eliminated from the

distal tip. The high velocity fluid stream 1 62 impinges on the tissue 1 66,

creating a channel 1 68 formerly created solely by dissecting distal end 1 64.

During the process fluid stream 1 62 alternately or optionally provides

deposition of an angiogenic agent or dissection fluid alone that serves as a

precursor to deposition. Additionally, in other embodiments similar to that

shown in FIGS. 1 6A-B where radial orifices are provided in the distal end

lateral fluid flow, e.g. liquids or gases like CO₂ can be forced through the

orifices and multiple jets will create dissection planes and other collateral

damage. Additionally, by selective administration of the appropriate fluid, tissue can be either ablated or denerved. Such embodiments and

administration methods will be employed to create sites more receptive to

many of the angiogenic agents contemplated for use with the present

invention. Preferably, several lateral orifices will permit the angiogenic agent

to be simultaneously delivered at several depths within the myocardium.

Finally, as explained in detail above with reference to FIG. 10, if the lateral

orifices are disposed at angles such that their discharge axes are inclined

toward the tissue surface the backwards-firing "jets" will help to push the

device into the tissue or at least assist to secure it within the surrounding

tissue when the device is inserted into the myocardium.

Another alternate technique to ensure stable placement of the distal

end of the delivery device is to heat a portion of the distal end of the device.

This heating may be to a temperature sufficient to ablate tissue, but may be

much lower so long as the "hot tip" causes the distal end to "stick" to the

tissue in order to maintain placement during substance delivery. Any of a

number of heat transfer techniques can be used, either by transmission of

energy through the catheter or intraoperative probe or via absorption of

energy emanating from an extracorporeal source.

Another aspect of the present innovation is the visualization of the

angiogenic agents both while in the reservoir, in situ during administration and

in vivo after administration. In order effect visualization of the bolus of

delivered substance, it is contemplated that, as explained above, in preferred

embodiments, the angiogenic agent or a diagnostic material or other substance be radiopaque. Referring to FIG. 1 7, a catheter 1 70 has a conduit

1 72 which is filled with one or more substances, preferably separated by

marker substances. In the example illustrated, a carrier fluid 1 74 fills a

section of the device. A radiopaque marker substance 1 76 precedes a dose

of the angiogenic agent 1 78, which in turn is followed by carrier fluid 1 74,

thereby separating doses. The portion of the conduit 1 72 distal of the

angiogenic agent 1 78 is preferably filled with the radiopaque marker

substance 1 76 to provide imaging/navigation. However, alternatively the

radiopaque marker substance 1 76 can be the angiogenic substance itself, in

which case the clear demarcation seen in FIG. 1 7 will not be present.

Alternatively, as shown in FIG. 1 7, a length of a separate radiopaque or other

marker substance 1 76 that can be expressed prior to delivery of the

angiogenic agent to the tissue may be provided.

In any of the embodiments of FIG. 1 7, the radiopaque fluid or other

marker substance, allows the physician to visualize delivery of the appropriate

volume of drug by visualizing the advance of the radiopaque separators.

When the angiogenic agent is delivered, the radiopaque fluid will be flushed

from tube, and thus it will be known that a full dose has reached tip of

delivery tube and there will be no waste or excess administration. In certain

embodiments, where the angiogenic agent is a semi-solid "pellet" instead of a

liquid, the pellet itself is preferably radiopaque. In any of these embodiments,

another function served by the administration of a radiopaque marker with the

angiogenic agent will be to mark the regions of deposition so that a surrounding area of the tissue region may be properly treated with other

doses.

Alternatively or in conjunction with an administered substance, the

device itself can be made visible by the inclusion of radiopaque markers,

which is illustrated in FIGS. 4-5 and well known by those skilled in the art

As disclosed in U.S. patent application Serial No. 08/438,51 2, filed

June 7, 1 995, which is incorporated herein by reference, it is advantageous

to place an angiogenic agent into the sites where energy has been introduced

to cause revascularization in a TMR procedure. It is believed, based upon

preliminary data, that delivery of an angiogenic agent to a TMR site results in

the most potent neovasculogenesis. TMR causes tissue damage in a region

surrounding the site where energy has been introduced. Various energy

sources have been used for TMR including laser energy, RF energy and

ultrasonic energy. It is believed that the tissue damage provides benefits by

denervating tissue and that it also stimulates new blood vessel growth. The

new blood vessel growth stimulated by TMR is apparently enhanced or

supplemented by the introduction of an angiogenic agent to the TMR site.

Conversely, the administration of growth factors alone may not be

optimal. Thus, in one preferred embodiment an optical fiber or RF electrode is

delivered down a central lumen of a first delivery catheter and then

withdrawn and replaced by a delivery tube, which is then used to administer

an angiogenic agent according to any of the techniques set forth above.

Alternatively, the physician can leave the first delivery catheter in place and deliver an angiogenic agent through the lumen of the first delivery catheter to

the TMR site. Alternatively, multiple lumen embodiments such as those

shown in FIGS. 1 4-1 5 permit energy and angiogenic agents to be delivered

sequentially, along with marker substances and other fluids as previously

described.

In terms of the adjunctive (with TMR) embodiments of the present

invention, the introduction of energy to a tissue site includes all forms of

TMR, whether the "channel" traditionally described is formed or not.

Additionally, the adjunctive use described herein includes the application of

energy to merely disturb or disrupt the tissue. The enhancement of

neovasculogenesis may occur due to subtle tissue effects. Such tissue

effects may be stimulated by limited energy introduction, such that, in

contrast to traditional TMR, no "channel" is formed. Such limited energy

deposition may only serve to disturb or disrupt tissue locally while enhancing

the uptake of angiogenic agents. For example, a device with a heated distal

tip would be used in place of either a sharp or a TMR channel forming device

in certain embodiments, e.g., the distal construction shown in FIGS. 1 6A-B.

This use may be preferable in cases where a simple injection or penetration

does not create the disruption of the other techniques discussed above. In

other embodiments, the addition of non-thermal ^' energy, particularly

ultrasound or acousto-optic affects can be used to drive the angiogenic agent

into the surrounding tissue or activate or alter the characteristics of the substance, including in certain embodiments, using adjunctive energy to

fracture microspheres containing angiogenic agent.

The present invention also encompasses methods of administering an

angiogenic agent. In methods performed in accordance with the present

invention, a delivery device is placed in contact with a heart wall and a dose

of an angiogenic agent is introduced into the heart tissue. The administration

may be timed to the heart cycle, and the step of placing the delivery device in

contact with the heart wall can be preceded by piercing the wall. In certain

adjunctive embodiments, the step of administering the angiogenic agent is

performed after a the delivery of energy has disturbed the tissue, or in some

cases the step of administering the angiogenic agent follows the step of

performing TMR.

Although certain embodiments of the present invention have been set

forth herein and described with particularity, these are provided for purposes

of illustrating the present invention and are not limiting. Upon review of the

foregoing description, those skilled in the art will realize that numerous

adaptations, modifications and variations of the embodiments set forth herein

are readily made without departing from the spirit of the inventions described.

For these reasons, the scope of the present invention can be ascertained only

by reference to the appended claims.

Claims

WHAT IS CLAIMED IS:

1 . Apparatus for delivering a dose of an angiogenesis substance to a

desired region of a patient's heart comprising an elongated shaft having a

proximal end, a distal end configured to penetrate the desired region of the

patient's heart, a handpiece proximal to the distal end, a reservoir containing

an angiogenesis substance, an inner lumen extending within the elongated

shaft to the distal end which is in fluid communication with the reservoir of

angiogenic substance, and at least one discharge port in the distal end for

delivering angiogenesis substance into the region of the patient's heart.

2. The apparatus of claim 1 wherein the elongated shaft is a

catheter.

3. The apparatus of claim 1 wherein the elongated shaft is an

intraoperative probe.

4. The apparatus of claim 1 , further comprising a metered

dispensing system.

5. The apparatus of claim 4, wherein the metered dispensing

system further includes dispensing control.

6. The apparatus of claim 5, wherein the dispensing control is

disposed on the handpiece.

7. The apparatus of claim 5, wherein the dispensing control is

automated.

8 The apparatus of claim 7 wherein the dispensing system includes

a signal receiver to detect signals generated by the heart and a circuit which synchronizes the activation of the automated dispensing apparatus

in response to heart signals received by the signal receiver.

9. The apparatus of claim 8 wherein the synchronizing circuit

inhibits activating the dispensing apparatus during a pre-determined portion

of the heart cycle.

1 0. The apparatus of claim 1 wherein the distal end of the shaft

further comprises at least one sharp.

1 1 . The apparatus of claim 1 wherein the distal end comprises one or

more radially oriented orifices.

1 2. The apparatus of claim 1 1 wherein the distal end further

comprises one or more elongated elements that deploy from a first position

that inhibits tissue engagement by the distal end to a second position that

permits tissue engagement by the distal end.

1 3. The apparatus of claim 1 1 wherein the distal end comprises at

least one barb aligned with a longitudinal axis of the elongated shaft and

disposed along an outside surface of the elongated shaft.

14. The apparatus of claim 1 3 wherein the barb deploys from a first

portion that inhibits tissue engagement to a second position that permits

tissue engagement.

1 5. The apparatus of claim 1 wherein the distal end has a bulbous

section.

1 6. The apparatus of claim 1 5 wherein the bulbous section is

inflatable.

1 7. The apparatus of claim 1 wherein the distal end has a radiopaque

marker.

1 8. The apparatus of claim 1 wherein the elongated shaft has a

depth stop to control the depth of penetration of the distal end into the heart

tissue.

1 9. The apparatus of claim 1 8 wherein the distal end comprises a

first distal section, a second proximal section having larger transverse

dimensions than the first distal section and a shoulder connecting the distal

and proximal sections which comprises the depth stop.

20. The apparatus of claim 1 8, wherein the depth stop comprises

one or more mechanical elements that extend radially outward from the distal

end.

21 . The apparatus of claim 1 wherein the elongated shaft has at

least one additional lumen.

22. The apparatus of claim 21 wherein at least one of the plurality of

lumens is in fluid communication with a source of a fluid other than an

angiogenic agent.

23. The apparatus of claim 1 including a distal tissue contact device

for tissue injury.

24. The apparatus of claim 23 wherein the distal tissue contact

device for tissue injury is a mechanical device affixed to the distal end.

25. The apparatus of claim 23 wherein the distal tissue contact

device for tissue injury is a laser energy conductor.

26. The apparatus of claim 23 wherein the distal tissue contact

device for tissue injury is an RF energy conductor.

27. The apparatus of claim 23 wherein the distal tissue contact

device for tissue injury is an ultrasound transducer.

28. The apparatus of claim 23 wherein the distal tissue contact

device for tissue injury includes a conduit connected to a source of fluid

which can be delivered at a pressure and velocity sufficient to disrupt tissue.

29. The apparatus of claim 23 wherein the distal tissue contact

device is an electrical current conductor.

30. The apparatus of claim 21 including a distal tissue contact device

for tissue injury slidably disposed within one of said additional lumens.

31 . An apparatus for injection of at least one dose of an angiogenic

agent to a patient's heart which is synchronized to a cardiac cycle of the

patient's heart, comprising:

an injection device;

an elongated shaft having a proximal end connected to the injection

device and at least one lumen extending within the elongated shaft in

fluid communication with the injection device; and

a solenoid connected to the injection device to control the

dosage amount of angiogenic agent dispensed by the injection device

when the solenoid is pulsed by a signal related to the cardiac cycle of

the patient's heart.

32. The apparatus of claim 31 wherein the solenoid controls the

same amount of angiogenic agent dispensed after each of one or more pulses.

33. The apparatus of claim 31 further comprising an energy probe in

contact with heart tissue and a switch for activating the energy probe,

whereby energy is introduced into the heart tissue by operation of the

activation switch.

34. The apparatus of claim 33 wherein the energy probe is a laser

fiber.

35. An apparatus for delivering a substance comprising a delivery

lumen extending from a distal end to a proximal point, and wherein at least a

first section of the delivery lumen is filled with the angiogenic substance.

36. The apparatus of claim 35 further comprising a second section of

the delivery lumen in fluid communication with the first section and containing

a substance other than an angiogenic agent.

37. The apparatus of claim 35 wherein the angiogenic agent is a

fluid.

38. The apparatus of claim 35 wherein the delivery lumen contains at

least an angiogenic agent, a fluid and a marker substance.

39. The apparatus of claim 35 further comprising at least a second

lumen.

40. A method of administering an angiogenic agent to a wall of a

patient's heart, comprising the steps of: penetrating the patient's heart wall with a distal end of an

administration device which has at least a pre-determined amount of

angiogenic agent;

activating the administration device so as to deliver a pre-determined

amount of an angiogenic agent into the patient's heart wall.

41 . The method of claim 40 further comprising the steps of:

monitoring a cardiac cycle and creating a signal representative of the

cardiac cycle; and

synchronizing the activation of the administration device in response

to the signal.

42. The method of claim 40 including the step of contacting the

heart wall with an energy delivery device prior to the step of activating the

administration device.

43. The method of claim 42 wherein the step of contacting the heart

wall further comprises the step of delivering energy to the heart wall to

disturb tissue in the heart wall.

44. The method of claim 43 wherein the step of delivering energy

performs a transmyocardial revascularization procedure.