Patent Application
20150367140
The invention relates generally to the field of treatment of invasive agents, such as pathogens and cancers, in living organisms such as the human body and, more particularly, to a system that generates an energy field for application to the living organism, to activate nano-particles which are infused into the living organism.
Any time low temperature heat is added to a living organism, such as the human body, as it is being treated for cancer with radiation and/or chemotherapy, the efficacy of the cancer treatment is substantially increased. The difficulty with this process has been in “adding heat” to only the cancerous region that is being treated, in a precisely controlled manner.
One prior cancer treatment method sought to place the entire living organism in a hot water wrap which often caused severe side effects, including death, since the control of the patient's body temperature is not precise. This cancer treatment method often caused conditions similar to heat shock or heat stroke, since the living organism is unable to adequately remove the applied heat to maintain a safe body temperature.
Another cancer treatment approach, called regional hyperthermia, uses microwave energy, applied to the living organism from an external source, to heat the tissue. This approach relies on the fact that tissue is largely composed of water, which is dipolar in nature and heats as the water molecules “physically flip” in concert with the applied alternating current magnetic field. This “flip” causes molecular friction, hence heat. However, the microwave heating of tissue causes hot spots and burns (as do microwave ovens). In addition, it is virtually impossible to direct the microwave energy to only heat the tissue of interest; and surrounding non-cancerous tissue is therefore also heated, sometimes to a burning level. Studies have shown patients can receive 2nd degree and 3rd degree burns from a microwave heating approach.
A third cancer treatment approach uses an “antenna”, such as a monopole, which is inserted via a catheter inside the body cavity to be heated. Again, as before, severe hot spots and burns can result from the non-uniform application of electromagnetic fields (at microwave frequencies) which has unintended damaging effects.
All of the cancer treatment methods embodied in the present prior art have significant deficiencies in terms of patient safety, treatment efficacy and cost. In addition, in the United States, the only approved procedure for the treatment of bladder cancer in humans is a pure chemotherapy based approach, without any heating of the bladder tissue or the chemotherapy medicine, to stress and help kill remaining cancer cells. Other approaches such as using microwave heating applied to the body from a source located outside the body are only in experimental, pre-clinical studies. The catheter based approach is only approved for use in certain European countries.
Thus, the present set of bladder cancer treatment methods can be characterized as:
Circulating chemotherapy fluids without a catheter-based system won't work because of the physical size of the urethra, non-uniform thermodynamics (can't only remove “cold” fluid and replace it with “warm” fluid), re-circulating chemotherapy agents thru the urethra is caustic and very damaging, the urethra can be easily damaged by large physical objects inserted into it and last, the chemotherapy agent (such as Mitomycin C) is very expensive. All of this increases the volume of Mitomycin C required to ensure that the chemotherapy agent concentration is uniform in the total circulated volume of fluid (upwards of 4 to 5 times the nominal amount of Mitomycin C is necessary if circulated fluids is used).
The present Apparatus for the Generation Of An Energy Field For The Treatment of Cancer in Body Cavities and Parts That Are Cavity-Like (termed “Body Cavity Cancer Treatment Apparatus” herein) eliminates the weaknesses and deficiencies of existing cancer treatment systems by implementing a process that creates a “Low Temperature Hyperthermia” condition in the body cavity in conjunction with ionizing radiation and/or chemotherapy. This combination of treatment protocols has the potential for improving the effectiveness of cancer treatments by at least 2-4 times in the long term, while lowering the level of required radiation or chemotherapy medicine. While the Body Cavity Cancer Treatment Apparatus could be used to heat cancer cells to a killing temperature (46° Celsius and higher), it is believed that heating the cancer cells to a 5° C.-6° C. temperature increase over the body's ambient temperature (Low Temperature Hyperthermia) realizes significant benefits without incurring the risks of heating to the higher cell killing temperatures. Unlike other cancer treatment systems, the Body Cavity Cancer Treatment Apparatus docs not directly kill or ablate the cancer cells with killing temperatures rather, the Body Cavity Cancer Treatment Apparatus stresses the cancer and cancer stem cells using Hyperthermia by keeping them at a nominal 42° C.-43° C. temperature for some period of time, for example 30 to 60 minutes, temperature and protocol dependent as set by the treating physician.
The Body Cavity Cancer Treatment Apparatus provides a systems level approach to cancer treatment that achieves extremely uniform temperatures inside the tissue surrounding the body cavity, thereby realizing optimal efficacy while avoiding harm or pain to the patient. This is accomplished by the inclusion of “target particles,” such as nano-particles, into the body cavity along with the chemotherapy agent to enable the Body Cavity Cancer Treatment Apparatus to externally generate an energy field to cause heating of the chemotherapy agent and the surrounding tissue of the body cavity by activation of the nano-particles. The proper selection of the characteristics of the applied energy field enables precise control of the heat generated by the movement of the nano-particles. The Body Cavity Cancer Treatment Apparatus uses exactly matched or paired nano-particles having a given material composition and set of material properties in concert with a precisely defined electromagnetic field, in this cast, a predominantly magnetic field. By using a magnetic field of certain properties and specifications, only the nano-particles heat while healthy tissue surrounding the region of cancer cells which contain the nano-particles does not heat.
An alternative to the procedure described above is the infusion of the chemotherapy agent into the bladder and the insertion of a “balloon” into the bladder. The balloon molds to the exact shape of the bladder, so nano-particles in a solution are put into the balloon, inflating the balloon and forcing the chemotherapy agent into the space between the balloon and the walls of the bladder. The solution of nano-particles in the balloon is heated via the application of an illumination energy field. The generated heat is transferred to both the bladder wall and the chemotherapy agent. At the end of the remaining portion of the procedure as noted above, the nano-particles are removed from the balloon and then the balloon is removed from the inside of the bladder, as is the chemotherapy agent. Alternatively, a fluid solution can be circulated through the balloon, without the use of the nano-particles, to maintain the temperature of the chemotherapy agent in the bladder.
In addition, the associated nano-particle delivery process is non-invasive, meaning the nano-particles are contained in a fluid which is inserted into the body cavity and then removed after the procedure. For certain types of cancer, this has many attendant advantages: (A) the nano-particles do not enter the bloodstream, (B) control the exact concentration of nano-particles in a composite fluid usually containing a chemotherapy substance in solution (unless the protocol is pure ionizing radiation), (C) the known concentration of nano-particles enables much more precise heating illumination protocol, (D) the nano-particles are removed after the procedure and do not stay in the body, (E) pre-mixing of a chemotherapy agent with the nano-particle solution is easily achieved.
While the preferred embodiment disclosed herein is the use of the Body Cavity Cancer Treatment Apparatus to implement a treatment protocol for bladder cancer, the apparatus described herein can be used for other “cavity-like” organs or body structures. Body organs such as the colon, uterus, vagina, cervix, esophagus, stomach, and so on, that are naturally a cavity or that can be blocked off to form a temporary cavity, are viable body parts for this safe and efficacious treatment protocol. Catheter based balloons can be placed on either end of a cancerous region in a tubular like structure to only treat that segment of the “tube”. Alternative body regions for treatment are also surgery developed cavities that leave a tissue void such as: remove a tumor in the brain, where the procedure fills the void with nano-particles and a chemotherapy agent, then heats the tissue and chemotherapy agent via the application of an externally generated magnetic field. Other surgical procedures that create a void, such as the removal of a tumor in the breast, could be treated using this approach.
There are a number of advantages that accrue using the treatment methods and protocol described herein:
The combination of Low Temperature Hyperthermia with ionizing radiation and/or chemotherapy has the potential for increasing the effectiveness of cancer treatments by 2-4 times, as noted above, while lowering the level of required radiation or chemotherapy medicine. One additional benefit of Low Temperature Hyperthermia is re-oxygenation, where the level of oxygen in the tumorous regions is greatly increased. This is highly stressful to cancer and cancer stem cells in particular, which most decidedly prefer a hypoxic environment. Other significant biological benefits accrue when cancer is kept at a Low Temperature Hyperthermia state; acute acidification and reduction of Heat Shock Protein release (HSP). Other benefits accrue since ionizing radiation and Low Temperature Hyperthermia each affect different phases of the cellular reproductive process, M and S.
From the body ambient temperature of 37° C. to a target temperature of between 42° C. and 43° C., every degree increase above 37° C. increases the effectiveness of chemotherapy medicines. Such enhancement of chemotherapy agent effectiveness can change the treatment outcome from a 10 year complete cure rate of say 15%-20% without nano-particle based hyperthermia, typically to upwards of 50%-60% with nano-particle based hyperthermia for certain cancers, such as bladder cancer. This improvement in bladder cancer complete cure results is dramatic; it is expected as this technique is applied to other cancers and even other diseases that the similar efficacy and cure rates is evident.
Medicines, such as PARP inhibitors, interfere with the ability of cancer cells to self-repair damaged DNA in a given cancer cell. Thus, if the DNA in a given cancer cell is intentionally damaged, and the PARP inhibitor prevents the cancer cell from “self-fixing” the DNA, the cancer cell will die. However, PARP inhibitors are not very effective unless the ambient temperature is elevated to the 42° C.-43° C. range. Note that hyperthermia is also very effective at interfering with cellular DNA reproduction. Thus, being able to increase the ambient temperature of the cancerous region from 37° C. to 42° C.-43° C. is essential for PARP inhibitors to be effective in stopping cancer cells to self-repair their intentionally damaged DNA. Both the PARP Inhibitor and the Low Temperature Hyperthermia protocol, individually and in concert, impact/prevent the cancer cell's ability to repair the damaged cancer cell DNA. At the moment, it is believed that concurrent-heating of the cancerous region is likely the most beneficial protocol but there may be reasons why a pre- or post-heating protocol relative to the timing of radiation or chemotherapy is preferred.
The nano-particles are activated by the Body Cavity Cancer Treatment Apparatus which generates a precisely crafted energy field to provide illumination of the nano-particles with the minimum energy that is required to create the selected effects. The energy field characteristics are selected from the characteristics of energy fields including: field type, frequency, field strength, duration, field modulation, repetition frequency, beam size and focal point, that are required to energize the nano-particles in a selected manner in the portion of the target living organism that is being treated. In addition, the mapping of characteristics of the energy field provides great flexibility and enables the concurrent use of multiple types of nano-particles.
It is important to note that the activation of nano-particles by the Body Cavity Cancer Treatment Apparatus is highly deterministic, meaning that a given particle is optimally activated or excited by a given energy field of pre-defined characteristics. Generic or random field excitations do not optimally excite a given particle. The field excitation of a nano-particle is considered to be the “input energy” or “input driving function” of the system. In general, the “input energy” is converted by the nano-particles to an “output energy” which is a thermal output.
At step 101A of
Alternatively, at step 110A, a mixture of a solution of nano-particles and one or more chemotherapy agents are added to the body cavity, with the mixture optionally being preheated to a predetermined desired temperature. At step 111A, the body cavity is illuminated by the application of an externally generated energy field, such as a magnetic field generated by the apparatus of
The treatment protocol is defined by the physician, who selects the time and temperature parameters. In addition, the solution of nano-particles and one or more chemotherapy agents may be combined, preheated, and then inserted into the body cavity. This reduces the treatment time and simplifies the process by implementing only one insertion step.
The process just described can be implemented for various body cavities as noted above and
When the bladder is stretched, this signals the parasympathetic nervous system to contract the detrusor muscle. This encourages the bladder to expel urine through the urethra, which passes through the Prostate Gland. For the urine to exit the bladder, both the autonomically controlled internal urethral sphincter and the voluntarily controlled external urethral sphincter must be opened. Problems with these muscles can lead to incontinence. If the amount of urine reaches 100% of the urinary bladder's capacity, the voluntary sphincter becomes involuntary, and the urine is ejected instantly. The urinary bladder usually holds 300-350 ml of urine. As urine accumulates, the wall of the bladder thins as it stretches, allowing the bladder to store larger amounts of urine without a significant rise in internal pressure.
The urge to urinate usually starts when the bladder reaches around 25% of its working volume. At this stage it is easy for the subject, if desired, to resist the urge to urinate. As the bladder continues to fill, the desire to urinate becomes stronger and harder to ignore. Eventually, the bladder will fill to the point where the urge to urinate becomes overwhelming, and the subject will no longer be able to ignore it.
The process just described can be implemented for various body cavities as noted above and
At step 101B of
In some situations, it may be desirable to not have the nano-particles touch or come into contact with human tissue, to include the bladder interior lining (mucosa). At the same time, it is still desirable to heat the interior of the bladder (or human tissue) to enhance the effectiveness of the chemotherapy agent or radiation, either or both intended to kill harmful cancer and cancer cells. In the cast of bladder cancer, it is desirable to enhance the efficacy of chemotherapy agents such as Mitomycin C (MMC). An alternative to the procedure described above is the infusion of the chemotherapy agent into the bladder and the insertion of a “balloon” into the bladder. By using a balloon based catheter assembly, the nano-particles can be both heated and still retain their physical isolation from human tissue—the bladder lining. The balloon molds to the exact shape of the bladder, so nano-particles in a solution are put into the balloon, inflating the balloon and forcing the chemotherapy agent into the space between the balloon and the walls of the bladder. The solution of nano-particles in the balloon is heated via the application of an illumination field. Alternatively, a fluid solution can be circulated through the catheter and into/out of the balloon, without the use of the nano-particles, to maintain the temperature of the chemotherapy agent in the bladder. The generated heat is transferred to both the bladder wall and the chemotherapy agent. At the end of the remaining portion of the procedure as noted above, the nano-particles are removed from the balloon and then the balloon is removed from the inside of the bladder, as is the chemotherapy agent.
Catheters are often constructed of extruded silicone or latex materials (the shaft is 1430, 1436 which is equipped with lumens 1420, 1422, 1424, 1426). The balloons (1432 and 1434) are often made via a “blown” methodology. Together, the extruded shaft 1430 plus the balloons 1432, 1434 are constructed to make the entire catheter assembly. Thermocouples 1440, 1442, and 1444 are added to enable a temperature control feedback mechanism to the energy controller 62 for managing the strength of the magnetic field, which in turn controls how warm the nano-particles get. For example, input lumen 1426 is connected to the output 1436 which is located at the tip of the catheter 1430 above the large balloon 1434. This particular lumen assembly is used to put fluid into or to take fluid out of the bladder 1401. At the beginning of the procedure, lumen pair 1426 could also be used to remove any excess urine and then, prior to the procedure starting it could be used to insert Mitomycin C, a chemotherapy agent, into the bladder 1401.
The combination of both heat and the chemotherapy agent are the basis of a treatment protocol that has significantly higher efficacy than just a chemotherapy agent alone (as is now practiced by urology oncologists). By adding heat to the bladder tissue and cancer for a nominal one hour treatment time frame, the efficacy of MMC to treat bladder cancer is quite dramatic—the ten year complete curt rate in increased from 15% to upwards of 53%.
Lumen pairing, 1424 (input) to 1434 (output into the larger balloon 1434), is used for instilling nano-particles into the balloon 1434. One advantage of using a balloon to contain the nano-particles is that the ureters 1402B and 1402A do not dilute the nano-particle concentration with urine from the kidneys. Thus, the nano-particle concentration is constant and it simplifies the heating control algorithm.
The MMC (chemotherapy agent) is instilled via lumen 1426 and output 1436 directly into the bladder 1401. Lumen 1422 is used to inflate the small balloon 1432, typically with air; the purpose of this small balloon 1432 is to keep the catheter 1430 seated in the bladder 1401 during the treatment time frame. It is desirable to keep the larger balloon 1434 off of the bladder wall since this balloon 1434 is the heat source and it is desirable to not have the warm balloon surface touching the balder wall to prevent either burns or excessive heating.
In this example, lumen 1420 is used to link three thermocouples 1440, 1442 and 1444 which sense the temperature in three different locations to the energy controller 62. Thermocouple 1440 senses the temperature of the fluid (MMC with some urine) in the bladder 1401 while thermocouple 1442 senses the temperature in the center of the balloon 1434 which holds the nano-particles (it is fed thru lumen 1420). It is important to check the temperature at the center of the balloon 1434 because it enables the energy controller 62 to know what the maximum temperature is and then what the thermal gradient is across the balloon 1434. The thermocouple 1444 is located on the outer edge of the balloon 1434 and is used to ensure that the external balloon temperature is safe for the bladder 1401 should it ever touch the bladder wall. Mathematically, the temperature difference between thermocouples 1442 and 1444 can be determined, as a gradient, and this calculation can be compared to measured temperatures as an error check to ensure no thermocouples are mis-reporting their data. Typically, thermocouple 1444 measures 2° C.-4° C. warmer than the temperature on the bladder wall. The thermocouples used are typically fiber optic based, using a Gallium Arsenide (GaAs) crystal which vibrates at a given frequency for a given temperature. This vibration frequency is sensed and is then converted to a temperature measurement and reported to the systems electronics in a temperature to magnetic field strength feedback loop. Fiber optic sensors are important since they are not affected by the presence of a magnetic field which is used to excite the particles in Brownian motion thereby causing frictional based heating.
This treatment is largely for Non-Muscle Invasive Bladder Cancer (NMIBC) which is polyp like and grows inward into the bladder wall of the bladder 1401 and, in general, has a stalk like structure. Current thermal projections indicate that the thermal treatment needs to penetrate only 0.5 mm into the bladder wall to treat Ta and T1 NMIBC types of bladder cancers. At step 1404, nano-particles are inserted into the larger balloon 1434 via lumen 1424. At step 1805, the chemotherapy agent, such as Mitomycin C (MMC), is inserted into the bladder 1401 directly via lumen 1426 to opening 1436. Next, the magnetic field is applied as previously described herein. At step 1806, the nano-particles are heated in balloon 1434 in the prescribed manner. The overall system temperatures are monitored by the energy controller 62 via thermocouples 1440, 1442 and 1444 at step 1807. Note that either or both the MMC and the nano-particles can be pre-heated to the nominal body temperature of 37° C. prior to insertion via catheter 1430 as described above. This pre-heating of the two materials shortens the overall procedure time-frame since they are at body temperature at insertion.
At step 1808, the energy controller 62 checks one or more of the thermocouples to ensure they are at the proper operating temperature and if too warm, the feedback to the amplifiers 404 feeding current into the coils 601, 602, is turned down which further lowers the magnetic field generated thereby reducing the heating rate. Once at the desired operating temperature, at step 1809, the magnetic field is managed to keep the nano-particles at the prescribed temperature, typically 42° C.-43° C. for low temperature non-ablative therapy.
At step 1810 the treatment protocol, using heated nano-particles and chemotherapy agent, is managed for the doctor prescribed timeframe, but typically for an hour at the therapeutic temperature. It is believed that a 1° C. temperature increase can reduce the treatment time frame by ½ and a 2° C. increase in temperature is a ¼ reduction in heating time frame. However, the pairing of temperature with time is to be determined and is ultimately the responsibility of the treating physician.
At step 1811, the treatment is done and the “reverse” process is now effected. At step 1812, the nano-particles are drained out of balloon 1434 via lumen 1424. And at step 1813, the chemotherapy agent can be drained via lumen 1426 or the catheter 1430 can be pulled and the patient urinates out the chemotherapy agent. This is how the chemotherapy agent is removed today. There is an advantage to removing the chemotherapy agent via catheter 1430 due to how caustic the chemotherapy agent is to the urethra and its lining. At step 1814, the catheter 1430 is removed and at step 1815 the procedure is completed.
For cells that are dividing, four (4) phases exist—M phase, G1-phase, S-phase and G2-phase—with radiation and hyperthermia each affecting different phases. Hyperthermia is most sensitive in the last half of the S-phase, DNA Reproduction. The next cellular phase which hyperthermia impacts are the M-phase, Cell Division. However, radiation sensitivity is high in the M-phase (Cell Division) but low in the S-phase (DNA Reproduction). Thus, hyperthermia is complimentary with radiation—particularly for the S-phase which is the DNA reproduction phase. That is why Low Temperature Hyperthermia (LTH) is so effective when combined with Radiation. As previously mentioned, PARP Inhibitors affect the DNA repair stage, similarly where hyperthermia works and, hyperthermia enhances the effectiveness of chemotherapy at an effectiveness doubling rate for every degree above body ambient.
The nano-particles that heat in a magnetic field must exhibit magnetism and are generally ferromagnetic in nature. Materials such as magnetite Fe3O4 and maghemite Fe2O3, when produced in nanometer sizes, will heat in magnetic fields of time varying nature. These AC or Alternating Current magnetic fields are typically in the kilohertz frequency range but can also be in the megahertz range. For the preferred Brownian heating mode, the optimal frequency range is 30,000 to 100,000 hertz (30-100 KHz). The particle sizes are sufficiently small in diameter to be characterized as predominantly a single domain.
Magnetic excitation is via an Alternating Current (AC) driven, where the change of the phase of the wave going from positive to negative to positive (and so on) causes changing magnetic alignments in the nano-particles which in turn cause heating. The changing magnetic alignment causes a portion of the induced energy to be converted as heat (by the nano-particles). The two forms of magnetic heating involve: One, friction based heating created by the nano-particles' movement with respect to the cytoplasm (for instance Brownian) and, Two, heating which is magnetic domain based (Neel), where the nano-particles are stationary and the magnetic domains in the nano-particle are changing. Depending on the particle size relative to the excitation frequency, the heating could involve both Brownian and Neel modes.
The first, friction based, is called Brownian heating and the nano-particle physically rotates, causing mechanical friction based heating. Because the nano-particle is physically rotating, there is a relaxation time that is optimal for maximal nano-particle heating where the relaxation time is related to both the nano-particle size and the excitation frequency. This unique pairing of nano-particle size with frequency causes optimal heating. In this case, the nano-particle size, composed of the core plus any coatings, is called the hydrodynamic diameter, and it is this composite size that is important for Brownian heating. Additionally, the material's properties, such as magnetization and anisotropy affect where and how well it heats.
The second method, where just the magnetic domains are changing, is called Neel heating. In this cast, a very narrow size and corresponding frequency match enables heating; and, any slight changes in those parameters can cause the nano-particle to not heat at all. It is this very sensitivity that makes Neel heating the less preferred approach.
Other modes of magnetic nano-particle heating include hysteresis and Rayleigh, where these modes are usually reserved for significantly bigger particles, say greater than 50 nanometers in size. In general, the single domain modes, where the nano-particles are smaller, less than 50 nm in general, having Brownian and/or Neel heating, are preferred. Presently the preferred magnetic field generation mechanism is a set of coils, which projects magnetic fields into tumorous regions, in which the fields create a uniform volume in the region where the cancer resides. Relatively uniform fields across a tumor is important for minimizing hot spots (we assume that nano-particle uptake is relatively uniform across a tumorous region).
The magnetic volumetric region of quasi uniform fields is on the order of 30 cm in body thickness dimension by an area of 35 cm in body width by 35 cm in body length, which is 11.8 inches in body thickness by 13.8 inches in body width by 13.8 inches in body length. Overall, this is 36,750 cubic centimeters of “uniform field” volume or 2,247 cubic inches of “uniform field” volume. It is believed that this uniform field volume is sufficient for virtually any type of regionally located cancer that hasn't metastasized. These uniform field regions can be further seen in
The coils 401, 402 of the Body Cavity Cancer Treatment Apparatus 40 require other passive components in order to allow them to efficiently and safely work with a given amplifier design. Most amplifiers 404 prefer a “real” input, in terms of the input impedance presented by the coil load. To realize “real” impedance in the Body Cavity Cancer Treatment Apparatus 40, the inductive reactance of the coil must be matched with an equivalent series connected capacitor 615 to cancel out the reactive voltages. This is to stay in compliance with the amplifier's operating requirements. As shown in
At resonance, what are left in the coils are AC resistive losses. The capacitors 615 have an Equivalent Series Resistance, which is frequency dependent; in order to get the Equivalent Series Resistance low, a number of capacitors need to be put into a parallel configuration (if the capacitors are at the system input); or, alternatively, as shown in
How the coil is wound and how the wires are juxtaposed to each other significantly affects the AC resistance or Equivalent Series Resistance (ESR). This also affects the field strength generated for a given current into the coil windings. If a gap of 0.6 to 0.75 inches (around 1 cm) is placed between the axial windings, the ESR can be significantly reduced. Presently, at 77 amps RMS of drive current, the AC resistance of the coil is around 0.3 ohms at 40 KHz. Radially, the wires (or rather the insulation of the wires) can be touching without much effect on a person's skin.
Other coil related issues must be managed, such as ensuring that corona inception is not possible at the given air pressure and temperature. Corona inception is where the voltage gradient or field strength is of a sufficient level, say 24.1 Kv per cm, at 6,000 feet altitude and 40° C.—if the voltage gradient on the outer edge of the wire insulation or say between the edges of two wires' insulation is greater than 24.1 Kv/cm—then a corona inception is possible. Corona is essentially the breakdown of the air gap and is evidenced by purplish or orangish light, a staccato like sound and then eventually a voltage arc.
Selections of the insulation, the spacing, the number of turns, how the coil is wound and so on all affect the likelihood or risk of corona. One key method of reducing the level of the voltage gradients is to add air gaps between the wires in the axial direction (direction of the human body 407 in
The B field and the H field are vectorially parallel to the human 407. The nominal treatment volume is on the order of a cylinder 10 cm in radius and about 20 cm long. The length of the uniform field volume is dependent on how far apart the two sub coils are spaced (again, not at a Helmholtz condition). This field volume is sufficiently large to have a uniform field for the treatment volume (particle balloon volume) and sufficiently large enough to not cause difficulty in centering this region onto the patient. There may be some eddy current heating advantages to the coil body relationship as shown in
The system shown in
When you have a Helmholtz pair of coils, the spacing between the coils is one half the diameter of the coils. If this were done for bladder cancer, the coils get very large (side to side) due to the minimum spacing for large people. When the coils get very large, it imposes magnetic lines of flux on greater portions of the body and hence the system has higher eddy current heating of healthy tissue. This is another design reason why side-to-side coils are not preferable for bladder cancer with a Helmholtz design. The axial coil as shown in
For wire that is carrying an AC current, an effect called “skin effect” occurs, which means that only the narrow outer core of a solid wire carries the current. Thus, the current carrying cross section has been dramatically reduced from the full wire area to a small height donut; therefore, the AC resistance can be significantly higher than the DC resistance. Special wire is used in the Body Cavity Cancer Treatment Apparatus to minimize this effect.
In addition, a second effect, called “proximity effect” happens when wires carrying current are placed near each other. The wires effectively couple to each other and subsequently reduce the physical region where current is being carried in the wires. This physical effect increases the AC resistance of the coil assembly. Again, like for “skin effect”, special wire is used to manage the issues of “proximity effect”.
The AC resistive loss of the wire used to implement the coils in the Body Cavity Cancer Treatment Apparatus, caused by “skin effect”, “proximity effect” and I2R losses, in the windings creates a voltage across the windings. To minimize this resistance and hence voltage, special wire called Litz Wire is used. Litz Wire has upwards of over 1,000 enameled individual conductors inter-wound and inter-woven, depending on frequency selected and maximum current used. At 30,000 Hz, the loss of Litz Wire at lower AC frequencies is virtually the same as the DC loss—thus, we have overcome the negative issue of skin effect and proximity effect. At moderately higher AC frequencies, the losses are quite manageable and significantly lower than what they would be if Litz Wire is not used.
The Litz Wire used has 2,600 strands of enamel insulated 36 gauge wire, where the individual strands are interwoven and the interwoven blocks are further woven. This interleaving of wires insures that no two wires are close to each other for any extended length. Braiding the wires into a structure where each strand spends and equal time in the center of the braid as all other strands helps to minimize both skin and proximity effect. Selecting the gauge of the strands, the number of strands, and other factors, is a design optimization process which optimizes AC losses, cost, usability, and so on.
However, the length of the wire in the coils of the Body Cavity Cancer Treatment Apparatus is sufficiently long (400 to 420 turns with a 60 cm diameter) that the AC voltage across the coil at 40 KHz is quite high for higher drive currents, approaching tens of kilo-volts and higher. So, the coil windings need to be broken down into “sub-coils” either in the Z-direction or the X-Y direction. By breaking up the coils into sub-coils, the inductive reactance is lowered, and therefore the AC voltage at 40 KHz is lowered. In addition, by breaking up a single coil winding length into shorter lengths of wire (using sub-coils), the sub-coil resistances are in parallel and resistances in parallel are lower than their original individual value, if they are driven in parallel. In
The equations used to design the coils are ideal. When the wire cross section is no longer an infinitely thin current source, the coil becomes less efficient than pure theory. In addition, if the coils are separated by more than their nominal Radius (R) separation, an additional “loss” occurs. These phenomena affect the overall “gain” of coil system and fortunately can be predicted by computer modeling using Finite Element Modeling or FEM.
The Biot-Savart Law describes the magnetic fields produced by an AC current. The magnetic field is given by the variable “B” in A/m or tesla. A dual coil system is created by taking “two” single Bio-Savart equations.
B=(uo)(n)(I)(R2)/((R2)+(x)2)1.5 in tesla
Or
Where
With a one amp current and a one turn winding, for a coil system that has a separation of 0.1 meters with a radius of 0.1 meters, the field strength is calculated as 7.155 A/m. This is considered the “gain” of the single coil system. In contrast, if that 0.1 meter optimal separation is changed to 0.3 meters, the “gain” falls off to 1.71 A/m. These values are also shown in the plot of
This “perfect” spacing condition where the radius of the coil is the same as the distance between the coils is defined as the Helmholtz relationship. The Biot-Savart Law can be further reduced to the Helmholtz relationship if the spacing of the two coils is always the same as the radius of the coil(s). To get the Helmholtz coil equation simply substitute x=R/2 in the aforementioned Biot-Savart equation and what results is this equation in A/m field strength.
Helmholtz Equation is:
A/m=(0.7155)(n)(I)/(R)
Or . . .
The proximity effect is an AC frequency sensitive issue that occurs when wires are wound side-by-side, lying next to each other. The current for this pair of wires in close proximity tends to “bulge” near where the wires are “touching”. This reduces the available cross section of the wire that is carrying current. For a single strand conductor, depending on its size in relationship to the skin depth, this additional loss due to the current being concentrated in a smaller portion of the conductor area, can be significant.
The proximity effect gets more pronounced when the wires are layered on top of each other in addition to laying side-by-side—the more layers, the bigger the proximity effect. Depending on the variables involved, the AC to DC resistance change caused by proximity effect can be 50 to 100 or greater increase in the effective AC resistance over the DC resistance. Fortunately, all of this can be managed by proper selection of the sub-wire size, how many sub-wires are used in a single wire, how the wires making the windings are inter-woven, and so on.
If Litz Wire is used, which has tens to hundreds to a thousand strands of inter-woven wire, the combined effects of skin effect and proximity effect are less of an issue, especially if the sub-wire strand size is substantially smaller, meaning the ratio of wire size to skin depth is a small number. Litz Wire is a wire assembly especially made for higher frequency magnetic coil or transformer applications. The smaller gauge helps solve the frequency skin effect problem and the many strands help solve the overall loss per unit length problem.
The key relationship to understand is the relative difference between the size of the conductor and the skin effect for the given frequency. Skin effect is the property of a conductor to carry most of the current in the outer “donut” of the wire's cross section. Thus, if the cross section of the wire is less than one skin depth, than the current is necessarily carried by the entire cross section of the given strand. Then, by using Litz Wire with many, many strands, the overall loss due to wire length can be managed back to a usable number.
The skin effect depth for 50 KHz is determined at the radial depth into the conductor where the current flow has fallen 1/c times that of the current on the surface of the conductor. For copper wire, at 100° C. (conservative value), having a Ur of 1 and a resistivity of p=2.3E-8 ohms-meter, the skin effect equation can be simplified to:
Depth=7.6/√{square root over (f)} in centimeters
So, at 50 KHz, the skin depth is 0.034 cm (centimeters).
One Litz Wire configuration has its sub-wire strands as 38AWG, which has a diameter of 0.003965 inches or around 4 mils in diameter or 0.01007 cm (centimeters). Comparing the two values, skin depth vs. wire size, for the Litz Wire, we see that all of the current is carried by the wire's cross section. The wire radius divided by skin depth is 0.15. Thus, all of the current in the Litz Wire's sub-wire strand is carried in the entire cross section of the sub-wire in the Litz Wire assembly.
From a systems perspective, there are a number of technical issues that are inherent with the design of the Body Cavity Cancer Treatment Apparatus. First, the frequency of illumination cannot be too low otherwise the body's nervous system can be excited; this is known to be in the 2,000 to 3,000 Hz range but practically is below 10,000 Hz. As a measure of safety, the present Body Cavity Cancer Treatment Apparatus docs not generate a magnetic field of frequency below 40 KHz. Next, the nano-particles being excited express predominantly Brownian heating, for this frequency. Brownian heating has the advantage of being able to put the nano-particles into physical motion, in a rotational or partial rotational sense when an AC (Alternating Current) is used to excite the nano-particles. Alternatively, Neel heating has the magnetic domains rotating and the physical nano-particle remains motionless. At around 254 KHz, the magnetic state of the nano-particle is half Brownian and half Neel. Below 254 KHz, Brownian heating begins to dominate; above 254 KHz Neel heating begins to dominate. The nano-particle size (radius) is highly correlated to the realm of heating. Neel uses much smaller nano-particles while Brownian uses larger nano-particles, in a relative sense. Thus, from a physical perspective, at 40 KHz, the optimal nano-particle size is in the 20 nm range. The optimal nano-particle size, from a biological perspective, is in the 15 to 30 nm diameter range. Smaller nano-particles, say in the 7 nm size range, tend to be “trapped” in healthy tissue. Larger nano-particles, say greater than 100 nm, tend to be “attacked” by white blood cells and quickly removed from the body. For a system that uses the nano-particles in a fluid contained in say a cavity or the bladder as an example, this is less of an issue biologically, but the sizing is important from a heating perspective (Brownian heating).
In addition, there are advantages to having the nano-particles in rotational motion to enhance diffusion. For an IV-based nano-particle delivery, having the nano-particles in motion likely enhances the diffusion thru the leaky vasculature of a tumor. For bladder cancer, having the nano-particles in motion ensures that uniform heating occurs. Coincidently, a nano-particle having a diameter of 20 nm is also the optimal size for Brownian heating (which is frequencies below 254 KHz).
To optimize heating for a given value of f*H, lower frequencies are optimal. In this cast, the frequencies being considered are 40-75,000 Hz. A researcher by the name of Brezovich learned empirically that if the product of f*H is on the order of 4.85 times 108, a researcher will begin to feel warm, not uncomfortable after one hour of being illuminated at that level. This nominal value of 4.85 E8 is termed herein as “One Brezovich Limit”.
This heating is due to an Ephi component generated by the magnetic field, which causes eddy currents in the tissue. Since tissue has a real conductivity value, the tissue heats as a result of the eddy currents. To be ultra conservative and have the f*H product no greater than one Brezovich limit, the system design docs not inadvertently heat healthy tissue from eddy currents.
The nominal bladder heat loss rate, per study, is 0.01 to 0.02 deg per second and the max heat loss rate is 0.05 deg per second (muscle is −0.03 deg/sec; kidney is −0.365 deg/sec; spleen is −0.131 deg/sec; liver is −0.124 deg/sec)
The bladder heating protocol described above with respect to
In Brownian excitation, the nano-particles actually physically rotate, based on the frequency of illumination and the viscosity of the fluid containing the particles. For this particular particle size, frequency and fluid viscosity, there is a very small contribution from N eel heating, but since it is de minimus, it is not considered. Neel heating is when the magnetic domains align and un-align; this process causes heat. In Neel heating, the particles do not physically move.
Since the system is not near the design maximum of 10,000 A/m, there is sufficient field strength headroom to heat even lower concentrations.
The Actium Condition is a state where nano-particle heating is optimized while the probability of tissue heating via unintended eddy currents is minimized. Brezovich, when he created the condition of f*H with respect to a constant of 4.85E8, did not do so in the context of nano-particle heating. He was only concerned with the unintended creation of eddy currents which heats tissue not having nano-particles, which in reality is measured to be f*H2. When the context of nano-particle heating is added to a fixed value of f*H2, an optimal operating point with respect to frequency is realized. Since the particle heating, prior to particle magnetic saturation, is a function of the field strength squared, it is desirable to maximize the field strength versus frequency. This means lower frequencies with a given field strength yields significantly higher rates of nano-particle heating without creating unintended eddy currents which heats tissue not nano-particles.
Since the frequency needs to be at least above 10 KHz to avoid nerve/muscle excitation, a safety zone is created by heating the nano-particles at 40 KHz, well above the frequencies where nerves are excited. Since f*H is the second constraint, the field strength for one Brezovich limit (an Actium derived term) is 9,700 A/m. Since this study shows a maximum field strength of around 3,100 A/m, the Body Cavity Cancer Treatment System now operates a level of 0.3 Brezovich limits—thus, the heating of the particles is optimized while minimized the possibility of unintended eddy currents.
The Helmholtz Coil configuration is:
The uniform field volume is 11.8 inches in height by 13.8 inches in body width by 13.8 inches in body length which is equivalent to 2,246 cubic inches.
As previously discussed, when the wire thickness goes from an infinitely thin wire to 4 inches of hundreds of wires, there is a 16% loss of field strength, from the theoretical predicted value using the Helmholtz Equation. When this coil is built in practice, sub-coils in the Z-Direction will be used to obtain resistances, voltages and currents that are within the specifications of the selected components of the machine. These sub-coils would be a minimum of 4 divisions of the 420 windings, as previously discussed.
At 50 KHz frequency, the four field strengths for the four Brezovich limits are:
This corresponds to the following Brezovich limits; note that only during heating to 42° C. at the lowest concentration do we even approach one Brezovich limit. the rest of the time, particularly the steady state heating timeframe, the Brezovich limit levels are very low. We are at 0.88 Brezovich Limit at our maximum operating level when heating a 5 mg/ml particle concentration for 2 minutes and 25 seconds to 42° C. All other points in our heating protocol are at significantly lower levels.
And, at one Brezovich limit, virtually zero unintended tissue heating occurs, even in muscle. The previous table shows that in normal operation, we are typically in the 0.3 Brezovich limits level and lower. This means it is virtually impossible for us to heat tissue in a magnetic field (without particles) much less exceed the SAR maximums stated for MRIs.
The Bladder Heating Model with Eddy Currents
Separately, full body models have been completed using a second simulation step where it uses biological heat removal models such as the Pennes Bio Heat Equations to predict what the body's heating is from the eddy currents. The Thermal model yielded a complete body temperature analysis which showed that for the 2,500-3,000 A/m illumination protocol previously shown, for the bladder example, the average tissue temperature from eddy currents is in the neighborhood of 0.4° Celsius . . . virtually indistinguishable. The peak temperature from eddy currents was seen to be around 0.9° C. for a very small tissue region. In addition to keeping the f*H product low, and keeping the magnetic field strength low (H), there are many other methods in the toolbox to manage eddy currents and unintended tissue heating.
It is important to note that the methods discussed next, to lower the probability and level of unintended tissue heating, are not necessary or required since the examples provided herein heat just fine. They are merely ideas and concepts created to use should this ever become an issue. Methods to manage unintended tissue heating:
When the nano-particles are delivered via an IV or Intravenous tubes, the nano-particles that are not taken up by the cancer are eventually removed by the body's filtering organs. This is not an issue for the “cavity” method such as for the bladder. Certain vital organs which are responsible for filtering out foreign objects from the body include the kidneys, the spleen and the liver. These vital organs remove nano-particles from the body which are not taken up in a cancerous region. It is conceivably possible that these organs could have nano-particles residing in them during a magnetic illumination protocol for cancer, where nano-particles purposefully reside in the cancerous region. It is desirous to block or shield these vital organs from illumination of the magnetic field to a level at least one order of magnitude, as an initial design objective. One order of magnitude in field reduction typically yields a 50 times reduction in heating rate (for the assumptions listed below).
Given that heating is a function of the magnetic field squared, a ten times reduction of the magnetic field results in a heating rate reduction of 50 times (Brownian heating, viscosity is 2× water, 40 KHz, 50 mg/ml, 20 nm diameter particles). The heating rate at 8,600 A/m is 0.4073° K/sec while the heating rate at 860 A/m is 0.0082° K/sec for a heating ratio of around 50 times (again, both are for 20 nm diameter particles). The field strength of 8,600 A/m is only used during the 2-3 minutes heating phase from 37° C. to 42° C.
In practice, when at 42° C., the rate of heat input needs to only match the rate of heat loss to stay at 42° C. The average tumor heat loss rate is 0.0075 deg/sec. However healthy tissue has an average heat loss rate significantly higher due to the more organized and more efficiently operating blood perfusion in healthy tissue. In a person that has cancer, the liver/kidneys/spleen could be taxed and working over-time to try and rid the body of cancerous cells, but the vital organs should have better perfusion and should be able to remove heat at a much higher rate than cancer.
During the steady state phases of maintaining a continuous temperature of 42° C., the field strength at 50 mg/ml is 2,722 A/m. Our target field strength for the vital organs is 272 A/m or less (one tenth or less the incident field strength in the cancerous region). At 272 A/m, the field strength is 0.0003427 Tesla (for the spreadsheet input); the particle concentration is assumed to be 50 mg/ml in the vital organs. Putting this Tesla value into computer models for Brownian heating, we get plus 0.0008 deg K/scc heat added into the vital organ containing nano-particles at 50 mg.ml.
Even fat, with its very poor blood perfusion, has a heat loss rate of minus 0.003 deg/sec; this means that even fat would easily remove this very low added heat with zero net temperature increase. The vital organs, with their enhanced perfusion, even if impaired in a cancer patient, would easily remove this level of added heat (plus 0.0008° K/sec). Thus, a ten times reduction in field strength for the vital organs seems to be a good starting point for the design goal of our blocking or shielding algorithms.
The heat loss rates for healthy” vital organs” is decidedly greater than that for other tissue types due to the large supply of blood perfusion. The Kidney is negative 0.365 deg per second, the Liver is negative 0.124 deg per second and the Spleen is negative 0.131 deg per second. These heat loss rates swamp the plus 0.0008 deg/sec heating rate after a ten times reduction in field strength is applied (50 mg/ml, 272 A/m or lower).
Thus, a ten times reduction in field strength in the volumetric region of vital organs is sufficient (ten times lower than the treatment field strength in the cancerous volumetric region). The natural heat loss rates of these organs further ensures that these organs, when they are removing nano-particles, in concert with a low level applied field, will not heat at all.
It is possible that 42° C. is not optimal, or is not optimal for a given person with a given cancer. Nothing herein limits these concepts to a fixed temperature of 42° C. The system can be adjusted to realize any new temperature, say 44° C. For example, some studies have indicated that 15 minutes at 44° C. is equivalent to 1 hour at 42° C. in terms of its biological benefit and effect.
At less than one Brezovich limit, the Body Cavity Cancer Treatment Apparatus causes virtually no unintended heating via eddy currents in tissue without particles. When compared to MRI maximum SAR limits (Specific Absorption Ratio), the Actium system is many orders of magnitude below the stated MRI heating maximums (MRI's use magnetic fields at higher frequencies). When running a full body model for a bladder cancer heating example at 3,000 A/m, the average temperature caused by an eddy current is plus 0.4° Celsius over body ambient-virtually zero. The fluid in the bladder is heated to a nominal 42° C. for a full hour or longer by using a magnetite nano-particle fluid in the bladder susceptible to heating by a magnetic field. It is important to protect organs that may have filtered out nano-particles IF the nano-particles are delivered via IV. Organs that may have taken up nano-particles include the: spleen, liver and kidneys. The first method is passive and uses a material that has a very high relative magnetic permeability (Ur of 80,000 to 100,000) to “block” the fields. This material would be used above and below the body in the region of the vital organs. The second method is “active” and involves the use of a smaller excited coil inside the larger 60 cm coil. By varying or adjusting both the magnitude and phase of the drive current of the smaller “blocking” coil, the fields can be “cancelled” in the region of the vital organs. Note that for either method, passive vs. active, energy is not “destroyed” meaning the magnetic fields are not “destroyed”; rather, the fields are re-directed or re-shaped away from the vital organs when the nano-particles are delivered via IV.
Field strengths sufficient to heat nano-particles at very low concentrations are easily achieved. The product of the excitation frequency and the field strength is sufficiently low to not cause unintended tissue heating while at the same time optimizing the heating of nano-particles in the Brownian magnetic region. Finally, the body's filtering organs, containing nano-particles, can be shielded so that they do not heat during a cancer treatment protocol. The tools available in the toolbox are versatile and many, there is nothing that can't solved.
The concept of using the body's natural cavities, or the creation of temporary cavities, enables very precise control of the nano-particles and the illumination process is very easily implemented. In addition, after the heating protocol is completed, the nano-particles are completely or nearly completely removed. This eliminates much of the issues and operating concerns if the nano-particles are delivered via IV.
The Body Cavity Cancer Treatment Apparatus generates the magnetic field for use in a combined “Low Temperature Hyperthermia” and ionizing radiation and/or chemotherapy cancer treatment protocol. Unlike other competing systems, the Body Cavity Cancer Treatment Apparatus does not directly kill or ablate the cancer cells with killing temperatures rather, the Body Cavity Cancer Treatment Apparatus stresses the cancer and cancer stem cells by keeping them at a nominal 42° Celsius for some period of time via the heating of nano-particles that have been infused into the bladder, using the generated magnetic field.
This application is related to an application filed on the same date hereof titled “Treatment of Cancer in Body Cavities And Parts That Are Cavity-Like”, and also claims the benefit of U.S. Provisional Patent Application Ser. No. 61/527,928 filed on Aug. 26, 2011, titled “Treatment of Cancer in Body Cavities And Parts That Are Cavity-Like” and U.S. Provisional Patent Application Ser. No. 61/527,973 filed on Aug. 26, 2011, titled “Apparatus For The Generation Of An Energy Field For The Treatment of Cancer in Body Cavities And Parts That Are Cavity-Like.”
| Number | Date | Country | |
|---|---|---|---|
| 61527928 | Aug 2011 | US | |
| 61527973 | Aug 2011 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 13590737 | Aug 2012 | US |
| Child | 14797526 | US |
