Combined angioplasty and intravascular radiotherapy method and apparatus

Apparatus and methods are provided for relieving a stenosed region of a blood vessel such as a coronary using a single catheter that relieves the angioplasty by conventional means and then delivers an easily controllable inherently uniform dosage of radiation to the walls of a blood vessel for preventing restenosis after angioplasty. An embodiment of the apparatus comprises a catheter having an angioplasty balloon that is inflatable with a liquid containing a suspended radioactive material such as .sup.125 I or .sup.32 P. The balloon is surrounded by a membrane to capture the radioactive liquid in the event the balloon ruptures. The catheter is advanced through the patient until the balloon is disposed in the stenosed region of the blood vessel. The stenosed region is relieved using the angioplasty balloon, after which the angioplasty balloon is emptied and re-filled with the radioactive liquid, which expands the balloon to engage the walls of the blood vessel thereby providing an inherently uniform dosage of radiation to the blood vessel walls. Another embodiment of the apparatus comprises a catheter having an angioplasty balloon surrounded by a radiotherapy treatment balloon that is separately inflatable with a radioactive liquid. The stenosed region is relieved using the inner angioplasty balloon after which the radiotherapy treatment balloon is filled with the radioactive liquid. An additional containment balloon outside the radiotherapy treatment balloon may also be provided to prevent loss of radioactive liquid in the event the treatment balloon ruptures. The angioplasty balloon may be partly filled during the radiation treatment to minimize the volume of radioactive liquid necessary to achieve the desired dosage.

BACKGROUND OF THE INVENTION 
This invention relates generally to treatment of selected tissue by 
inter-vivo radiation, specifically to radiation treatment of traumatized 
regions of the cardiovascular system to prevent restenosis of the 
traumatized region, more specifically to radiation treatment to prevent 
restenosis of an artery traumatized by percutaneous transluminal 
angioplasty (PTA). 
PTA treatment of the coronary arteries, percutaneous transluminal coronary 
angioplasty (PTCA), also known as balloon angioplasty, is the predominant 
treatment for coronary vessel stenosis. Approximately 300,000 procedures 
were performed in the United States (U.S.) in 1990 and an estimated 
400,000 in 1992. The U.S. market constitutes roughly half of the total 
market for this procedure. The increasing popularity of the PTCA procedure 
is attributable to its relatively high success rate, and its minimal 
invasiveness compared with coronary by-pass surgery. Patients treated by 
PTCA, however, suffer from a high incidence of restenosis, with about 35% 
of all patients requiring repeat PTCA procedures or by-pass surgery, with 
attendant high cost and added patient risk. More recent attempts to 
prevent restenosis by use of drugs, mechanical devices, and other 
experimental procedures have had limited success. 
Restenosis occurs as a result of injury to the arterial wall during the 
lumen opening angioplasty procedure. In some patients, the injury 
initiates a repair response that is characterized by hyperplastic growth 
of the vascular smooth muscle cells in the region traumatized by the 
angioplasty. The hyperplasia of smooth muscle cells narrows the lumen that 
was opened by the angioplasty, thereby necessitating a repeat PTCA or 
other procedure to alleviate the restenosis. 
Preliminary studies indicate that intravascular radiotherapy (IRT) has 
promise in the prevention or long-term control of restenosis following 
angioplasty. It is also speculated that IRT may be used to prevent 
stenosis following cardiovascular graft procedures or other trauma to the 
vessel wall. Proper control of the radiation dosage, however, is critical 
to impair or arrest hyperplasia without causing excessive damage to 
healthy tissue. Overdosing of a section of blood vessel can cause arterial 
necrosis, inflammation and hemorrhaging. Underdosing will result in no 
inhibition of smooth muscle cell hyperplasia, or even exacerbation of the 
hyperplasia and resulting restenosis. 
U.S. Pat. No. 5,059,166 to Fischell discloses an IRT method that relies on 
a radioactive stent that is permanently implanted in the blood vessel 
after completion of the lumen opening procedure. Close control of the 
radiation dose delivered to the patient by means of a permanently 
implanted stent is difficult to maintain because the dose is entirely 
determined by the activity of the stent at the particular time it is 
implanted. Additionally, the dose delivered to the blood vessel is 
non-uniform because the tissue that is in contact with the individual 
strands of the stent receive a higher dosage than the tissue between the 
individual strands. This non-uniform dose distribution is especially 
critical if the stent incorporates a low penetration source such as a beta 
emitter. 
U.S. Pat. No. 5,302,168 to Hess teaches use of a radioactive source 
contained in a flexible carrier with remotely manipulated windows. H. 
Bottcher, et al. of the Johann Wolfgang Goerhe University Medical Center, 
Frankfurt, Germany report in November 1992 of having treated human 
superficial femoral arteries with a similar endoluminal radiation source. 
These methods generally require use of a higher activity source than the 
radioactive stent to deliver an effective dose. Accordingly, measures must 
be taken to ensure that the source is maintained reasonably near the 
center of the lumen to prevent localized overexposure of tissue to the 
radiation source. Use of these higher activity sources also dictates use 
of expensive shielding and other equipment for safe handling of the 
source. 
The aforementioned application Ser. No. 08/352,318, incorporated herein by 
reference, discloses IRT methods and apparatus for delivering an easily 
controllable uniform dosage of radiation to the walls of the blood vessel 
without the need for special measures to center the radiation source in 
the lumen, the need for expensive shielding to protect medical personnel, 
or the need for expensive remote afterloaders to handle the higher 
activity sources. This is accomplished by introducing a radioactive liquid 
into a balloon catheter to expand the balloon until it engages the blood 
vessel walls. The aforementioned application also discloses methods and 
apparatus for relieving the stenosed region of the blood vessel and 
performing the IRT procedure with a single apparatus, which may include an 
angioplasty balloon with a separately inflatable outer IRT balloon. 
In certain applications, however, the size of the blood vessel is too small 
to admit a catheter with a profile large enough to accommodate separate 
inflation lumens for an outer and inner balloon. A smaller profile IRT 
catheter be obtained, however, by eliminating the IRT inflation lumen, 
thereby converting the outer IRT balloon to a containment membrane. 
Where the blood vessel size permits, a further advantage may be obtained, 
if a combination angioplasty and IRT catheter includes means for extending 
the IRT treatment area beyond the angioplasty treatment area to irradiate 
a region extending proximal and distal of the angioplasty treatment area. 
By providing for IRT treatment that covers a wider area than the 
angioplasty treatment area, all of the tissue traumatized by the 
angioplasty is irradiated with the measured dosage, even if the catheter 
is displaced between the angioplasty and IRT procedures. Accordingly, 
proper inhibition of smooth muscle cell hyperplasia is more reliably 
achieved. 
SUMMARY OF THE INVENTION 
According to the present invention, a single treatment catheter is used to 
perform all, or at least the final stage, of the angioplasty procedure and 
to perform the entire IRT procedure. In an embodiment of the present 
invention, the treatment catheter comprises a flexible elongate member 
having an angioplasty balloon that is surrounded by an IRT treatment 
balloon having a separate inflation lumen. The catheter is advanced 
through the cardiovascular system of the patient until the balloons are 
positioned at a targa area comprising the stenosed region of the blood 
vessel. The stenosis is first relieved using the inner angioplasty 
balloon, then the target tissue is irradiated by filling the IRT treatment 
balloon with a radioactive liquid until the outer wall of the balloon 
gently engages the inner wall of the blood vessel. 
The radioactive liquid comprises a suspension of a beta emitting material 
such as .sup.32 P or a photon emitting material such as .sup.125 I in a 
liquid carrier. The radiation emitted by such sources is quickly absorbed 
by surrounding tissue and will not penetrate substantially beyond the 
walls of the blood vessel being treated. Accordingly, incidental 
irradiation of the heart and other organs adjacent to the treatment site 
is substantially eliminated. Because the radioactive liquid has a 
substantially uniform suspension of radioactive material, the radiation 
emitted at the surface of the balloon in contact with the target area of 
the blood vessel is inherently uniform. Accordingly, uniform irradiation 
of the blood vessel wall is also inherent. 
According to an embodiment of the present invention, the outer IRT 
treatment balloon is made longer than the inner angioplasty balloon. 
Accordingly, when filled, the IRT treatment balloon will irradiate a 
section of the blood vessel that extends on both sides beyond the area 
treated with the angioplasty balloon. This extended IRT treatment area 
provides a margin of safety to ensure that, even if the catheter shifts 
slightly during the treatment, the entire traumatized region of the blood 
vessel will be treated to prevent smooth muscle cell hyperplasia. 
The catheter of the present invention may also be equipped with perfusion 
ports proximal and distal of the balloon to permit blood flow past the 
balloon when inflated. 
According to another embodiment of the present invention, a third balloon 
is provided that completely envelopes the IRT treatment balloon. This 
containment balloon acts as a containment vessel in the event the IRT 
treatment balloon ruptures when filled with the radioactive liquid. In 
use, prior to filling the treatment balloon with the radioactive liquid, 
the containment balloon is filled, preferably with a non-toxic 
radio-opaque fluid, to verify the integrity of the containment balloon. 
The radio-opaque fluid filled containment balloon may also be used to 
verify correct positioning of the catheter within the target area of the 
blood vessel. 
After the angioplasty procedure is performed, the angioplasty balloon may 
be deflated, or left partially inflated. Leaving the angioplasty balloon 
partially inflated reduces the amount of radioactive liquid that must be 
used to fill the treatment balloon by occupying space within the IRT 
treatment balloon. Because of the self-attenuation of the radioactive 
liquid itself, most of the radioactivity originates at the surface of the 
treatment balloon. Accordingly, the surface radiation is not reduced 
substantially as a result of the center being filled with an inert 
material. 
According to another embodiment of the present invention, a proximal and 
distal blocking balloon are also provided to contain the radioactive 
liquid in the target area in the event of a total failure of all 
containment systems. 
According to another embodiment of the present invention, where a very low 
profile is required to access small blood vessels, the catheter comprises 
an inner angioplasty balloon and an outer balloon, however, the outer 
balloon inflation lumen is eliminated, thereby converting the outer 
balloon to a containment membrane. The IRT procedure is then carried out 
by filling the angioplasty balloon itself with the radioactive liquid 
after the angioplasty procedure has been performed. The containment 
membrane contains the radioactive liquid in the unlikely event that the 
angioplasty balloon, which previously withstood angioplasty pressures, 
ruptures under the more moderate IRT pressure.

DESCRIPTION OF PREFERRED EMBODIMENTS AND METHODS 
FIGS. 1A and 1B illustrate a suspended-isotope IRT catheter according to 
the present invention. The IRT catheter comprises shaft 10 having an 
angioplasty inflation lumen 11, IRT inflation lumen 12, a conventionally 
formed tip that seals the end of the inflation lumens, and may include 
longitudinal guidewire/injection/perfusion lumen 14 which passes through 
the tip. Shielded injector 16, which may be a manual or automated syringe 
containing a radioactive liquid 30, or a pump connected to a reservoir of 
radioactive liquid 30, is connected to the proximal end of shaft 10 and is 
in fluid communication with IRT inflation lumen 12. To prevent possible 
spillage and corresponding radioactive contamination of the operating room 
and/or its personnel, the shielded injector 16 is permanently attached to 
shaft 10, or preferably, injector 16 is equipped with a fail-safe 
non-detachable connector 18, which cannot be detached from the 
corresponding receptacle 20 of shaft 10 once it is attached thereto. 
Non-detachable connector 18 also prevents the radioactive liquid 30 from 
being discharged from injector 16 until the connector is connected to the 
receptacle in shaft 10. Connectors having ring-detents and other 
non-detachable fluid fittings are well known in the art, as are piercing 
valves and other common methods of preventing fluid flow prior to 
attachment of a fluid fitting. The proximal end of shaft 10 also includes 
angioplasty luer fitting 15 in fluid communication with angioplasty 
inflation lumen 11, and guidewire lumen luer fitting 17 in fluid 
communication with guidewire lumen 14, through which drugs may be injected 
directly into the patient's blood stream. 
FIG. 1C is an enlarged view of the distal end of the present embodiment of 
the catheter. Angioplasty balloon 32 comprises a conventional elastic or 
preferably an inelastic balloon, which may preferably be made from 
polyethylene terephthalate (PET), polyvinyl chloride (PVC), or other 
medical grade material suitable for constructing a strong non-compliant 
balloon. Angioplasty balloon 32 is in fluid communication with angioplasty 
inflation lumen 11 via ports 34. Immediately inside proximal and distal 
ends of balloon 32 are markers 36, comprising bands of silver or other 
suitable x-ray opaque material. Markers 36 aid in the proper positioning 
of angioplasty balloon 32 within the target area of the blood vessel under 
fluoroscopy. 
IRT Treatment balloon 42 is disposed at the distal end of shaft 10 
surrounding angioplasty balloon 32. IRT treatment balloon is an elastic or 
preferably an inelastic balloon, which may preferably be made from 
polyethylene terephthalate (PET), polyvinyl chloride (PVC), or other 
medical grade material suitable for constructing a strong non-compliant 
balloon. IRT treatment balloon 42 is sealed at its proximal and distal 
ends to catheter shaft 10 in fluid communication with inflation lumen 12 
via inflation lumen ports 44. 
Immediately adjacent to and outside the ends of IRT treatment balloon 42 
are perfusion ports 48, which are in fluid communication with guidewire 
lumen 14. Perfusion ports are well known in the art as a means of 
permitting some blood flow past a balloon that is inflated within and 
otherwise blocking a blood vessel. 
In operation, an appropriately sized catheter according to the present 
invention is selected and positioned within the patient's blood vessel by 
conventional means so that the balloon is within the target area 
comprising the stenosed region of the blood vessel. The stenosis is 
relieved by inflating the angioplasty balloon according to conventional 
methods. After the angioplasty procedure has been performed, shielded 
injector 16 is connected to the receptacle at the proximal end of the 
catheter shaft and the air evacuated from the IRT treatment balloon and 
the inflation lumen. In the case of a shielded syringe, this is done 
simply by withdrawing the plunger. The balloon is then filled with the 
liquid containing the suspended isotope until the outer wall of the 
balloon gently engages the inner wall of the blood vessel. The balloon is 
maintained in this inflated state for a predetermined period of time 
calculated to deliver an effective dose of radiation to the wall of the 
blood vessel. The radioactive liquid is then withdrawn from the balloon 
and the catheter withdrawn from the patient's body. 
To reduce the chances of overpressurizing the treatment balloon and causing 
a rupture, pressure feedback device 22 is connected to the proximal end of 
inflation lumen 12. Pressure feedback device 22 may be a pressure gauge, 
or preferably a solid-state pressure transducer, which in the in the event 
an overpressure condition is detected, operates an alarm 24 and/or a waste 
gate 26 that discharges the inflation lumen 12 into a shielded container. 
Alternately, the solid state pressure transducer may be positioned at the 
distal end of the inflation lumen to monitor pressure in the balloon 
directly. 
For added safety, prior to filling IRT treatment balloon with radioactive 
liquid, IRT treatment balloon may be filled with a commonly used non-toxic 
radio-opaque contrast medium to verify integrity of the IRT treatment 
balloon. Once the integrity is verified, the contrast medium would be 
evacuated and shielded syringe 16 connected to the receptacle at the 
proximal end of the catheter shaft. Although the small amount of contrast 
medium that would remain in the IRT treatment balloon would dilute the 
radioactive liquid, the amount of dilution would be measurable and could 
be compensated. 
FIGS. 2A-2C illustrate an alternate embodiment of the present invention 
further including an outer containment balloon 52. Containment balloon 52 
is an inelastic or preferably an elastic balloon, which is preferably made 
of latex or other medical grade material suitable for constructing 
puncture-resistant elastic balloons. Containment balloon 52 is attached at 
its proximal and distal ends to shaft 10 and completely surrounds 
treatment balloon 32. Containment balloon 52 is in communication with 
containment balloon inflation lumen 54 via containment balloon inflation 
lumen port 56, which in turn is in fluid communication with containment 
balloon luer fitting 58 at the proximal end of shaft 10. 
In operation, after the IRT catheter is in position, but before IRT 
treatment balloon 42 is filled with the radioactive liquid, containment 
balloon 52 is filled with a commonly used non-toxic radio-opaque contrast 
medium injected through containment balloon luer fitting 58. The integrity 
of containment balloon is verified by fluoroscopy, pressure, or other 
suitable means and, if integrity is confirmed, the radio-opaque liquid is 
withdrawn and the procedure for injecting the radioactive liquid into 
treatment balloon 42 carried out. If the integrity of the containment 
balloon has been compromised (for example by sharp edges in guide 
catheters, guide wires, stents, etc.) a new catheter is selected and 
repositioned. By verifying integrity of the containment balloon after the 
balloon is in position, but before the radioactive liquid is injected, a 
substantial degree of safety against accidental injection of radioactive 
liquid into the patient's blood stream is achieved. Where a containment 
balloon is used (or blocking balloons as discussed with reference to FIGS. 
3A-3C are used), pressure feedback device 22 may also be used to activate 
an emergency evacuation system. In the event the pressure feedback device 
detected a sudden drop in pressure (indicating rupture of the treatment 
balloon) the pressure feedback device would initiate an immediate 
withdrawal of all radioactive liquid from the patient, for example by 
opening a valve to a shielded vacuum accumulator 28. 
Several important considerations must be balanced in the design of an 
apparatus for safely and effectively injecting a radioactive liquid into a 
patient to irradiate a blood vessel to prevent restenosis. Although 
.sup.125 I and .sup.32 P are both emitters of low penetrating radiation 
suitable for use according to the present invention, .sup.32 P is 
preferred because it has a half-life of only 14.3 days as compared with 
the 60 day half-life of .sup.125 I. A shorter half life renders .sup.32 P 
safer to use because, in the event of a catastrophic failure involving 
leakage of radioactive liquid into the patient's blood stream, for a given 
calculated dose rate, a shorter half life will result in a lesser total 
body dosage. .sup.32 P is also a relatively pure beta radiation emitter. 
.sup.32 P has been used in the treatment of chronic leukemia, where it is 
injected directly into a patient's blood stream. Accordingly, substantial 
medical knowledge exists as to the effects of .sup.32 P in the blood 
stream. 
In the leukemia treatment, depending on the patient's weight, a suspended 
radiation source of about 6 to 15 millicuries of .sup.32 P is used. 
Accordingly, for maximum safety, the preferred suspended-isotope IRT 
catheter should also use a source of no more than 6 millicuries. Prior 
experiments have shown that a dose of about 1000 to 3500 rads delivered to 
the blood vessel wall from a gamma radiation source is effective to 
inhibit the smooth muscle cell hyperplasia that causes restenosis. For low 
penetration sources, such as beta radiation emitters, it is believed a 
dosage up to 5,000 rads may be tolerated. For a 6 millicurie .sup.32 P 
source to deliver such a dose to the surface of the blood vessel, the 
balloon must be in position for substantially in excess of one minute, 
thus necessitating the perfusion ports. 
For example, it is estimated that the balloon will absorb approximately 15% 
of the radiation delivered by the radioactive liquid. Accordingly, to 
deliver 2000 rads to the blood vessel wall, 2350 rads must be delivered to 
the inner wall of the balloon. A typical treatment balloon comprises a 
cylindrical balloon having an internal diameter of 3 millimeters, a length 
of about 30 millimeters, and an interior volume of approximately 0.2 cubic 
centimeters. Accordingly, to limit the total source to no more than 6 
millicuries, 0.2 cubic centimeters of a liquid having a source 
concentration of no more than 30 millicuries per cubic centimeter must be 
used. A 30 millicurie per cubic centimeter source, however, requires about 
6 minutes to deliver 2350 rads to the interior of the 3 millimeter 
diameter treatment balloon and thus requires about 6 minutes to deliver 
2000 rads to the interior wall of the blood vessel. 
The larger the balloon, the lower the concentration of the radiation source 
in the liquid must be to maintain the safe limit of 6 millicuries. 
However, the lower the concentration, the lower the dose rate and the 
longer the balloon must remain inflated to deliver an effective dose to 
the blood vessel wall. 
To reduce the volume of radioactive liquid that must be used, angioplasty 
balloon 32 may be left partially or substantially filled during the IRT 
treatment. Because the liquid near the center of a body of radioactive 
liquid does not contribute significantly to the radiation emitted from the 
surface of the body, by leaving the angioplasty balloon partially filled 
in the center of the IRT treatment balloon, a smaller volume of 
radioactive liquid can be used without significantly affecting the 
radiation delivered to the vessel wall. Without the angioplasty balloon 
acting as an inert filler, to avoid exceeding the 6 millicurie limit, the 
same size treatment balloon would require a larger volume of lower 
concentration radioactive liquid, with a commensurately lower dose rate 
and longer required treatment interval. 
FIGS. 3A-3C illustrate an additional embodiment of the present invention 
incorporating blocking balloons 62. Blocking balloons 62 are inelastic or 
preferably elastic balloons, which are preferably made of latex or other 
medical grade material suitable for constructing puncture-resistant 
elastic balloons. Blocking balloons 62 are sealed to shaft 10 proximal and 
distal of treatment balloon 42 between perfusion ports 48, and are in 
fluid communication with a common blocking balloon inflation lumen 64 via 
blocking balloon inflation ports 66. Blocking balloon inflation lumen 64 
is, in turn, in fluid communication with blocking balloon luer fitting 68 
at the proximal end of shaft 10. 
In operation, after the angioplasty procedure is completed, blocking 
balloons 62 are inflated in the blood vessel until the blood flow past the 
balloons is substantially stopped (the flow of blood in the vessel itself 
continues through the perfusion ports). The treatment balloon 42 is then 
inflated with the radioactive liquid for treatment of the blood vessel 
walls. In the event treatment balloon 42 ruptures and, where present, 
containment balloon 52 also fails, the radioactive liquid is still 
contained in the blood vessel between blocking balloons 62. The 
radioactive liquid can then be withdrawn either through any of the 
inflation lumens that, because of the breach, are in fluid communication 
with the interior of the blood vessel between the blocking balloons 62, or 
preferably withdrawn automatically using the emergency evacuation system 
discussed with reference to FIGS. 2A-2C. Blocking balloons may also be 
used in lieu of containment balloon 52, especially in particularly small 
lumens where a smaller profile is desirable. 
FIGS. 4A-C illustrate an embodiment of the present invention for use in 
blood vessels that are too small to admit a catheter having a profile 
large enough to support independent inflation lumens for an angioplasty 
and an IRT balloon. The reduced-profile IRT catheter comprises shaft 10 
having a single multi-purpose inflation lumen 81, a conventionally formed 
tip that seals the end of the inflation lumens, and may include 
longitudinal guidewire/injection/perfusion lumen 14 which passes through 
the tip. 
FIG. 4C is an enlarged view of the distal end of the embodiment of the 
catheter. Angioplasty balloon 32 comprises a conventional elastic or 
preferably an inelastic balloon, which may preferably be made from 
polyethylene terephthalate (PET), polyvinyl chloride (PVC), or other 
medical grade material suitable for constructing a strong non-compliant 
balloon. Angioplasty balloon 32 is in fluid communication with 
multi-purpose inflation lumen 81 via ports 84. Preferably, angioplasty 
balloon 32 is surrounded by IRT containment membrane 92, which is sealed 
to catheter shaft 10. 
In a preferred method of operation, after the distal end of the catheter is 
properly positioned in a stenosed region of the blood vessel, angioplasty 
balloon 32 is filled with a non-toxic fluid contrast medium injected 
through fitting 20 by means of an injector that mates with, but is 
detachable from fitting 20. The fluid is injected until angioplasty 
balloon 32 expands the stenosed region to an appropriate size. The fluid 
is then evacuated and, preferably, inflation lumen 81 exposed to a vacuum 
to remove as much of the fluid contrast medium as possible. Balloon 32 is 
then filled with radioactive liquid 30 until the walls of the balloon 
engage the walls of the blood vessel. The balloon is maintained in this 
inflated state for a predetermined period of time calculated to deliver an 
effective dose of radiation to the wall of the blood vessel. The 
radioactive liquid is then withdrawn from the balloon and the catheter 
withdrawn from the patient's body. A small amount of contrast medium will 
remain in balloon 30 after the angioplasty procedure to dilute the 
radioactive liquid. However, the dilution may be compensated, by 
increasing the initial concentration of the radioactive liquid or, 
preferably by increasing the treatment interval. The containment membrane 
92 contains the radioactive liquid in the event the angioplasty balloon 
ruptures when filled with the radioactive liquid. 
Thus, the present invention provides safe and effective method and 
apparatus for combining angioplasty and restenosis prevention into a 
single apparatus capable of relieving angioplasty and delivering an easily 
controllable inherently uniform dosage of radiation to control restenosis 
in the region of the blood vessel traumatized by the angioplasty 
procedure. 
Although certain preferred embodiments and methods have been disclosed 
herein, it will be apparent from the foregoing disclosure to those skilled 
in the art that variations and modifications of such embodiments and 
methods may be made without departing from the true spirit and scope of 
the invention. Accordingly, it is intended that the invention shall be 
limited only to the extent required by the appended claims and the rules 
and principles of applicable law.