Patent Abstract:
A system and method for treating subcutaneous histological features without affecting adjacent tissues adversely employs microwave energy of selected power, frequency and duration to penetrate subcutaneous tissue and heat target areas with optimum doses to permanently affect the undesirable features. The frequency chosen preferentially interacts with the target as opposed to adjacent tissue, and the microwave energy is delivered as a short pulse causing minimal discomfort and side effects. By distributing microwave energy at the skin over an area and adjusting power and frequency, different conditions, such as hirsuitism and telangiectasia, can be effectively treated.

Full Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
       [0001]    This is a continuation of pending U.S. application Ser. No. 13/280,032, filed Oct. 24, 2011; which is a continuation of U.S. application Ser. No. 09/637,923, filed Aug. 14, 2000, now U.S. Pat. No. 8,073,550; which is a divisional of U.S. application Ser. No. 08/904,175, filed Jul. 31, 1997, now U.S. Pat. No. 6,104,959; all of which are incorporated herein by reference. 
     
    
     FIELD OF THE INVENTION 
       [0002]    This invention relates to effecting pathological changes in subcutaneous histological features so as to eliminate unsightly or potentially harmful vascular and cellular conditions, without side effects and with fewer steps and less discomfort than has heretofore been possible. 
       BACKGROUND OF THE INVENTION 
       [0003]    Radiation therapy is an accepted treatment for a wide variety of medical conditions. High intensity radiant energy sources in the visible band, such as lasers, are now being widely used for both internal and extracorporeal procedures. While the microwave band, between 300 MHz and 30 GHz affords the capability of penetrating deeper than visible light while interacting differently with body tissue it has heretofore been employed primarily only in a variety of dissimilar medical procedures. 
         [0004]    Microwave energy exerts its effect on tissue through controlled regional heating (hyperthermia) of affected features through interaction between the wave energy and magnetically polarizable tissue matter. By using microwaves to establish a regional hyperthermia, it is possible to preferentially increase the temperature of diseased or unwanted histological features to levels which are pathologically effective. At the same time, a necessary objective is to maintain adjacent tissue at acceptable temperatures, i.e., below the temperature at which irreversible tissue destruction occurs. Such microwave induced hyperthermia is well known in the field of radiology where it is used in the treatment of individuals with cancerous tumors. 
         [0005]    A number of specific methods for treating histological features by the application of microwave radiation are described in the medical literature. For example, a technique for treating brain tumors by microwave energy is disclosed in an article entitled “Resection of Meningiomas with Implantable Microwave Coagulation” in Bioelectromagnetics, 17 (1996), 85-88. In this technique, a hole is drilled into the skull and a catheter is invasively inserted into the hole to support a coaxial radiator or antenna. Microwave energy is then applied to the antenna to cause the brain tumor to be heated to the point where the center of the tumor shows coagulative necrosis, an effect which allows the meningioma to be removed with minimal blood loss. Another technique in which microwave energy is utilized to treat prostate conditions is disclosed by Hascoet et al. in U.S. Pat. No. 5,234,004. In this technique, a microwave antenna in a urethral probe connected to an external microwave generating device generates microwaves at a frequency and power effective to heat the tissues to a predetermined temperature for a period of time sufficient to induce localized necrosis. In a related technique disclosed by Langberg in U.S. Pat. No. 4,945,912, microwave energy is used to effect cardiac ablation as a means of treating ventricular tachycardia. Here, a radiofrequency heating applicator located at the distal end of a coaxial line catheter hyperthermically ablates the cardiac tissue responsible for ventricular tachycardia. As with the described methods of tumor treatment, this method of cardiac ablation operates by preferentially heating and destroying a specifically targeted area of tissue while leaving surrounding tissue intact. 
         [0006]    While the general principle of propagating microwave energy into tissue for some therapeutic effect is thus known, such applications are usually based on omnidirectional broadcasting of energy with substantial power levels. The potential of microwave energy for use with subcutaneous venous conditions and skin disorders has not been addressed in similar detail, probably because of a number of conflicting requirements as to efficacy, safety, ease of administration and side effects. 
         [0007]    As a significant number of individuals suffer from some type of subcutaneous but visible abnormality, therapeutic techniques which effectively address these conditions can be of great value. Such features which are potentially treatable by microwave energy include conditions such as excessive hair growth, telangiectasia (spider veins) and pigmented lesions such as cafe-au-lait spots and port wine stains (capillary hemangiomas). Of these conditions, excessive hair growth and spider veins are by far the most common, affecting a large percentage of the adult population. 
         [0008]    Unwanted hair growth may be caused by a number of factors including a genetic predisposition in the individual, endrocrinologic diseases such as hypertrichosis and androgen-influenced hirsuitism as well as certain types of malignancies. Individuals suffering from facial hirsuitism can be burdened to an extent that interferes with both social and professional activities and causes a great amount of distress. Consequently, methods and devices for treating unwanted hair and other subcutaneous histological features in a manner that effects a permanent pathological change are very desirable. 
         [0009]    Traditional treatments for excessive hair growth such as depilatory solutions, waxing and electrolysis suffer from a number of drawbacks. Depilatory solutions are impermanent, requiring repeated applications that may not be appropriate for sensitive skin. Although wax epilation is a generally safe technique, it too is impermanent and requires repetitive, often painful repeat treatments. In addition, wax epilation has been reported to result in severe folliculitis, followed by permanent keloid scars. While electrolysis satisfactorily removes hair from individuals with static hair growth, this method of targeting individual hairs is both painful and time consuming. In addition, proper electrolysis techniques are demanding, requiring both accurate needle insertion and appropriate intensities and duration. As with wax epilation, if electrolysis techniques are not performed properly, folliculitis and scarring may result. 
         [0010]    Recently developed depilatory techniques, utilizing high intensity broad band lights, lasers or photochemical expedients, also suffer from a number of shortcomings. In most of these procedures, the skin is illuminated with light at sufficient intensity and duration to kill the follicles or the skin tissue feeding the hair. The impinging light targets the skin as well as the hair follicles, and can burn the skin, causing discomfort and the potential for scarring. Further, laser and other treatments are not necessarily permanent and may require repeated applications to effect a lasting depilation. 
         [0011]    Like hair follicles, spider veins are subcutaneous features. They exist as small capillary flow paths, largely lateral to the skin surface, which have been somewhat engorged by excessive pressure, producing the characteristic venous patterns visible at the skin surface. Apart from the unsightly cosmetic aspect, telangiecstasia can further have more serious medical implications. Therefore, methods and devices for treating spider veins and other subcutaneous histological features in a manner that effects a permanent pathological change to the appropriate tissues are highly desirable. 
         [0012]    The classical treatment for spider veins is sclerotherapy, wherein an injection needle is used to infuse at least a part of the vessel with a sclerotic solution that causes blood coagulation, and blockage of the blood path. With time, the spider veins disappear as the blood flow finds other capillary paths. Since there can be a multitude of spider veins to be treated over a substantial area, this procedure is time-consuming, tedious, and often painful. It also is of uncertain effectiveness in any given application and requires a substantial delay before results can be observed. 
         [0013]    Another procedure for the treatment of shallow visible veins, which is similar to techniques used in depilation, involves the application of intense light energy for a brief interval. This technique exposes the skin surface and underlying tissue to concentrated wave energy, heating the vein structure to a level at which thermocoagulation occurs. In particular, these energy levels are so high that they cause discomfort to some patients, and they can also be dangerous to those in the vicinity, unless special precautions are taken. In addition, some patients can be singed or burned, even though the exposure lasts only a fraction of a second. 
         [0014]    Due to the serious problems that the subcutaneous abnormalities can create in individuals, there is a general need to be able to treat such features in a manner that effects beneficial pathological change without adverse side effects or discomfort. An optimal therapeutic technique should effect a permanent pathological change without requiring repeated applications to reach the desired effect. Moreover, these procedures should be noninvasive, should cover a substantial target area that is not limited to a single hair follicle or spider vein, and should make optimum use of the energy available. Finally, pathological changes should occur only in the targeted feature, and not in intervening or underlying layers. 
       SUMMARY OF THE INVENTION 
       [0015]    The present invention overcomes the deficiencies in previously described methods for treating subcutaneous features by delivering a dosage of microwave energy that is maintained for only a short duration but at an energy level and at a wavelength chosen to penetrate to the depth of a chosen histological feature. The subcutaneous features are destroyed or pathologically altered in a permanent fashion by the hyperthermic effect of the wave energy while the surrounding tissue is left intact. 
         [0016]    In accordance with the invention, the effective delivery of microwave energy into the subcutaneous feature can be maximized in terms of both the percentage of energy transmitted into the body and a preferential interaction with the target feature itself. The microwave energy is specifically targeted to the chosen depth and the targeted feature is heated internally to in excess of about 55° C., to a level which thromboses blood vessels and destroys hair follicles. The ability to target a wide area containing a number of features simultaneously enables a single procedure to supplant or reduce the need for repetitive applications. 
         [0017]    Methods in accordance with the invention utilize certain realizations and discoveries that have not heretofore been appreciated in relation to wave energy-tissue interactions at a substantial depth (up to 5 mm below the skin surface). The wavelengths that are selected are preferentially absorbed by a targeted feature such as a blood vessel more readily than by skin surface and tissue. Thus, a chosen frequency, such as 14 GHz, penetrates through surface tissue to the chosen depth of the target feature, but not significantly beyond, and the energy heats the target more than adjacent tissue. Dynamic thermal characteristics are also taken into account, because transfer of thermal energy from small target features such as minute heated blood vessels to the surrounding tissue (the “thermal relaxation time”) is much faster than that for larger vessels. The duration of a dosage, typically in the range of 100 milliseconds, is varied to adjust for this size factor. 
         [0018]    Immediately prior to, concurrently with, or after the application of penetrating microwave energy, the skin surface is advantageously cooled. This cooling may be effected in a number of ways such as through the delivery, as rapidly expanding gas, of known coolants into a small space between the microwave emitter and the skin surface. The use of coolant enables the surgeon not only to minimize patient discomfort and irritation, but also to adjust energy dosages in terms of intensity and duration, because heat extraction at the surface also affects heating to some depth below the surface. The surgeon can also employ air cooling to minimize irritation while assuring results over a larger subcutaneous area and with fewer applications. 
         [0019]    While it is advantageous to cool the skin surface with a separate medium in the target area immediately prior to or during wave energy application, it is also shown that the wave energy emitting device itself can be used to draw thermal energy off the skin surface. Again, the skin is heated minimally, giving the patient little, if any discomfort, and avoiding skin irritation. Comfort may be ensured for sensitive patients by a topical anesthetic, or by a conductive gel or other wave energy complementary substance introduced between the applicator and the skin surface. 
         [0020]    The energy applied is generally in excess of about 10 Joules, and the duration is typically in the range of 10 to 1,000 milliseconds, with about 100 milliseconds being most used. The total energy delivered is typically in the range of 10-30 Joules, although the energy delivered as well as frequency may be changed in accordance with the nature of the targeted features, the target volume and depth. In a depilation process, for example, 10 to 20 Joules will usually suffice when a compact applicator is used, while a higher input level, such as 20 to 30 Joules, is used for a telangiectasia treatment. 
         [0021]    A system in accordance with the invention for use in such procedures may employ a tunable power generator, such as a tunable power source operable in the microwave range from 2.45 GHz to 18 GHz, and means for gating or otherwise controlling the power output to provide selected pulse durations and energy outputs. The system also can incorporate power measurement sensors for both forward power and reflected power or circuits for measuring impedance directly. Thereby, tuning adjustments can be made to minimize reflection. Power is delivered through a manipulatable line, such as a flexible waveguide or coaxial line, to a small and conveniently positionable applicator head which serves as the microwave launcher or emitter. The applicator head may advantageously include, in the wave launching section, a dielectric insert configured to reduce the applicator cross-section, and to provide a better match to the impedance of the skin surface. Furthermore, the dielectric insert is chosen so as to distribute the microwave energy with more uniform intensity across the entire cross section, thus eliminating hot spots and covering a larger area. 
         [0022]    If the dielectric is of a material, such as boron nitride or beryllium, oxide, which is a good thermal conductor, it can be placed in contact with the skin and thermal energy can be conducted away from the skin as microwave energy is transferred. Different clinical needs can be met by making available a number of different dielectric element geometries fitting within an interchangeable mount. The applicator head may further include a pressure limiting mechanism to insure that the head does not compress vessels as the procedure is being carried out. 
         [0023]    In addition to the range of capabilities thus afforded, the surgeon can use ultrasound or other inspection techniques to identify the locations of the subcutaneous features for the precise mapping of target sites. Using an indexing or aiming device or element on the applicator head, energy can be applied a minimum number of times at precise locations to encompass a maximum number of targets. Because skin and tissue characteristics vary, pretesting target characteristics and varying the frequency or phase applied can increase efficiency and reduce the possibility of side effects. 
         [0024]    In another application in accordance with the invention, the skin target area may be more readily visualized by using a microwave launcher positionable within an end unit in one of two alternate positions. In one position, the target area can be viewed and the launcher indexed for movement into precise proximity to the target area. In yet another example, a rectangular waveguide of standard size and therefore larger cross-section is used, with air cooling of the skin surface. For depilation, a peel-off, attachable label locating a number of delineated contiguous target areas can be placed on the skin. When the applicator has been energized at each target area, the label sheet can be peeled off, removing hair residue with it. 
         [0025]    The applications of the process and method are not limited to conditions such as spider veins and unwanted hair, but further encompass pigmented lesions and related abnormalities, as well as other temporary and permanent skin disorders. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0026]    A better understanding of the invention may be had by reference to the following specification, taken in conjunction with the accompanying drawings, in which: 
           [0027]      FIG. 1  is a combined block diagram and perspective view of a system in accordance with the invention; 
           [0028]      FIG. 2  is a side view, partially in section, of a microwave applicator for use in the system of  FIG. 1 ; 
           [0029]      FIG. 3  is a fragmentary view of the beam launching end of a microwave applicator in relation to a graphical representation of electric field strength across the applicator; 
           [0030]      FIG. 4  is a simplified, perspective view of a section of subcutaneous structure, depicting different layers therein in relation to blood vessels and hair follicles; 
           [0031]      FIG. 5  is an enlarged sectional view of a hair structure from root to shaft; 
           [0032]      FIG. 6  is a simplified depiction of method steps in accordance with the invention; 
           [0033]      FIG. 7  is a graphical depiction of loss factor curves showing the comparative absorption of microwaves in blood and tissue at different frequencies; 
           [0034]      FIG. 8  is a graphical depiction of the temperature changes at and below the skin surface during practice of methods in accordance with the invention; 
           [0035]      FIG. 9  is a graphical depiction of the variation in thermal relaxation time for different blood vessel diameters; 
           [0036]      FIG. 10  is a simplified perspective view of a different microwave applicator used in conjunction with a removable positioning sheet; and 
           [0037]      FIG. 11  is a perspective, partially broken away, view of an alternative applicator head including internal cooling and a viewing system. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0038]    A system in accordance with the invention; referring now to  FIG. 1 , is depicted in an example intended for use in hair removal, the treatment of spider veins and other skin disorders. This configuration includes a hand-held applicator that is suitable for potential use at any frequency within a suitable range, as well as for measurement of skin or tissue properties. Such a system can be used for treating any of a variety of skin disorders, including hirsuitism, telangiectasia, pigmented lesions and the like. It will be apparent to those skilled in the art that where such degrees of versatility and usage in different possible applications are not required, a simpler and less expensive system will often suffice. In addition, if a manually moveable applicator head is not required, the system can be simplified in this respect as well. In the most rudimentary example, a monofrequency unit with means for adjusting dosage driving a fixed applicator head may be adequate. 
         [0039]    Referring to  FIG. 1 , in a system  10  in accordance with the invention microwave energy of a selected frequency can be generated by any one of a number of conventional devices, such as a variable frequency synthesizer  14  that covers a range from about 2 GHz to about 20 GHz. A number of other conventional microwave generators are tunable in the range of 2.45 GHz to 18 GHz, for example, but here a suitable combination includes the frequency synthesizer  14  and a traveling wave tube system  12  having internal power and a high power output amplifier. Where operating conditions are well-defined and wide tunability is not needed, a conventional low cost source such as a magnetron may be used. The output of the traveling wave tube system  12  is gated open for selected intervals by control pulse circuits  16 , which can be set, in this example, for any interval from 10 to 1000 milliseconds. Thus, the selected frequency is delivered as a pulse burst to provide from 50 W to as much as 4 KW output, the power level most often being of the order of a few hundred watts. In transmission to the operative site, the power bursts are directed through a power sensor  18 , which diverts both forward and reverse propagated energy samples to a power meter  20 . Readings at the power meter  20  enable the surgeon to fine tune power, phase or frequency settings to improve impedance matching and energy efficiency. 
         [0040]    Preinspection of the target site is dependent on the nature of the target. Although visual inspection is sometimes alone sufficient for target area selection, as with hirsuitism, target veins at depth below the surface can often better be identified, located, and dimensioned by conventional analytical instruments, such as those using ultrasound imaging. As is described hereafter, the power, duration and frequency applied can also be adjusted in relation to the thermal relaxation characteristics of a target blood vessel, which in turn is dependent on size and location. 
         [0041]    A microwave transmission line  24 , here including a flexible rectangular waveguide or a flexible coaxial section  26  that may be manually manipulated, supplies the microwave energy through a phase shifter or other kind of tuner  27  to a hand applicator  30  shown here as positioned against a limb  32  exposed within a surgical drape  34 . The handpiece  30 , shown in greater detail in  FIGS. 2 and 3 , is essentially a rectangular waveguide device having a stepped or other impedance matching section  36  coupled to the flexible coaxial line  26 . The handpiece  30  includes a converging tapered body  38  having an open aperture end  40  serving as the wave launching terminus. Internal to the tapered waveguide section  38  is a dielectric insert  44  here formed of two high dielectric (K=16) tapered strips  46 ,  47  held in place between low dielectric constant (K=2.5) spacers  48  of a virtually microwave transparent material such as “Rexolite”. This configuration of dielectrics, as seen in  FIG. 3 , spreads the electric field distribution toward the sidewalls, enlarging the target area that is effectively acted upon by the wave energy and eliminating any hot spot tendency within the target area. In addition, the dielectric insert  44  provides a better impedance match to the skin, reducing reflective losses, which can further be minimized by adjustments at the tuner  27 . The dielectric  44  also reduces the cross-sectional area and size of the waveguide, thereby making the handpiece  30  easier to handle. In addition, the internal taper matches the waveguide impedance to the different impedance of the dielectric loaded section, so as to minimize reflection. 
         [0042]    The flexible coaxial line  26  allows a surgeon to move the applicator  30  to place its open end manually wherever desired on the body surface  32 . At the frequency range of 12-18 GHz, a standard WR 62 waveguide section with 0.622″×0.311″ orthogonal dimensions can be employed at the output end of the impedance matching section  36 . The tapered section  38 , loaded by the dielectric  44  in this example, reduces the waveguide dimension to 0.250″×0.150″ at the output terminal face  40 . The end face  40 , however, is set off from the limb or other body surface  32  against which it is juxtaposed by an encompassing and intervening spacer element  54 , best seen in  FIGS. 2 and 3 . The spacer element  54  includes an interior shoulder  56  extending around the periphery of the end  40  of the tapered section  38 , defining a standoff volume of a height of about 0.020″ (0.5 mm). A coolant can thus be injected via a side conduit  58  from a pressurized coolant gas source  60  ( FIG. 1 ), via a coupling conduit  62  extending through a solenoid controlled valve  64 . The pulse control  16  opens the valve  64  in timed relation to the microwave pulse to be delivered from the traveling wave tube system  12 . This timing relation can be controlled, so that the target skin area can be precooled prior to delivery of the microwave pulse, cooled concurrently with the delivery or cooled after the start of the delivery of the microwave pulse. Furthermore, a temperature sensor  68 , shown only generally in  FIG. 1 , may be disposed within the standoff volume, in contact with the skin or otherwise, to sense the lowering of temperature at the target surface. In this example, the coolant is a pressured gas, such as 1,1,1,2 tetrafluoroethane, held under high pressure in liquefied or gaseous phase. When injected by actuation of the valve  64 , the gas expands vigorously within the standoff volume, rapidly lowering the temperature because of the expansion effect. Since the boiling point of the tetrafluoroethane is approximately −26° C. at 1 atm, it is extremely effective in extracting thermal energy from the target area, even for the short bursts of the order of a fraction of a second that are involved in the present procedure. The temperature sensor  68  may be a Luxtron fiber optic device for measuring temperature, or it may be a thermistor which is coupled in a circuit that triggers the microwave pulse when the coolant has adequately lowered the temperature at the skin surface or in the standoff volume. Other coolants, including air, can alternatively be used to reduce the skin surface temperature within the standoff volume during the procedure. 
         [0043]    Other alternative approaches may be utilized to minimize discomfort and, separately or additionally, provide improved efficiency. A compound that is complementary to the delivery of the microwave energy, in the sense of neither being reflective or absorptive, and therefore not appreciably heated, can be placed on the skin prior to microwave pulse application. For example, a topical anesthetic having short term effectivity may be all that is needed to reduce the discomfort of some patients to an acceptable level. Other patients may require no coolant or topical anesthetic whatsoever. Another alternative is to employ a surface gel or other substance that improves impedance matching between the microwave pulse launching device and the surface tissues. 
         [0044]    The microwave delivery system provided by the applicator  30  delivers microwave energy over an advantageously broad field distribution into a subcutaneous surface area as best understood by reference to  FIG. 3 . The dielectric loading introduced by the spaced apart dielectric elements  46 ,  47 , which diverge toward the output end as the sidewalls converge in the tapered section  38 , alters the normal horizontal electric field distribution from its normal half sine wave characteristic so that there is substantial field strength at the two sidewalls and no high central energy peak. A single, appropriately shaped, dielectric element can be used to modify the field distribution to like effect. By thus spreading the energy across the target area, there is both elimination of localized energy concentrations (and therefore localized heating) and a larger effective treatment area. As seen in the graphical portion of  FIG. 3 , in the solid line, the calculated electric field at the skin surface when the outlet end  40  of the microwave launcher is 0.5 mm off the surface, is more than twice that at the edges. This differential is reduced when the field distribution is modeled at a depth of 0.5 mm below the skin surface. In both instances, there is a degree of dispersion outside the perimeter of the applicator face  40  because of the setoff spacing, but this aids in equalizing the power distribution and poses no radiation danger. 
         [0045]    In accordance with the present invention, advantage is taken of the results of an analysis of the interaction of microwaves with biological tissues at different frequencies. The complex permittivity ε* of any given matter, including biological matter, in a steady state field is conventionally analyzed using the following equation: 
         [0000]      ε*=ε 0 (ε′−jε″),
 
         [0000]    in which ε 0  is the dielectric constant of free space and the real component, ε′, is the dielectric constant, while the imaginary component, ε″ is the loss factor. As seen in  FIG. 7 , the loss factor (ε″) of blood, in the range of 2 to 20 GHz, shown by tests to be substantially higher than that of skin tissue. Further analysis has ascertained that by considering both relative and absolute factors, the most advantageous conditions exist at about 14 GHz. From published work, the dielectric constant of skin is known to be about 22 at 10 GHz and to decrease with increasing frequency to a value of 12 at 18 GHz. The loss factor for skin reaches a peak of 18 at 9 GHz and decreases with increasing frequency to a value of 12 at 14 GHz. The loss factor ε″ for skin is approximately one-half that for blood in the frequency range between 14 GHz and 20 GHz, and above 10 GHz the loss factor for blood increases somewhat more than for skin, as seen in  FIG. 7 . Therefore, the heat generated per unit volume in blood and to some extent in differentiable cellular structures other than skin, can be expected to be twice that of skin. Consequently, differential heating results when microwave energy penetrates subcutaneous regions. Because these subcutaneous regions are of depths up to 5 mm, they are directly within the range of interest that includes hair follicles and roots, telangiectasia, pigmented lesions, and other histological features that are visible through the epidermis and/or dermis, or actually protrude at the skin. 
         [0046]    The structure of skin is somewhat idealistically and simplistically depicted in  FIG. 4 , in order to show the physical relation and relative proportions (although not to scale) between the epidermis and dermis layers that lie above subcutaneous tissue, and to further represent histological features of interest in the structure. Sweat glands, nerve endings, corpuscular structures and sebaceous glands are not included for clarity. The hair shafts, most deeply embedded at their roots at 4 to 5 mm depth in the dermis, extend outwardly through the dermis and the relatively more robust epidermal layer. Relatively large arteries and veins branch into the arteriole and venule vessels which feed and derive blood, respectively, as the smallest capillaries that normally are invisible from the skin surface, and that form the termini of the blood paths. When these capillaries, either or both arterioles and venules, become engorged for some reason, as in the telangiectasia condition, they form the lateral and visible pattern, known collectively as spider veins, at a depth of 0.1 to 1.0 mm below the surface of the epidermis. Typically of the order of 0.2 mm in diameter, the spider veins can actually sometimes protrude at the surface, and be larger in diameter as well. Reticular or feeder veins can lie as much as 5 mm in depth below the surface, and are substantially larger, of the order of 1.0 to 2.0 mm in diameter, being large enough to be identified by a non-invasive inspection technique, such as imaging with ultrasound. The reticular or feeder veins sometimes create the overpressure condition causing engorgement of the spider veins. 
         [0047]      FIG. 5  shows further details, again somewhat idealized, of an enlarged hair shaft, extending outwardly from a root into the growing cellular structure of the follicle and the follicle casing that transforms into the hair shaft body that passes through the epidermis. The hair follicle is nourished by at least one artery that feeds the papillae structure at the root and is encompassed in a crown of associated matrix cells. Attack on the cellular follicle structure or on the papillae or the arterioles or venules to and from the papillae can result in permanent destruction of the hair shaft. 
         [0048]    With these considerations in mind, appreciation of the operation of the system of  FIG. 1  can more readily be gained. The surgeon can use a suitable frequency for a chosen histological feature within the range of the frequency synthesizer  14 . It is assumed here that the frequency chosen is about 14 GHz. The traveling wave tube system  12  is set to generate approximately 100 to 300 watts, the control pulse circuits  16  being set to open the solenoid valve  64  prior to getting a short pulse from the microwave system  12 . It has been found that a 100 millisecond pulse is satisfactory for both efficacy and safety, although other durations can be used with wattage adjustments to compensate. The output from the traveling wave tube system  12  is directed through the power sensor  18 , the transmission line  24 , the flexible section  26 , through the tuner  27  and to the applicator  30 . If the operator desires, short test pulses of low amplitude can first be sent to obtain readings of the reflected power at the power meter  20 , and fine tuning adjustments can be made at the tuner  27 , in a conventional manner. In addition, the operator can use ultrasound or another non-invasive diagnostic system to analyze the substructure to identify the position of target features, such as reticular veins and arteries, both as to size and location. The procedure initially to be described, however, pertains to depilation, so that the target area is not only readily visible, but is also substantially uniform in depth and structure, as per  FIG. 5 . 
         [0049]    When the control pulse circuits  16  operate, they first provide a control impulse to open the solenoid valve  64 , in this example, and then turn on the traveling wave tube system  12  for the selected interval. Because the valve requires a few milliseconds (e.g., 20 to 35) to operate and a few milliseconds are also needed for the pressurized coolant from the source  60  to pass through the outer conduit  62  and the side conduit  58  in the spacer  54 , it is preferred to delay the microwave pulse until cooling has actually begun or is contemporaneously begun. Alternatively, as previously noted, a temperature sensor  68  that detects a temperature drop at the skin surface may be used to either trigger the microwave pulse or to preclude its operation until after the coolant has become effective. 
         [0050]    For depilation, pulses in the range of 10 to 20 Joules in terms of total work output have been shown to effect permanent depilation without significant discomfort or significant adverse side effects. Tests were run using the dielectric loaded applicator  30  having a 0.250″×0.150″ output area (5 mm×3 mm, or 15 mm 2 ), and employing a pulse duration of 100 milliseconds in all instances. A substantial number of experiments were run on test rabbits with this applicator, varying only the power applied so as to change the total energy in Joules. The results were examined by a pathologist and the accompanying Tables 1 and 2, appended following the specification, show the results of his examination. 
         [0051]    The system of  FIG. 1  was also employed in a number of tests on rabbits to determine the changes occurring in veins and arteries under different pathological changes, and side effects on tissues and vessels with a protocol using cooling as well as no cooling to determine if pigmentation has an effect are shown in appended Table 3. These tests showed no significant difference in pigmentation versus non-pigmentation; indicating that coloration, and/or the presence of melanin, is not a significant factor in absorption of microwave energy. A different protocol was followed in amassing results shown in appended Table 4, which represents an analysis by a pathologist blinded to the dosages used. Cooling was not used in this example. These results with test rabbits show that pigmentation is not a significant factor and that at 16 Joules dosage and above, there is effective occlusion of target veins and arteries with minimal changes or only mild induration of tissues. The indication of dermal fibrosis again is not indicative of scar development. 
         [0052]    Pathological examination of these animal studies consistently demonstrated destruction of hair follicles over a wide range of microwave energy levels. The destruction extended to the base of the follicle, which is significant to permanent hair removal. The amount of hair destruction within the target area varies in accordance with the total amount of energy, but destruction is substantially complete at 14 Joules and higher. Furthermore, until the energy delivered is in excess of 20 Joules, the appearance of the skin is normal in all cases and the epidermis is histologically intact. Minor indications of dermal fibrosis are not indicative of clinical scar formation. Minor vascular changes, such as intimal fibrosis of small arteries, constitute neither damaging nor permanent conditions. Consequently, a dosage in the range of 14 to 20 Joules is found both to be effective and to be free of deleterious side effects. 
         [0053]    The effects of delivery of microwave energy, with surface cooling, are illustrated graphically in  FIG. 8 , which indicates temperature changes at both the surface of animal skin tissue (0.75 mm thick) and 1.5 mm below the surface, in water, under conditions of delivery of up to 12 Joules total energy level over 100 milliseconds duration, accompanied by cooling using expanded tetrafluorethane gas. As shown, the baseline temperature for the test animal skin is approximately 32° C., and that for the body at a depth of 1.5 mm is approximately 37° C. Applying the microwave energy with cooling, the skin surface temperature rose very slightly, but was essentially unchanged. Beneath the skin surface, however, the temperature rise at 1.5 mm depth was at a substantially higher rate, reaching approximately 60° C. at 100 milliseconds. Higher temperatures would of course be reached with the application of higher energy levels. It is posited that even such a temperature is sufficient to cause cellular degradation of the hair follicles near the root, and it may well also thermocoagulate blood in the feeder artery, in the papillae at the hair root, or in the cell matrix surrounding the papillae. Although the hair follicles are not conductive, they may be particularly susceptible to the impinging microwave energy because they are thin dielectric elements which can cause energy concentration and therefore greater heating. Whether one or more effects are observable, permanent destruction has been shown by pathological examination, as in the annexed tables. 
         [0054]    The microwave energy does not significantly penetrate beyond the depth of the targeted histological features because of attenuation, the limitation on total energy delivered and the lower loss factor in tissue. 
         [0055]    Where the histological defects are benign vascular lesions, as with the telangiectasia condition, different tests and operating conditions may be employed, as shown in the steps of  FIG. 6 , to which reference is now made. While spider veins can cover a substantial area, and visual targeting may be sufficient, it is often desirable to analyze the target area in greater detail. Thus, ultrasound examination may be utilized to identify and estimate the size of reticular veins feeding a substantial area of spider veins, as an optional first step  80 , which can precede marking of the target surface  82  in any appropriate way. Again, the dielectric constant, skin impedance or other characteristics may be tested in a preliminary step  84 , prior to choosing operative frequency in step  86 . Fine tuning, phase adjustment or another impedance matching option  88  may be employed to reduce reflective losses and increase efficiency. Given the size and location of the target vascular feature, thereafter, the power level and pulse duration may be selected in a step  90 . 
         [0056]    The pulse duration is a significant parameter in relation to the vessel diameter, since the smaller the vessel diameter, the shorter is the thermal relaxation time. Even though the loss factor of blood is higher than that of the tissue, dissipation of heat to surrounding tissue is much faster with a small blood vessel and consequently shorter term heating is needed. As seen in  FIG. 9 , thermal relaxation time increases monotonically with vessel diameter, and thus a longer duration pulse is needed, perhaps at the same or a greater power, if the vessel diameter is of a larger size. Given the power level and pulse duration, the operator can select one of the cooling options, which also includes no cooling whatsoever, in step  92 . Typical anesthetics or other anesthetics may be employed at the same time, as shown by optional step  94 . 
         [0057]    Consequently, when the microwave pulse is delivered, the subcutaneous target is heated to the range of 55° C. to 70° C., sufficient to thrombose the vascular structure and terminate flow permanently. The specific nature contributing factors to disappearance of the vessels with time may be one or more factors, including thermocoagulation of the blood itself, heating of the blood to a level which causes thrombosis of the vessel or some other effect. The net result, however, is that a fibrous structure forms in the vessel which clogs and terminates flow, so that the resultant fibrous structure is reabsorbed with time, as new capillary flow paths are found. In any event, heating in the 55° C. to 70° C. is sufficient to effect (step  96 ) the permanent pathological change that is desired (step  98 ). 
         [0058]    An alternative applicator that covers a larger area and is employed with a peelable indicia label as shown in  FIG. 10 . The standard WR 62 waveguide for transmission of microwave energy at 14 GHz has, as previously mentioned, interior dimensions of 0.622″×0.311″. An applicator  100  employing such a waveguide section  101  is used directly, without internal dielectric loading, to cover a substantially larger target area while employing air cooling. The waveguide section  101 , coupled via a flexible waveguide and an impedance matching transition (not shown), if necessary, to a microwave feed system  102  has side wall ports  104  coupled to an external coolant source  105  which may deliver coolant through a control device  106  triggered, in relation to the microwave pulse, as previously described. Under some circumstances, when air is used as the coolant, it may simply be delivered continuously into the waveguide, the end of which can be blocked off by a microwave transmission window so that only the launching end and the skin surface are cooled. For use in a depilation procedure, the skin surface of a patient to be treated is covered with a sheet  108  having numbered guide indicia  109  for marking successive applicator  100  positions. These positions overlap because of the fact that the energy concentration is in the central region of the waveguide  101 , at the normal maximum amplitude of the electric field in the TE 10  mode. The peel off label sheet  108  is covered on its skin-adhering side by a separable adhesive. Consequently, when the applicator  100  is moved between successive overlapping index positions marked 1,1,2,2 etc. at the side and corner of each position, the internal areas that are pathologically affected within each location are essentially contiguous, until the entire applicator  100  has been moved through all positions on the sheet  108 , with dosages applied to all of the areas. Hair follicles having been destroyed in those areas, the procedure is terminated and the sheet  108  is peeled off, with the destroyed hair follicles and shafts adhering to it. 
         [0059]    With the arrangement of  FIG. 10 , a longer microwave pulse duration or more wattage is needed for increasing the number of Joules because of the broader beam distribution, which means that, heating is at a slower rate (e.g., in the approximate proportion of 0.7° C. rise in skin temperature per joule for the large applicator versus 2.4° C. per joule for the dielectric filled smaller applicator). The skin temperature rise was reduced by a factor of 2 when using air at a temperature of between 0° C. and −5° C. 
         [0060]    It should be noted, furthermore, that a standard open rectangular waveguide can be loaded with dielectric elements in a manner which enables size to be reduced without restricting coolant flow. 
         [0061]    Another alternative that may be used, but is not shown in the figures, relates to a modification of the spacer element that is employed in the example of  FIGS. 2 and 3 . One can configure the spacer element with two alternative but adjacent positions for the applicator open (emitter) end, and arrange the applicator so that the emitter end can be shifted between the two positions. In a first or reserve position of the applicator, the target surface can be viewed through the spacer element, and positional adjustments can be made. This part of the spacer element is then used as a frame for visualizing the operative target on the skin surface when the applicator is in the reserve position. As soon as the target area is properly framed, the applicator is simply shifted from the reserve position to the operative position, in proper alignment with the target area, and the procedure can begin. 
         [0062]    A different approach to a useful applicator is shown in  FIG. 11 , to which reference is now made. This also illustrates a different means for cooling the skin surface, as well as for viewing the target area. In this example, the applicator  120  comprises an open-ended wave propagation segment  122  fed via a transition section  124  from a coaxial line  126 . The unit may be physically manipulated by an attached handle  128 . The open end of the waveguide  122  is filled by a dielectric element  130  which is not only of suitable electrical dielectric properties but a good heat conductor as well, such as boron nitride or beryllium oxide. The dielectric insert  130  extends beyond the open end of the waveguide, into contact with a skin surface that is to be exposed to microwave radiation. The interior end of the dielectric  130  is urged in the direction toward the skin surface by a non-conductive, non-absorptive microwave leaf spring  134  of selected force and compliance. Thus, the dielectric insert  130  presses on the skin surface with a yieldable force, selected to assure that contact is maintained but that any protruding veins or arteries are not closed simply by the force of the applicator  120 . This applicator  120  and dielectric insert  130  are externally cooled by an encompassing sleeve  136  through which coolant is passed via internal conduits  137 ,  138  that communicate with an external supply (not shown) via external conduits  141 ,  142 . Consequently, heat is extracted from the surface of the skin via the contacting dielectric  130  itself. 
         [0063]    In addition, a target mark placed on the skin surface by the surgeon may be viewed by a system including a fiber optic line  145  that extends through the dielectric  130  and leads via a flexible fiber optic line  147  to an image viewing system  149 . 
         [0064]    In use, this applicator  120  of  FIG. 11  covers a substantial chosen area, with the viewing and cooling features that simplify placement and minimize discomfort. The movable dielectric insert  130  can be a replaceable element, with different shapes of dielectrics being submitted where different conditions apply. It will be appreciated that other expedients may be utilized for shaping the microwave beam, including lens and diffuser systems. 
         [0065]    Although a number of forms and modifications in accordance with the invention have been described, it will be appreciated that the invention is not limited thereto, but encompasses all forms and expedients in accordance with the appended claims. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 ANIMAL STUDY PROTOCOL NP970305 
               
               
                 Applicator Tip: 0.250″ × 0.150″; Cooling 
               
             
          
           
               
                   
                 Dose 
                 Description 
                 Histologic Description 
               
             
          
           
               
                 Rabbit 
                 (Joules) 
                 of Skin 
                 Tissue 
                 Hair Follicles 
                 Vasculature 
               
               
                   
               
             
          
           
               
                 B9 
                 13 
                 skin intact; 
                 some 
                 few hair follicles 
                 vessels patent 
               
               
                   
                   
                 decreased 
                 fibrosis; 
               
               
                   
                   
                 density of 
                 mild edema 
               
               
                   
                   
                 hair 
               
               
                 B10 
                 15.2 
                 skin intact; 
                 dermal 
                 relative absence 
                 vessels patent 
               
               
                   
                   
                 decreased 
                 fibrosis 
                 of hair follicles 
               
               
                   
                   
                 density of 
               
               
                   
                   
                 hair 
               
               
                 B11 
                 19.6 
                 skin intact; 
                 normal 
                 paucity of hair 
                 vessels patent 
               
               
                   
                   
                 decreased 
                   
                 follicles 
               
               
                   
                   
                 density of 
               
               
                   
                   
                 hair 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 ANIMAL STUDY PROTOCOL NP970505 
               
               
                 Applicator Tip: 0.250″ × 0.150″; Cooling 
               
             
          
           
               
                   
                 Dose 
                 Description 
                 Histologic Description 
               
             
          
           
               
                 Rabbit 
                 (Joules) 
                 of Skin 
                 Tissue 
                 Hair Follicles 
                 Vasculature 
               
               
                   
               
             
          
           
               
                 B1/R 
                 22.4 
                 skin intact; 
                 tissue 
                 absent, 
                 veins patent; 
               
               
                   
                   
                 hairless 
                 viable, 
                 squamous 
                 arteries 
               
               
                   
                   
                   
                 dermal 
                 metaplasia 
                 patent; 
               
               
                   
                   
                   
                 fibrosis 
                   
                 increased 
               
               
                   
                   
                   
                   
                   
                 intimal 
               
               
                   
                   
                   
                   
                   
                 fibroblasts 
               
               
                 B1/L 
                 22.4 
                 skin intact; 
                 tissue 
                 hair follicle 
                 veins patent, 
               
               
                   
                   
                 hairless 
                 viable, 
                 destruction 
                 arteries 
               
               
                   
                   
                   
                 dermal 
                   
                 patent, 
               
               
                   
                   
                   
                 fibrosis 
                   
                 intimal 
               
               
                   
                   
                   
                   
                   
                 fibrosis 
               
               
                 B2/R 
                 20.0 
                 skin shiny; 
                 tissue 
                 hair follicle 
                 possible 
               
               
                   
                   
                 hairless 
                 viable, 
                 destruction 
                 fibrous cord 
               
               
                   
                   
                   
                 dermal 
                   
                 in small vein; 
               
               
                   
                   
                   
                 fibrosis 
                   
                 arteries not 
               
               
                   
                   
                   
                   
                   
                 seen in these 
               
               
                   
                   
                   
                   
                   
                 sections 
               
               
                 B2/L 
                 20.0 
                 skin intact, 
                 tissue 
                 hair follicle 
                 veins patent; 
               
               
                   
                   
                 shiny and 
                 viable, 
                 destruction 
                 arteries 
               
               
                   
                   
                 hairless 
                 dermal 
                   
                 patent, 
               
               
                   
                   
                   
                 fibrosis 
                   
                 increased 
               
               
                   
                   
                   
                   
                   
                 intimal 
               
               
                   
                   
                   
                   
                   
                 fibroblasts, 
               
               
                   
                   
                   
                   
                   
                 mild edema 
               
               
                 B3/R 
                 24.1 
                 skin shiny 
                 tissue 
                 hair follicle 
                 veins patent; 
               
               
                   
                   
                 and 
                 viable, 
                 destruction; 
                 arteries not 
               
               
                   
                   
                 hairless, 
                 dermal 
                 squamous 
                 seen in these 
               
               
                   
                   
                 fine 
                 fibrosis, 
                 metaplasia 
                 sections 
               
               
                   
                   
                 granularity 
                 small area 
               
               
                   
                   
                   
                 of necrosis 
               
               
                   
                   
                   
                 on opposite 
               
               
                   
                   
                   
                 side of ear 
               
               
                   
                   
                   
                 (no cooling) 
               
               
                 B3/L 
                 23.6 
                 three 
                 subacute 
                 absence of hair 
                 vessels not 
               
               
                   
                   
                 indurated 
                 granulation 
                 follicles 
                 seen in these 
               
               
                   
                   
                 areas, 
                 tissue 
                   
                 sections 
               
               
                   
                   
                 crusting of 
               
               
                   
                   
                 epidermis, 
               
               
                   
                   
                 hairless 
               
               
                   
                   
                 single 
               
               
                   
                   
                 punched 
               
               
                   
                   
                 out area 
               
               
                 B4/R 
                 23.7 
                 skin shiny 
                 tissue 
                 absence of hair 
                 fibrous cord 
               
               
                   
                   
                 and 
                 viable, 
                 follicles 
                 in small vein; 
               
               
                   
                   
                 hairless; 
                 dermal 
                   
                 arteries not 
               
               
                   
                   
                 fine 
                 fibrosis 
                   
                 seen in these 
               
               
                   
                   
                 granularity 
                   
                   
                 sections 
               
               
                 B4/L 
                 23.6 
                 four 
                 tissue 
                 hair follicle 
                 congestion of 
               
               
                   
                   
                 indurated 
                 viable, 
                 destruction 
                 small caliber 
               
               
                   
                   
                 areas 
                 dermal 
                   
                 veins; intimal 
               
               
                   
                   
                   
                 fibrosis 
                   
                 fibrosis, 
               
               
                   
                   
                   
                   
                   
                 narrowing of 
               
               
                   
                   
                   
                   
                   
                 small arteries 
               
               
                 B5/R 
                 20.7 
                 skin intact; 
                 tissue 
                 absence of hair 
                 vein possibly 
               
               
                   
                   
                 hairless 
                 viable, 
                 follicles, 
                 narrowed; 
               
               
                   
                   
                   
                 dermal 
                 squamous 
                 arteries 
               
               
                   
                   
                   
                 fibrosis 
                 metaplasia 
                 patent, 
               
               
                   
                   
                   
                   
                   
                 intimal 
               
               
                   
                   
                   
                   
                   
                 fibrosis 
               
               
                 B5/L 
                 21.4 
                 skin intact, 
                 tissue 
                 absence of hair 
                 veins patent; 
               
               
                   
                   
                 hairless, 
                 viable, 
                 follicles 
                 arteries 
               
               
                   
                   
                 tiny hole 
                 dermal 
                   
                 patent, 
               
               
                   
                   
                   
                 fibrosis 
                   
                 intimal 
               
               
                   
                   
                   
                   
                   
                 fibrosis 
               
               
                 B6/R 
                 22.0 
                 skin intact, 
                 tissue 
                 absence of hair 
                 veins patent; 
               
               
                   
                   
                 hairless, 
                 viable, 
                 follicles, 
                 narrowed 
               
               
                   
                   
                 fine 
                 dermal 
                 squamous 
                 small artery 
               
               
                   
                   
                 granularity 
                 fibrosis 
                 metaplasia 
                 with intimal 
               
               
                   
                   
                   
                   
                   
                 fibrosis 
               
               
                 B6/L 
                 22.0 
                 punched 
                 dermal 
                 hair follicle 
                 arteries and 
               
               
                   
                   
                 out area 
                 fibrosis 
                 destruction, 
                 veins patent 
               
               
                   
                   
                   
                   
                 squamous 
               
               
                   
                   
                   
                   
                 metaplasia 
               
               
                 B7/R 
                 19.2 
                 skin intact, 
                 minimally 
                 focal area of hair 
                 veins patent; 
               
               
                   
                   
                 hairless 
                 affected 
                 follicle 
                 partial 
               
               
                   
                   
                   
                   
                 destruction 
                 thrombois of 
               
               
                   
                   
                   
                   
                   
                 small artery 
               
               
                 B7/L 
                 20.5 
                 skin intact, 
                 dermal 
                 focal paucity of 
                 veins patent; 
               
               
                   
                   
                 hairless 
                 fibrosis 
                 hair follicles, 
                 arteries 
               
               
                   
                   
                   
                   
                 squamous 
                 patent, 
               
               
                   
                   
                   
                   
                 metaplasia 
                 minimal 
               
               
                   
                   
                   
                   
                   
                 intimal 
               
               
                   
                   
                   
                   
                   
                 fibrosis 
               
               
                 B8/R 
                 19.0 
                 skin intact, 
                 focal areas 
                 focal destruction 
                 veins patent; 
               
               
                   
                   
                 hairless 
                 of dermal 
                 of hair follicles 
                 occlusion of 
               
               
                   
                   
                   
                 fibrosis 
                   
                 small artery 
               
               
                   
                   
                   
                   
                   
                 with fibrous 
               
               
                   
                   
                   
                   
                   
                 cord 
               
               
                 B8/L 
                 21.4 
                 skin intact, 
                 dermal 
                 destruction of 
                 veins patent; 
               
               
                   
                   
                 hairless 
                 fibrosis, 
                 hair follicles 
                 arteries not 
               
               
                   
                   
                   
                 small zone 
                   
                 seen in these 
               
               
                   
                   
                   
                 of nodular 
                   
                 sections 
               
               
                   
                   
                   
                 fibrosis 
               
               
                 B9/R 
                 23.0 
                 skin intact, 
                 small zone 
                 relative absence 
                 veins patent; 
               
               
                   
                   
                 hairless 
                 of dermal 
                 of hair follicles, 
                 arteries patent 
               
               
                   
                   
                   
                 fibrosis 
                 squamous 
               
               
                   
                   
                   
                   
                 metaplasia 
               
               
                 B9/L 
                 23.0 
                 skin intact, 
                 dermal 
                 destruction of 
                 veins patent; 
               
               
                   
                   
                 hairless 
                 fibrosis 
                 hair follicles, 
                 arteries patent 
               
               
                   
                   
                   
                   
                 squamous 
                 with mild 
               
               
                   
                   
                   
                   
                 metaplasia 
                 intimal 
               
               
                   
                   
                   
                   
                   
                 fibrosis 
               
               
                 B10/R 
                 24.6 
                 skin intact, 
                 mild 
                 destruction of 
                 veins patent; 
               
               
                   
                   
                 hairless 
                 fibrosis 
                 hair follicles 
                 arteries patent 
               
               
                   
                   
                   
                   
                   
                 with mild 
               
               
                   
                   
                   
                   
                   
                 intimal 
               
               
                   
                   
                   
                   
                   
                 fibrosis 
               
               
                 B10/L 
                 24.7 
                 skin intact, 
                 dermal 
                 destruction of 
                 veins patent; 
               
               
                   
                   
                 hairless 
                 fibrosis 
                 hair follicles 
                 partial 
               
               
                   
                   
                   
                   
                   
                 thrombosis of 
               
               
                   
                   
                   
                   
                   
                 small artery 
               
               
                 B11/R 
                 22.4 
                 skin intact, 
                 minimal 
                 minimal changes 
                 veins patent; 
               
               
                   
                   
                 hairless 
                 changes 
                   
                 arteries patent 
               
               
                 B11/L 
                 21.5 
                 skin intact, 
                 dermal 
                 destruction of 
                 veins patent; 
               
               
                   
                   
                 hairless 
                 fibrosis 
                 hair follicles, 
                 arteries patent 
               
               
                   
                   
                   
                   
                 squamous 
               
               
                   
                   
                   
                   
                 metaplasia 
               
               
                 B12/R 
                 20.6 
                 skin intact, 
                 dermal 
                 destruction of 
                 veins patent; 
               
               
                   
                   
                 hairless 
                 fibrosis 
                 hair follicles, 
                 arteries patent 
               
               
                   
                   
                   
                   
                 squamous 
               
               
                   
                   
                   
                   
                 metaplasia, 
               
               
                   
                   
                   
                   
                 remnants of 
               
               
                   
                   
                   
                   
                 follicles seen 
               
               
                 B12/L 
                 19.6 
                 skin intact, 
                 zone of 
                 destruction of 
                 veins patent; 
               
               
                   
                   
                 hairless 
                 dermal 
                 hair follicles 
                 arteries patent 
               
               
                   
                   
                   
                 fibrosis 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 ANIMAL STUDY PROTOCOL NP970603 
               
               
                 Applicator Tip: 0.250″ × 0.150″ 
               
             
          
           
               
                   
                   
                 Dose 
                   
                   
               
               
                 Rabbit 
                 Pigmented 
                 (Joules) 
                 Cooling 
                 Appearance of Skin 
               
               
                   
               
             
          
           
               
                 A1 
                 No 
                 5.3 
                 No 
                 skin intact - back and ear 
               
               
                   
                   
                   
                 Yes 
                 skin intact - back and ear 
               
               
                 A2 
                 Yes 
                 5.6 
                 No 
                 skin intact - back and ear 
               
               
                   
                   
                   
                 Yes 
                 skin intact - back; tiny dot 
               
               
                   
                   
                   
                   
                 left ear 
               
               
                 B1 
                 No 
                 9.4 
                 No 
                 back - minimal pallor 2/3 
               
               
                   
                   
                   
                   
                 sites; skin on ear intact 
               
               
                   
                   
                   
                 Yes 
                 skin intact - back and ears 
               
               
                 B2 
                 Yes 
                 9.3 
                 No 
                 skin on back obscured by hair 
               
               
                   
                   
                   
                   
                 growth; skin on ear intact 
               
               
                   
                   
                   
                 Yes 
                 skin on back obscured by hair 
               
               
                   
                   
                   
                   
                 growth; skin on ear intact 
               
               
                 C1 
                 No 
                 14.3 
                 No 
                 back - slight abrasion 2/3 
               
               
                   
                   
                   
                   
                 sites, small scab 3; skin on 
               
               
                   
                   
                   
                   
                 ear intact 
               
               
                   
                   
                   
                 Yes 
                 skin intact - back and ear 
               
               
                 C2 
                 Yes 
                 14.8 
                 No 
                 skin on back obscured by hair 
               
               
                   
                   
                   
                   
                 growth; skin on ear intact 
               
               
                   
                   
                   
                 Yes 
                 skin on back obscured by hair 
               
               
                   
                   
                   
                   
                 growth; skin on ear intact 
               
               
                 D1 
                 No 
                 18.4 
                 No 
                 back - scabs all 3 sites; 
               
               
                   
                   
                   
                   
                 ear - tiny scab 
               
               
                   
                   
                   
                 Yes 
                 back - slight pallor 2/3 
               
               
                   
                   
                   
                   
                 sites, minimal change at site 
               
               
                   
                   
                   
                   
                 3; ear - minimal change 
               
               
                 D2 
                 Yes 
                 18.6 
                 No 
                 back - small, raised areas at 
               
               
                   
                   
                   
                   
                 all 3 sites; ear - small 
               
               
                   
                   
                   
                   
                 raised area 
               
               
                   
                   
                   
                 Yes 
                 skin intact - back and ear 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 ANIMAL STUDY PROTOCOL NP970208 
               
               
                 No Cooling 
               
             
          
           
               
                   
                   
                 Histology- 
                 Histology- 
                 Histology- 
                 Clinical- 
                 Clinical- 
               
               
                 Rabbit 
                 Joules 
                 Tissue 
                 Vein 
                 Artery 
                 Tissue 
                 Vessels 
               
               
                   
               
               
                 D1/R 
                 10.4 
                 Viable, 
                 Patent 
                 Narrowed 
                 Intact 
                 Vein sl. 
               
               
                   
                   
                 dermal 
                   
                   
                   
                 Purple 
               
               
                   
                   
                 fibrosis 
               
               
                 D1/L 
                 10.4 
                 Viable, 
                 Partial 
                 &gt; occlusion 
                 Intact 
                 Narrowing 
               
               
                   
                   
                 dermal 
                 occlusion 
                 than vein 
               
               
                   
                   
                 edema 
               
               
                 D2/R 
                 10.4 
                 Viable, 
                 Sl. altered, 
                 Sl. altered, 
                 Small area 
                 Patent, sl. 
               
               
                   
                   
                 dermal 
                 but patent 
                 but patent 
                 of 
                 darkening 
               
               
                   
                   
                 fibrosis 
                   
                   
                 blanching 
               
               
                 D2/L 
                 10.4 
                 Viable, 
                 Patent 
                 Tiny, vessel 
                 Small area 
                 Patent, sl. 
               
               
                   
                   
                 dermal 
                   
                 collapsed 
                 of 
                 darkening 
               
               
                   
                   
                 fibrosis 
                   
                   
                 blanching 
               
               
                 C1/R 
                 12.0 
                 Viable, 
                 Micro- 
                 Patent 
                 Sl. 
                 Vein segmentally 
               
               
                   
                   
                 dermal 
                 thrombosis 
                   
                 blanching 
                 narrowed 
               
               
                   
                   
                 fibrosis 
               
               
                 C1/L 
                 12.0 
                 Viable, 
                 Ghosted, 
                 Narrowed 
                 Sl. 
                 Vein 
               
               
                   
                   
                 dermal 
                 without 
                 and focally 
                 blanching 
                 narrowed 
               
               
                   
                   
                 fibrosis 
                 endothelium, 
                 thrombosed 
                   
                 segmentally 
               
               
                   
                   
                   
                 but 
               
               
                   
                   
                   
                 patent. 
               
               
                   
                   
                   
                 Venular 
               
               
                   
                   
                   
                 congestion 
               
               
                 C2/R 
                 12.0 
                 Viable, 
                 Organization 
                 Not 
                 Mild 
                 Vein 
               
               
                   
                   
                 dermal 
                 with 
                 described 
                 blanching 
                 narrowed 
               
               
                   
                   
                 fibrosis 
                 evidence of 
                   
                   
                 segmentally 
               
               
                   
                   
                   
                 recanalization 
               
               
                 C2/L 
                 11.6 
                 Viable, 
                 Thrombosis 
                 Not 
                 Mild 
                 Vein 
               
               
                   
                   
                 dermal 
                 with 
                 described 
                 blanching 
                 narrowed 
               
               
                   
                   
                 fibrosis 
                 organization 
                   
                   
                 segmentally 
               
               
                 B1/R 
                 14.0 
                 Viable, 
                 Patent; not 
                 Not well 
                 Mild 
                 Vessel seen 
               
               
                   
                   
                 dermal 
                 well seen in 
                 visualized 
                 blanching 
               
               
                   
                   
                 fibrosis 
                 areas of 
               
               
                   
                   
                   
                 fibrosis 
               
               
                 B1/L 
                 13.7 
                 Viable, 
                 Ghosted, 
                 Patent 
                 Mild 
                 Vessel seen 
               
               
                   
                   
                 dermal 
                 necrotic, 
                   
                 blanching 
               
               
                   
                   
                 fibrosis 
                 contains 
               
               
                   
                   
                   
                 blood 
               
               
                 B2/R 
                 14.0 
                 Viable, 
                 Patent 
                 Lumina 
                 Mild 
                 Vessel seen 
               
               
                   
                   
                 dermal 
                   
                 narrowed by 
                 blanching 
               
               
                   
                   
                 fibrosis 
                   
                 intimal 
               
               
                   
                   
                   
                   
                 hyperplasia 
               
               
                 B2/L 
                 13.6 
                 Viable, 
                 Occlusion 
                 Not 
                 Minimal 
                 Vein 
               
               
                   
                   
                 dermal 
                 focally 
                 described 
                 changes 
                 narrowed 
               
               
                   
                   
                 fibrosis 
                   
                   
                   
                 segmentally 
               
               
                 A7/R 
                 16.0 
                 Viable, 
                 Focally 
                 Focally 
                 Minimal 
                 Mild 
               
               
                   
                   
                 dermal 
                 occluded 
                 occluded 
                 changes 
                 blushing 
               
               
                   
                   
                 fibrosis 
                   
                   
                   
                 around 
               
               
                   
                   
                   
                   
                   
                   
                 vein 
               
               
                 A7/L 
                 16.3 
                 Viable, 
                 Partial 
                 &gt; occlusion 
                 Mild 
                 Blushing 
               
               
                   
                   
                 dermal 
                 occlusion, 
                 than vein 
                 induration 
                 around 
               
               
                   
                   
                 fibrosis 
                 congestion 
                   
                   
                 vein 
               
               
                   
                   
                   
                 of venules 
               
               
                 A6/R 
                 15.5 
                 Viable, 
                 Patent 
                 Focal 
                 Minimal 
                 Veins seen 
               
               
                   
                   
                 dermal 
                   
                 occlusion 
                 changes 
               
               
                   
                   
                 fibrosis 
               
               
                 A6/L 
                 15.5 
                 Viable, 
                 Focally 
                 Focally 
                 Mild 
                 Vein segmentally 
               
               
                   
                   
                 dermal 
                 absent 
                 absent 
                 blanching 
                 narrowed 
               
               
                   
                   
                 fibrosis 
               
               
                 A5/R 
                 17.4 
                 Viable, 
                 Thrombosis 
                 Thrombosis 
                 Mild 
                 Vein 
               
               
                   
                   
                 dermal 
                 with 
                 with 
                 blanching 
                 narrowed 
               
               
                   
                   
                 fibrosis 
                 organization 
                 organization 
               
               
                 A5/L 
                 17.5 
                 Viable, 
                 Occlusion 
                 Not 
                 Mild to 
                 Vein 
               
               
                   
                   
                 scale crust 
                 (organzation) 
                 described 
                 moderate 
                 narrowed 
               
               
                   
                   
                 present, 
                   
                   
                 induration 
               
               
                   
                   
                 dermal 
               
               
                   
                   
                 fibrosis

Technology Classification (CPC): 0