BACKGROUND OF THE INVENTION For both cosmetic reasons and for promotion of general health, it is desirable to reduce the amount of non-essential fat in the body. Most fat is oxidized in the body to produce energy.

Some fat becomes an essential part of cells. Fat that is not required immediately as a source of energy is stored in layers of fatty (adipose) tissue under the skin. The stored fat also surrounds and protects internal organs, such as the kidneys, and acts as insulation that prevents heat loss.

Certain fatty acids are required for normal metabolism and health. Fat also provides an environment in which vitamins A, D, E, and K can dissolve. Some fat is stored in the livcr.

There are two types of fat cells (adipocytes) in human body: White Adipose Tissue (WAT) and Brown Adipose Tissue (BAT). The body uses WAT to store energy ; BAT burns energy to maintain body temperature (non-shivering thermogenesis). BAT is abundant in infants. The body loses BAT as it agcs. Obesity is caused by an excess of White Adipose Tissue.

WAT cells are active living cells, and compete with lean tissue for nutrients. The human body maintains a reserve of preadipocytcs. Thesc cclls arc vcry small and onlv cause an obesil ! problem when they differentiate into the much larger adipocytes. Once the adipucylcs have formed the amount of stored fat in them may increase or decrease depending on dict and physical activity. Reeular dieting and exercise can force adipocytes to grive up their stored tat and shrink in size. Once food intake increases and/or the level of physical activity decrcaacs. adipoeytes can rapidly replenish the fat they store. This leads to rapid fat/weight regain following the termination of a weight reduction schedule. If adipose tissue is exterminated instead of depleted, it will take much longer for the body to regrow the adipocytcs. This leads to a longer-lasting weight loss.

Fat stored in adipose tissue should be distinguished from fatty deposits under the skin, near tendons, etc. such as xanthelasma and xanthoma. For example, xanthelasma is a condition in which small, soft, often yellow spots form on the upper and lower eyelids. It is most

commonly seen in the elderly. The condition is often associated with increased amounts of cholesterol in the blood, with lipemia, and with the appearance of a xanthoma elsewhere in the body. It is known to remove these fatty lesions by surgery or by C02 laser vaporization. See: Rosenbach A, Alster TS,"Multiple trichoepitheliomas successfully treated with a high-energy, pulsed carbon dioxide laser"Dermatol Surg 1997; 23: 708-710 ; Apfelberg DB, Maser MR, Lash H, et al,"Superpulse CO, laser treatment of facial syringomata", Lasers Surg Med 1987; 7: 533- 537; Alster TS, West TB,"Ultrapulse CO2 laser ablation of xanthelasma", J Am Acad Dermatol 1996; 34: 848-849. These fatty lesions are not living cells. They are simply collections of fat that the body has chosen to isolate and deposit under the skin. The laser techniques referenced above are invasive procedures that are used as alternatives to conventional surgery.

The most commonly used technique for excision of adipose tissue is liposuction, whereby unwanted fatty tissue is loosened and physically suctioned away. This is an invasive procedure normally carried out by a cosmetic surgeon in a hospital or a surgical suite. Recovery period ranges from 3 weeks to 3 months.

There are variations in the administration of liposuction. In tumescent liposuction, unwanted fat is first plumped with a special anesthetic solution that also limits potential bleeding. Ultrasonic liposuction involves inserting an ultrasound transducer under the skin to break up the adipose tissue prior to suctioning.

Liposuction has the risks and disadvantages of invasive procedures, e. g. scarring, bleeding, pain and long recovery time. See F. M. Grazer and R. H. de Jong,"Fatal Outcomes from Liposuction: Census Survey of Cosmetic Surgeons"in Plastic and Reconstructive Surgery , Vol. 105, No. 1, pp. 436-446, January 2000. It is desired to employ a non-invasive procedure which will eliminate the risks and inconveniences attendant to invasive procedures generally.

The use of heat for achieving various therapeutic goals dates back to early recorded history. The technique of"diathermy"which uses high frequency waves to directly heat deep- seated tissues was first introduced in early 1900s in Germany. Its use expanded throughout Europe and America. By the 1930's diathermy was in wide use for many conditions including acute cystitis, prostatitis, epididymitis, pneumonia, gonorrhea, arthritis, herpes zoster, neuritis, sinusitis, sprains and strains, along with many other conditions [Sampson, C. M., A practice of physiotherapy, C. V. Mosby Company, 1926]. The advent of antibiotics in 1950's and the availability of other drugs to treat many of these conditions reduced the need for diathermy.

Currently, diathermy is used either as medical diathermy (thermopenetration) where the tissues are warmed but not damaged, or surgical diathermy (hyperthermia and thermal ablation) where tissue damage and cell killing are achieved.

The use of medical diathermy is mainly in physical therapy and rehabilitation. Some temporary weight loss may also be achieved by the application of external heat through saunas and hot pads. This weight loss is simply due to water loss by perspiration and has no documented long-term benefit.

Surgical diathermy is used marginally for cosmetic removal of various forms of dilated blood vessels, soft palette size reduction for the treatment of sleep apnea, etc., but its main applications are in the treatment of cancer and BPH (Benign Prostate Hyperplasia). Thermal energy used for selective elimination of tissue in cancer treatment is known as hyperthermia. See Hornback, N. B., Hvperthermia and Cancer : Hurnan Clinical Trial Erperience, CRC Press, Inc., Boca Raton, FL 1984. Hyperthermia, as an isolated treatment modality, has not gained widespread acceptance in cancer treatment. The main reason is that it is difficult to control the temperature over the entirc malignant region and therefore a complete elimination of the malignant tissue is often not achieved. This is a serious shortcoming in tumor control. We propose to use hyperthermia for selective removal of fatty tissue (Adipose Tissue Sculpting, "ATS"). For the purposes of the present invention a partial removal of fat cells is often most desirable.

Table 1 shows the differences between hyperthermia applied to cancer therapy vs. fat removal: Table 1 CancerTherapy ATS Penetration depth Deep in most cases Shallow Fractional cell kill 100% in target volume-5% per application Fractionation Needed for tissue differentiation Needed to allow necrosed cell absorption Targeting Three dimensional Diffuse two-dimensional Side effects Fibrosis, abscesses, etc. tolerated Fibrosis, abscesses, etc. not tolerated Partialresponse Not acceptable Desirable While it is known to dissipate energy in the form of heat within the body by RF, ultrasound, infrared laser and the like, these different modalities have not previously been directed to the specific function of selective necrosis of adipose cells.

SUMMARY OF THE INVENTION In the present invention, thermal energy is delivered sub-cutaneously to selected fatty tissues, between skin and muscle tissue of the patient's body at a rate and for a period sufficient to achieve cell necrosis in the selected volume without substantial effect to neighboring tissue. A temperature distribution having a maximum in the range 41°C-46°C is achieved in a region between skin and muscle tissue. This procedure is repeated at intervals selected to permit the scavenging of the necrosed adipose tissue by the natural elimination processes of the immune system. The immune system response is taken as a limit to the incremental amount of cell necrosis achieved in any single session of the treatment BRIEF DESCRIPTION OF DRAWINGS Figure 1 schematically illustrates the context of the invention.

Figure 2 describes the general applicator and cooling pad concepts of the invention.

Figure 3 describes an applicator for practice of the invention.

Figure 4 shows ideal and practical temperature profiles for practice of the invention.

Figure 5 shows cell survival data following the application of heat. This figure has been redrawn from published data [Dewey, W, Hopwood, L, Sapareto, S, Gerwech, L, in Radiology, Vol. 123, pp. 463-474,1977]. Redrawing is necessary because published data tends to emphasize higher thermal doses used for cancer treatment.

Figure 6 shows a schematic diagram of the microwave heating system assemble for the ATS proof of concept.

Figure 7 shows the phantom used for calibrating the heating rate to produce a peak temperature at a desired depth from the surface.

Figure 8 describes a hypothetical course of treatment.

Detailed description is in the following section.

DETAILED DESCRIPTION OF THE INVENTION The present invention employs any controlled energy deposition technology in general. and hyperthermia technology in particular to cause controlled necrosis of unwanted fatty tissue.

In the present application of hyperthermia to adipose cells, the temperature of the target volume is normally raised to anywhere in the range from about 41 to about 46 degrees Celsius. Cell necrosis occurs in this temperature range. The elevated temperature is maintained for a period in the range from about 5 minutes to about 2 hours, depending on cell kill rate to be achieved. It is important to limit the kill rate so as not to exceed the capacity of the immune system to

scavenge the resulting dead cells and their fat reserves, converting same for dispersal and removal from the body. It is desired to produce sufficient cell injury (such as membrane rupture) to result in cell death, but not to produce effective cell incineration or chemical fusion of cell materials.

The amount of adipose tissue removed at any given time should be limited by the capacity of the body to safely absorb the necrosed tissue. If tissue necrosis occurs too fast, the dead tissue or the fat within that tissue is isolated in the form of lumps under the skin. Due to this limitation, a multi-session treatment schedule is needed to remove any appreciable amount of fatty tissue. In order to avoid heat tolerance that develops in the remaining living tissue after each session, there needs to be an interval in the range from about two to four days between sessions.

In addition, care must be taken in the case of patients with vascular disease to prevent the excess absorbe fat from dead adipose cells to deposit, or otherwise to adversely affect the condition of the patient. A special diet and/or activity level may be necessary in general to ensure satisfactory outcome.

Fat removal efficacy can be monitored in the simplest manner by calipers and other physical measurement tools in the course of the treatment. In the case of a patient where the transport of necrosed tissue away from the treatment volume needs to be monitored more immediately, simple tests of lipoprotein concentration and blood pressure, etc. may be administered periodically in the course of treatment.

Turning now to figures 1 and 2, there is shown an exemplary arrangement for practice of the invention. A power source 11 delivers ultrasonic, RF or microwave energy through a transducer 22 and thence through a cooling pad 23 to the selected region 25 of subcutaneous fat for treatment of the patient 14. Damage to skin is controlled by the cooling pad 23 that keeps the surface temperature at an acceptablv low value. The cooling pad 23 has a connection 27 to the circulating pump within unit 12 that also monitors the amount of heat delivered to the pad 23.

The amount of heat delivered in every session and the rate of delivery is prescribed for every patient. The applicator 10 is either as large as the area to be treated, or smaller, in which case it will be scanned periodically over the treatment area. The scanning is either done manually as shown in Figure 1, or automatically by a pre-programmed mechanical scanner. Scanning protocol and duration of each treatment session (e. g. 15 minutes) is determinable from experimental data. Such data is obtainable from phantoms and like sources. The goal is to generate and maintain an elevated temperature with the profile described below, uniformly distributed over the treatment area. This will lead to controlled necrosis of adipose tissue in the

region of interest.

Turning now to figure 3 there is shown one form of applicator apparatus for practice of the invention. The applicator consists of multiple parallel elements 33 carrying RF current in alternating directions 32 separated approximately 1 cm apart. One way to do this is by a serpentine wiring geometry. The frequency of the RF current is any of the lower frequencies allocated to diathermy (e. g. 27.12 MHz). Since the period of the current distribution is much smaller than the wavelength of the electromagnetic field, the falloff of the electromagnetic field strength in the body (z direction) is controlled by the separation of the current elements. More T specifically, the field falloff is proportional to e 2, where T is the spatial period of the current distribution.

A common prior art method of controlling the depth of heat generation is through the (temporal) frequency of the radiation rather than the spatial frequency technique described above. Among the RF and microwave frequencies assigned to diathermy and hyperthermia, 433,918, and 2450 MHz are suitable for creating a temperature variation characterized by a peak within the subcutaneous fatty layer. Similarly, non-focusscd ultrasound frequencies in the range of 2-5 MHz together with surface cooling can provide a temperature distribution characterized by a peak a few centimeters below the skin [Benkescr, P. J. Frizzell, L. A., Goss, S. A., and Cain, C. A.,"Analysis of a Multielement Ultrasound Hyperthermia Applicator", IEEE Trans. Ultrasonics, Ferroelectrics, and Frequency Control, Vol. 36, No. 3, May 1989].

The ideal temperature profile 41 for fat removal is as shown in Figure 4. The temperature of the skin (dermis and epidermis) 24 is preferably maintained at or below 37"C. The temperature of a target portion of the subcutaneous fat layer 25 would be raised to 41"-4 ()"Cg and the muscle layer 26 preferably remains at 37"C. In the fatty layer 25 it is desirable to keep the temperature near the skin lower than the temperature near the muscle. Some fat underneath the skin should be preserved in order to protect hair folliclcs and sweat glands as wcll as to maintain the form and the support foundation of the skin. Natural removal of necrosed fat cells would be facilitated near the fat to muscle boundary than in the middle of the fatty layer due to increased vasculature in that area. This same vasculature in muscle tissue serves to transport heat from muscle tissue and its near environs. A practical temperature distribution for practice of the invention is shown by curve 40 characterized by a peak 40a.

The well-known bio-heat equation (see B. Gao, S. Langer, and P. Corry,"Application of the time-dependent Green's function and Fourier transforms to the solution of the bioheat equation", Int. J. Hyperthermia, Vol. 11, No. 2, pp. 267-285, Feb. 1995) governs the relationship

between tissue temperature, and the physical parameters of the tissue and the heating source.

The bio-heat equation may be written as: c=r- (r-7,) + (), where T (x, t) is tissue temperature at location x and time t, Tb is blood temperature, Q is the RF or ultrasound heating power density, aois blood perfusion parameter (power carried away per unit volume and unit temperature difference), k is thermal conductivity of tissue, p is tissue density, and Cp is the specific heat of tissue. At equilibrium, where the left hand side of the equation is zero, the external energy deposited in the tissue is balanced by heat conduction and, more importantly, by blood perfusion. Since blood perfusion is both time varying and strongly dependent on vasculature, it is very difficult to predict the temperature distribution with high precision. However, judicious choice of an upper limit to the energy applied, the manner of application, and empirical modeling with the aid of a phantom can lead to a temperature maximum in adipose tissue spaced from proximate muscle. The relative thermal properties of adipose and muscle tissue, the relative lack of vasculature in that adipose tissue and the thermal gradient from muscle to skin surface all contribute to the realization of a temperature peak in the region 25 provided that the rate of thermal power deposition in the layer 25 is not large compared to the cooling capacity of the muscle vasculature. The curve 40 shows an achievable temperature profile under typical conditions. Thermal power deposition in individual treatments is applied to realize a profile of this form.

There are simple but invasive techniques to monitor the generated temperature profile in the patient. These prior techniques generally involve the insertion of a thin thermocouple or other temperature sensor into the region to be heatcd. The feedback from such sensors may bc used to actively control the temperature profile. In order to keep the procedure completcly non- invasive it is possible to establish heating protocols through experiments with phantoms, animal models and human trials. The tissue structure that lends itself to fat removal by heat is often naturally receptive of the temperature profile that we try to generate and can correct for lack of precision in the application of heat. This is due to the fact that increased blood perfusion in muscle tissue makes it more difficult to raise the temperature of muscle. Therefore, an apparatus that targets heat generation to the general area of muscle-fat boundary will be successful in placing the temperature peak in the fatty layer close to the boundary as is desired for fat removal.

More complex arrangements are known in the practice of hyperthermia. Spatially delimited nuclear magnetic resonance (NMR) measurements have been employed to monitor

temperature dependent NMR phenomena concurrently with hyperthermia, laser ablation and heat surgery. See US 5,327,884 and 5,368,031.

Apparatus for application of heat to the desired target region includes medical diathermy equipment, ultrasound apparatus, microwave applicators and the like. The ability to direct thermal power deposition as in coherent ultrasound apparatus provides a highly preferred added element of power deposition control; however, substantial utility is obtainable through other heating arrangements where dermal layers are protected against overheating and the vasculature cooling in muscle tissue is not overburdened. Particle beams (protons, helium, carbon, etc.) may also be used to cause adipose cell necrosis in a controllable way. Heavier charged particles in particular do not lose their energies linearly with penetration depth. Instead, the rate of energy deposition in the tissue is small upon entry, and builds to a sharp peak near the end of the particle's range. This peak is called the Bragg peak and occurs at a depth that is related to the initial energy of the charged particle. By choosing the energy of the particle beam appropriately, the tissue at a precise depth can be targeted. See [Phillips, T. L., Principles of Cancer Treatment, Chapter 7, McGraw-Hill, New York: 1982].

It is theoretically possible to establish an equilibrium between the rate of necrosis for adipose cells and the metabolic rate of absorption of those necrosed cells. As a practical matter the metabolic rate of absorption is best regarded as a limit on the duration/intensity of any individual treatment session. A measurement or monitoring protocol is necessary to ascertain this metabolic rate. It may be possible to enhance the metabolic rate by additional physical activity, dict, and dietary supplements.

The present method contrasts with other therapics designed for destruction of ccll populations of a type, e. g., cancer. Cancer therapy is directed toward destruction of the entire population of the target type cells, whereas the present therapy is directed to destruction of a relatively small percentage of the target (adipose) cells. Multi-session cancer therapy is segmented to provide a recovery time for healthy tissue. Segmentation of treatment in the present method is further designed to permit natural removal of the necrosed tissue in measured synchronization with the causative treatment.

Energy deposited in the target tissue is sufficient to exceed a threshold for necrosis of adipose cells but ideally less than corresponding thresholds for other tissue in the target region.

This is due to the fact that there is poor blood circulation in the adipose tissue and therefore the body can not cool it very effectively. Similarly, the duration of the dose is best limited to produce adipose cell necrosis at a rate less than the removal rate thereof by metabolic mechanisms during the interval between treatments.

The initial treatment parameters (principally the treatment duration, or integrated dose) and the following interval before a subsequent treatment must be determined. Intensity and duration of heat application (known as heat dose) in the initial session is estimated by using published cell necrosis data summarized in Figure 5 from the work of Dewey, Hopwood, Sapareto and Gerwich, Radiology, v. 123, pp. 463-474,1977. For practice of the present invention, the goal is to destroy less than approximately 5% of the adipose tissue in each session. Also, keeping the temperature of the target volume in the lower range of the therapeutic window (closer to 41°C than 46°C) is desirable in order to avoid any pain sensation. For example, raising the peak 40a of the temperature profile to 41.5 degrees Celsius for a 15 minute session or 42 degrees for a 7-minute session are typical thermal prescriptions for an adult. The amount of thermal power to be delivered to the target region in order to maintain this temperature is estimated from vascularization and blood flow present in that part of the body.

The upper limit for rate of power deposition is estimated from the"bioheat"equation and verified by examining similar mammalian muscle-fat examples. In our experiments and average power of approximately 40 watts was delivered to the treatment area.

Following treatment, metabolic processes will operate to absorb the necrosed cells. A base measurement (discussed below) taken prior to the treatment and one or more subsequent measurements serve to monitor the metabolic processes. It is desired to avoid saturation of these metabolic processes, in scheduling a subsequent treatment, in prescribing the subsequent treatment parameters, and in defining the interval between treatments.

The metabolic absorption of necrosed adipose cells falls off as a function of time as such cells are absorbed and a conveniently selected point of absorption is taken as an end point for the inter-treatment interval. A subsequent treatment is thcn timely. Moreover, the metabolic process for that particular patient becomes known to some extent and expected time dependence in the next inter-treatment interval may be measured and compared to the prior corresponding measurement. A hypothetical course of treatment is shown in figure 7 where the ordinate is a quantity for which the decay properties reflect the metabolic mechanism for removal necrosed adipose cells. For example, edema, as a consequence of treatment, provides a convenient measurable quantity which decreases over time as metabolic processes operate in the affected region as discussed below.

The process of the present invention involves measurement of a parameter indicative of the metabolic absorption of necrosed cells. This may take the form of a measurement of the remaining adipose tissue (referenced to a prior similar measurement) which may be obtained by a quantitative imaging modality (magnetic resonance, ultra-sound or the like). A different form

of measurement of the metabolic absorption process may be had from the edema (local swelling) that is caused by the treatment. Edema is caused by increased porosity of the blood vessels due to heat as well as due to histamines released due to the injury. Histamine release enhances the diffusion of macrophages out of the blood vessels for scavenging the dead cells. The edema is evident within a short time (of order minutes) following treatment and gradually subsides after a few days. This phenomenon can be used as the signal to proceed with the subsequent treatment after the edema has substantially subside. The amount of power deposited in the subsequent treatment is limited so as not to exceed the previously selected limit.

Figure 8 shows the increase and decrease of inflammation over a hypothetical course of treatment. A treatment fraction 81 includes thermal dose 81 a of the target region, producing an inflammation which is observed to follow a decay characteristic (81b) over a time interval. This inflammation may be quantitatively observed over such time interval. Note that the first fraction (81) is used as a gauge of the body's response to adipose tissue necrosis and a basis for subsequent heat-dose prescriptions. Subsequent treatment dosage may or may not exceed the prior treatment dose. Moreover, one would forego a subsequent treatment if the decay portion 82b, 83b, etc, were found to differ significantly from the previous corresponding decay characteristic Experimental Results A proof of concept subcutaneous heating system was assembled as shown in Figure 4.

The system consists of a Sharp 700 W DC magnetron and its controller, a water circulation unit and a cooling pad. Microwave power at 2450 MHz is delivered to the body via a WR-430 waveguide through the cooling pad. The power delivered to the tissue is regulated by the duty cycle of the magnetron.

The system was calibrated using a tissue phantom made of"poly sodium acrylate"gel in a plastic container with a liquid crystal temperature monitor as shown in Figure 7. The liquid crystal strip 73 is normally black, but changes color 75 when its temperature is between 45 and 50 degrees Celsius. Cooling rates and duty cycles were adjusted to obtain the temperature peak at a distance of approximately one centimeter from the surface 74 as indicated by region 75.

Based on this phantom study the circulating cooling water rate and temperature, the pre-cooling time, and the duty cycle of the microwave source were selected to achieve the desired temperature peak.

Animal Tests The concept described above was successfully tested on a Yucatan pig at Northview Pacific Laboratories in Hercules, California. The general tissue properties and metabolism for these animals are quite close to corresponding properties in humans. One notable difference being the abundance of multiple layers of thin skeletal muscle sandwiched between layers of fat in the pig that can get damaged during the application of heat. Successful controlled cell necrosis close to the muscle-fat boundary was achieved without skin damage. Heat was applied non-uniformly to two adjacent sections of the body in independent treatments. A section subjected to higher heat dose (10% duty cycle for 30 minutes) developed an inflammation that did not subside in the 10-day duration of the study. This effect sets the upper limit on the heat dose to be applied to the region and confirms that the heat dose per fraction should be limited to necrotizing approximately 5% or less of the targeted cells (Figure 5). The second section was subject to three separate treatments at intervals of two and three days. Each treatment was done at 10% duty cycle (corresponding to approximately 40 watts of power delivered to the tissue) for 15 minutes. Following the three treatments, biopsy samples of treated tissue were taken at three locations from this section representing differing thermal doses arising from nonuniform power application. Evidence of fat cell membrane damage was seen in the two samples that received higher heat doses. There was also evidence of damage to the thin skeletal muscle layers within the subcutaneous fat. Such muscle layers are absent in most human fatty tissue.

In another embodiment, instead of limiting the rate of cell death to a threshold level below reported side effects, certain preventative therapics may bc administered and the thermal dose increased in accord with such preventative therapy to enhance the process of fat removal.

Examples of such known therapies are the administration (prior to treatment) of anti- inflammation agents to reduce the swelling or the introduction of fibrosis reversal substances such as Super Oxide Dismutase (SOD) [Delanian S, Baillet F, Huart J, Lefaix JL, Maulard C, Housset M,"Successful treatment of radiation-induced fibrosis using liposomal Cu/Zn superoxide dismutase: clinical trial"Radiother Oncol, Vol 32 (1) Jul 1994].

Although this invention has been described with reference to particular embodiments and examples, other modifications and variations will occur to those skilled in the art in view of the above teachings. lt should be understood that, within the scope of the appended claims, this invention can be practiced otherwise than as specifically described.