U.S. patent application number 11/833466 was filed with the patent office on 2007-12-27 for apparatus and method for the treatment of infectious disease in keratinized tissue.
This patent application is currently assigned to WAVERX, INC.. Invention is credited to Peter A. Hoenig, B. Stuart Trembly.
Application Number | 20070299486 11/833466 |
Document ID | / |
Family ID | 35393959 |
Filed Date | 2007-12-27 |
United States Patent
Application |
20070299486 |
Kind Code |
A1 |
Hoenig; Peter A. ; et
al. |
December 27, 2007 |
APPARATUS AND METHOD FOR THE TREATMENT OF INFECTIOUS DISEASE IN
KERATINIZED TISSUE
Abstract
Apparatus and methods for the treatment of keratinized tissue
infected with a pathogen are provided. In certain examples,
electromagnetic energy, such as microwave energy, may be used in
the treatment process to reduce the amount of or eliminate the
pathogen from the keratinized tissue.
Inventors: |
Hoenig; Peter A.; (Sudbury,
MA) ; Trembly; B. Stuart; (Hanover, NH) |
Correspondence
Address: |
LOWRIE, LANDO & ANASTASI
RIVERFRONT OFFICE
ONE MAIN STREET, ELEVENTH FLOOR
CAMBRIDGE
MA
02142
US
|
Assignee: |
WAVERX, INC.
300 Bear Hill Road
Waltham
MA
02451
|
Family ID: |
35393959 |
Appl. No.: |
11/833466 |
Filed: |
August 3, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10990283 |
Nov 16, 2004 |
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11833466 |
Aug 3, 2007 |
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10845761 |
May 14, 2004 |
7292893 |
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10990283 |
Nov 16, 2004 |
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10845010 |
May 13, 2004 |
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10990283 |
Nov 16, 2004 |
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60471230 |
May 16, 2003 |
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60471230 |
May 16, 2003 |
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Current U.S.
Class: |
607/88 |
Current CPC
Class: |
A61P 17/00 20180101;
A61N 5/04 20130101; A61P 31/04 20180101; A61B 18/18 20130101; A61P
43/00 20180101; A61P 31/10 20180101; A61P 33/00 20180101 |
Class at
Publication: |
607/088 |
International
Class: |
A61B 18/18 20060101
A61B018/18 |
Claims
1-48. (canceled)
49. A method for the prevention or treatment of a skin or nail
infection comprising applying electromagnetic energy to skin or a
nail to reduce or prevent growth of a microbe causing the skin or
nail infection.
50. The method of claim 49, wherein the microbe is selected from
the group consisting of bacteria and fungi.
51. The method of claim 49, wherein the electromagnetic energy has
a wavelength greater than 400 nm.
52. The method of claim 49, further comprising applying a chemical
to the skin or nail.
53. The method of claim 49, wherein application of the
electromagnetic energy results in heating of the skin or nail.
54. A method for the prevention or treatment of a skin or nail
infection comprising drying skin or nail by application of
electromagnetic energy to reduce or prevent growth of a microbe
causing the skin or nail infection.
55. The method of claim 54, wherein the microbe is selected from
the group consisting of bacteria and fungi.
56. The method of claim 54, wherein the electromagnetic energy has
a wavelength greater than 400 nm.
57. The method of claim 54, further comprising applying a chemical
to the skin or nail.
58. The method of claim 54, wherein application of the
electromagnetic energy results in heating of the skin or nail.
59. A method for the prevention or treatment of a skin or nail
infection comprising altering skin or a nail by application of
electromagnetic energy to reduce or prevent growth of a microbe
causing the skin or nail infection.
60. The method of claim 59, wherein the microbe is selected from
the group consisting of bacteria and fungi.
61. The method of claim 59, wherein the electromagnetic energy has
a wavelength greater than 400 nm.
62. The method of claim 59, further comprising applying a chemical
to the skin or nail.
63. The method of claim 59, wherein application of the
electromagnetic energy results in heating of the skin or nail.
64. A method for the prevention or treatment of a skin or nail
infection comprising heating skin or a nail using electromagnetic
energy to reduce or prevent growth of a microbe causing the skin or
nail infection.
65. The method of claim 64, wherein the microbe is selected from
the group consisting of bacteria and fungi.
66. The method of claim 64, wherein the electromagnetic energy has
a wavelength greater than 400 nm.
67. The method of claim 64, further comprising applying a chemical
to the skin or nail.
68. The method of claim 64, wherein application of the
electromagnetic energy results in heating of the nail.
69. A method for the prevention or treatment of a skin or nail
infection comprising applying electromagnetic energy to skin or a
nail.
70. The method of claim 69, wherein the infection is caused by a
microbe selected from the group consisting of bacteria and
fungi.
71. The method of claim 69, wherein the electromagnetic energy has
a wavelength greater than 400 nm.
72. The method of claim 69, further comprising applying a chemical
to the skin or nail.
73. The method of claim 69, wherein application of the
electromagnetic energy results in heating of the skin or nail.
Description
PRIORITY APPLICATIONS
[0001] This application is a continuation-in-part of U.S.
application Ser. No. 10/845,761 filed on May 14, 2004, and is a
continuation-in-part of U.S. application Ser. No. 10/845,010, filed
on May 13, 2004, each of which claims priority to U.S. provisional
application No. 60/471,230, filed May 16, 2003, and the entire
disclosure of each of which is hereby incorporated herein by
reference for all purposes.
FIELD OF THE TECHNOLOGY
[0002] Certain examples relate to the field of medicine,
particularly the treatment of infectious diseases. More
specifically, certain examples relate to treatment of keratinized
tissue infected with a pathogen.
BACKGROUND
[0003] Infectious diseases of keratinized tissues are a difficult
problem for medical treatment. Keratins are a class of
scleroprotein that serve as the major protein components of hair,
wool, nails, the organic matrix of the enamel of teeth, horns,
hoofs, and the quills of feathers. These proteins generally contain
large quantities of the sulfur-containing amino acids, particularly
cysteine. Keratins provide a tough, fibrous matrix for the tissues
in which they are found. These proteins are characterized as being
extremely water insoluble. Because keratins contain few polar amino
acids, there is little or no moisture content in the tissues they
form. This presents difficulties for the medical treatment of
infected keratinized tissues because medicaments are not easily
delivered into this type of tissue.
[0004] By way of example, onychomycosis is clinically defined as an
infection of the nail plate caused by any fungus, including
dermatophytes, non-dermatophytes and yeasts. This disease accounts
for up to 50% of all nail disease and affects 2% to 18% or more of
the world's population. There are four clinical types of
onychomycosis: (1) distal subungual onychomycosis, (2) proximal
subungual onychomycosis, (3) white superficial onychomycosis, and
(4) candidal onychomycosis. The target sites for the treatment of
onychomycosis reside in the nail plate, nail bed and nail matrix.
Characteristically, infected nails coexist with normal-appearing
nails.
[0005] The most common form of treatment for onychomycosis is the
oral administration of terbinafine (Novartis International AG,
Basel, Switzerland) or itraconazole (Janssen Pharmaceutical
Products, L.P., Titusville, N.J.). These drugs dominate the current
market for the treatment of onychomycosis.
[0006] However, there is a need for the development of other forms
of treatment. Hay, R J (British Journal of Dermatology
145(S60):3-11, 2001) teaches that these drugs have a clinical
failure rate of approximately 25-40%. In addition, both drugs carry
label precautions about potential organ toxicity and interactions
with common prescription and non-prescription drugs. The Physicians
Desk Reference (2003) teaches that rare cases of hepatic failure
(including death) have been reported following oral treatment with
Terbinafine and Itraconazole. Rare cases of serious cardiovascular
events, including death, also have been associated with
Itraconazole (Id.). Treatment times are long (several months) and
costly. Hay, 2001 teaches that 5-10% of the nail surface still
remains abnormal even with a full cure (defined by negative
re-culturing). Mandell et al (Principles and Practice of Infectious
Diseases, Fifth edition, Chapter 257 by Hay R. J., p. 2765, 2000)
teach that the relapse rate is 40%. Treatment options using topical
agents are usually of little benefit, and chemical or surgical
removal of the infected nail(s) are not adequate therapies, since
these treatments can lead to nail bed shrinkage and dorsal
dislocation of the nail bed.
[0007] Thus, there remains a need in the art to develop improved
methods for the treatment of keratinized tissue infected with a
pathogen.
SUMMARY
[0008] Certain aspects and examples described herein provide an
apparatus and methods for the medical treatment of keratinized
tissue infected with a pathogen. The methods according to the
invention enable an efficacious, localized, speedy, and
non-invasive medical treatment with little or no side effects.
[0009] In a first aspect, a method of treating keratinized tissue
infected with a pathogen is provided. In certain examples, the
method comprises exposing the keratinized tissue to an effective
amount of electromagnetic energy having a wavelength greater than
about 0.0004 mm, e.g., microwave energy or millimeter wave energy,
sufficient to kill the pathogen infecting the keratinized tissue.
In a particularly preferred embodiment, the keratinized tissue is
human keratinized tissue, e.g., nail tissue, infected with a
pathogen. In one specific embodiment, the nail tissue is human nail
tissue. In certain embodiments, the electromagnetic energy is
microwave energy, e.g., microwaves having frequencies of about 15
MHz to about 30 GHz, or millimeter wave energy.
[0010] In a second aspect, an applicator for the delivery of
electromagnetic energy to keratinized tissue infected with a
pathogen is disclosed. In certain examples, the applicator
comprises one or more conductors configured to deliver energy to
the anatomical site. In certain embodiments, a pair of conductors
has a coaxial cable geometry. In one embodiment, the outer
conductor of a coaxial cable has been removed for part of its
circumference to expose tissue in proximity to the applicator to
electromagnetic energy. In another embodiment, the inner conductor
of the coaxial cable geometry is connected to a disk at its
terminal end to form an end-loaded monopole that transfers energy
efficiently to tissue in proximity to the applicator. In some
embodiments, the applicator further comprises a cable, e.g.,
coaxial cable, and an electromagnetic energy source.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] Certain illustrative examples and embodiments are described
below with reference to the accompanying figure in which:
[0012] FIG. 1 is an exploded view of one example of an applicator,
in accordance with certain examples of aspects of the
invention;
[0013] FIG. 2 is a perspective view of the assembled applicator of
FIG. 1, in accordance with certain examples of aspects of the
invention;
[0014] FIG. 3 is a perspective view of an alternative embodiment of
the applicator of FIG. 1, in accordance with certain examples of
aspects of the invention;
[0015] FIG. 4 is a schematic view of an embodiment comprising an
applicator, cable, and electromagnetic energy source, in accordance
with certain examples of aspects of the invention; and
[0016] FIG. 5 is a schematic view of an embodiment that includes a
radiometry sensor to measure temperature in treated tissue, in
accordance with certain examples of aspects of the invention.
[0017] It will be recognized by the person of ordinary skill in the
art, given the benefit of this disclosure, that the figures are not
necessarily to scale and that certain features of the figures may
have been enlarged, distorted or emphasized to facilitate a better
understanding of the illustrative aspects and examples described in
more detail below.
DETAILED DESCRIPTION
[0018] Certain examples disclosed herein provide significant
advances in the treatment of keratinized tissues not heretofore
recognized by practitioners. For example, it was a surprising
discovery that the high water content of fungi, bacteria, and
parasites relative to keratinized tissue renders the fungi,
bacteria, and parasites sensitive to electromagnetic energy,
particularly microwave energy. Such application of energy can
result in "superheating" and explosion of the bacterial, fungal, or
parasitic cells. Certain examples of the methods described herein
do not rely on an electrical conduction current flowing through
tissue between two or more metallic conductors in direct contact
with tissue (resistive heating). Instead, examples of the methods
described herein use an electric field of electromagnetic energy,
e.g., microwave energy, to penetrate into tissue. The
rapidly-oscillating field in tissue causes polar molecules, such as
water in fungal, bacterial, or parasite cells, to rotate in place,
thereby producing local frictional heating. Without wishing to be
bound by any particular scientific theory or this example, the
pathogens are destroyed when the heating process has sufficient
magnitude and duration. The penetrating electric field permits
transmission of energy through tissue of low water content, which
can effectively be an electrical insulator. In this way, a
penetrating electric field of electromagnetic energy applied, for
example, at the surface of the nail plate, which has low water
content, can sterilize a pathogen below the surface of the nail
plate. In contrast, a conduction current, e.g., a radio frequency
current, applied to the nail plate would have little or no heating
effect on a pathogen below the nail plate.
[0019] Advantages of the use of electromagnetic energy, e.g.,
microwave energy, are the speed, efficiency, localized effect,
ability to intervene without surgery, rapid patient recovery, and
absence of toxic, hazardous or polluting residues. Further
advantages are the stimulation of the immune system to assist in
the destruction of pathogens and the stimulation of blood perfusion
in nearby tissues to enhance the delivery of agents of the immune
system to, or near, the site of pathogen infection.
[0020] Microwave irradiation is an efficient means of
sterilization. For example, U.S. Pat. No. 4,092,800 teaches the
sterilization of soil with microwave irradiation. Baker, K F et al
(Phytopathology 59(2):193-197, 1969) teach the sterilization of
garbage with microwave irradiation. Lagunas-Solar M. C. et al (Food
and Agriculture Applications of Pulsed Power Technologies as
Alternatives to Methyl Bromide, 1994 Annual International Research
Conference on Methyl Bromide Alternatives and Emissions Reductions.
Nov. 13-16, 1994) teach the sterilization of food with microwave
irradiation. Kissimme et al. (Yonaga Acta Medica 41:83-88, 1998)
teach the sterilization of towels with microwave irradiation.
[0021] Lantis, J C (Surg. Endosc. 12:170-176, 1998) teach that
microwave energy has been used in medicine for many clinical
applications since the development of reliable magnetrons in the
1960's. For example, microwave energy therapy has been used for the
treatment of malignant and benign neoplasia. It is being explored
as a modality to improve the healing of infected wounds. It is
being studied as a therapy for the treatment of duodenal ulcer
disease, benign prostatic hypertrophy and for heart disease.
Microwave energy is also being used to warm dialysate fluid for
continuous ambulatory peritoneal dialysis and as a way to sterilize
docking connectors.
[0022] Unlike resistance that organisms may develop to
therapeutics, fungi, bacteria, or parasites are unlikely to develop
resistance to the methods of treatment provided herein. There have
been no reports of fungi, bacteria, or parasites developing
resistance to, for example, microwave energy. In fact, microwave
heating has been used to treat infected wounds. Korpan, et
al.(Korpan N N, Resch K L, & Kokoschinegg P, "Continuous
microwave enhances the heating process of septic and aseptic wounds
in rabbits" Journal of Surgical Research 57 (6): 667-671, December
1994.) teach that microwave irradiation at an intensity of 1
mW/cm.sup.2 at a frequency of 37 GHz stimulates the immune system
and enhances the healing process of wounds.
[0023] Deacon, J W ("Introduction to Modern Mycology", 2nd Edition.
Blackwell Scientific Publications. 1984) teaches that most fungi
have a tough, protective wall that surrounds the protoplasm within
the fungal cell. Several fungi have pigments in this wall that
protects the cell interior against damage from ultra-violet (UV)
light. Microwave energy can penetrate the protective wall to
overheat the high-water-content protoplasm within and thus kill the
fungal cell. The pigments that block UV light have no effect on
microwave energy. Microwave energy is a safer treatment modality
for infection by pathogen than UV light, because it does not pose
the known cancer risk that UV light does for skin tissue.
[0024] Referring now to FIG. 1, an exploded view of an embodiment
of an applicator is shown. Outer conductor 10 may be made of an
electrical conductor, such as aluminum, copper, or brass; in this
embodiment, it has the shape of a cylindrical shell with a portion
of the circumference cut away. Other suitable shapes, however, will
be readily selected by the person of ordinary skill in the art,
given the benefit of this disclosure. In the example shown in FIG.
1, conductor 10 may have an opening 11 that has a length and
breadth about equal to the length and breadth of the anatomical
site to be treated. Conductor 10 may slide onto internal spacer 12,
which has the shape of a cylinder; it may be made of an insulating
material, such as nylon, PTFE or other suitable insulating
materials. Conductor 10 may be secured to spacer 12 by means of a
set screw 13. Inner conductor 14 may have the shape of a rod, and
it may slide into spacer 12; conductor 14 is typically made of an
electrical conductor, such as aluminum, copper, gold, brass or
other suitable conductive materials that will be readily selected
by the person of ordinary skill in the art, given the benefit of
this disclosure. Conductor 14 may be fixed to spacer 12 by means of
a set screw 15, which can be made of plastic, or other suitable
material, to prevent a short circuit between conductors 10 and 14.
Conductor 14 can pass through hole 17 in cap spacer 16, and then
may continue to make electrical contact with end cap 18. Cap spacer
16 and end cap 18 generally have the shape of a section of a disk.
Cap spacer 16 may be made of an electrical insulator, such as
delrin or PTFE. End cap 18 may be made of an electrical conductor,
such as aluminum, copper, gold, brass, etc. Conductor 14 may be
fixed to end cap 18 by a means that maintains electrical contact,
such as brazing, soldering, or a threaded connector, such as a
metal screw (not shown).
[0025] Referring now to FIG. 2, perspective view of the assembled
applicator of FIG. 1 is shown. Threading 19 permits the applicator
to be connected to a coaxial cable through a connector, such as an
N-type connector, or other suitable connector which will be readily
selected by the person of ordinary skill in the art, given the
benefit of this disclosure. The applicator can be coupled to a
source of electromagnetic energy that provides electromagnetic
signals, such as in the microwave frequency bands, through the
connector and other signal carrying device, such as cables,
waveguides, and the like. Inner conductor 14 has a suitable
diameter to permit it to connect to the inner conductor of a
connector, such as a standard N-type connector; alternatively, the
conductor 14 has this diameter only near the end that mates with a
standard connector, and conductor 14 may taper or may expand so as
to have a different diameter for the rest of its length. In some
configurations, the end spacer 16 and end cap 18 may extend to some
degree into as plane defined by opening 11, but in the example
shown in FIG. 2, end spacer 16 and end cap 18 do not extend into
the plane defined by opening 11. This feature permits the tissue to
be treated to be placed in juxtaposition with opening 11 without
interference. For example, to treat a toe notionally present in
FIG. 2 with its nail oriented upwards, the applicator shown in FIG.
2 would be inverted and applied to bring the nail of the toe into
juxtaposition with opening 11.
[0026] For most of its length, conductor 14 may have a diameter
that gives an advantageous value of characteristic impedance in
conjunction with the value of the inner diameter of outer conductor
10. As will be recognized by those skilled in the art, given the
benefit of this disclosure, the reflection coefficient of the
applicator can be reduced when its characteristic impedance is
substantially equal to that of a standard coaxial cable connected
to it. Again, those skilled in the art will understand, given the
benefit of this disclosure, that the end cap 18 may serve to reduce
the reflection coefficient of the applicator through capacitive
end-loading and thus increase power transfer into tissue placed in
proximity to opening 11. U.S. Pat. No. 5,708,445 issued Jan. 13,
1998 to Moller, et al. teaches that a capacitive plate ("top hat")
placed near the end of a length of wire reduces the frequency at
which the antenna transmits power most efficiently, or equivalently
that the top hat antenna functions like a simple wire antenna of
greater length. Moller, et al. do not teach the use of a capacitive
plate for reducing the reflection coefficient of a coaxial cable
with a portion of the circumference removed, as in FIG. 2. The end
cap 18 in FIG. 2 reduces the reflection coefficient of the
applicator while permitting the applicator to have a truncated
length, suitably matched, for example, to the nail of a toe. It is
to be appreciated that other devices and techniques for matching an
arbitrary load to a source impedance, can be used, and will be
readily apparent to the person of ordinary skill in the art, given
the benefit of this disclosure.
[0027] FIG. 3 shows an alternative embodiment, in which the
capacitance of the folded end cap 20 is increased by folding it to
lie parallel, or substantially parallel, with the long axis of the
outer conductor 10. Those skilled in the art will appreciate, given
the benefit of this disclosure, that greater capacitance of the end
cap may decrease the reflection coefficient of the applicator and
that increased capacitance is accomplished in the applicator in
FIG. 3 without increasing the diameter of the end cap 18 shown in
FIG. 2
[0028] In accordance with other embodiments, the pathogen may be a
fungus, e.g., the illustrative fungi listed in Bold, H C et al.,
Morphology of Plants and Fungi, 5.sup.th Ed. (1987). In some
embodiments the pathogen may be a bacterium. In some embodiments
the pathogen may be a unicellular parasite (protozoa); in some
embodiments the pathogen may be a multicellular parasite
(helminthes, arthropods). Additional pathogens that cause or
contribute to infections of the skin, keratinized tissues, etc.
will be readily recognized by the person of ordinary skill in the
art, given the benefit of this disclosure.
[0029] In some embodiments, the infected keratinized tissue is nail
tissue, the corneum stratum of epidermis, hair tissue, hoof tissue,
horny tissue, or teeth. In certain embodiments, the infected
keratinized tissue is from a mammal, such as for example, human,
bovine, or equine tissue. In a particularly preferred embodiment,
the keratinized tissue is human keratinized tissue infected with a
pathogen. In one specific embodiment, the nail tissue is human nail
tissue.
[0030] In some embodiments the electromagnetic energy is microwave
energy, infrared energy, or millimeter waves. The microwave
frequency band is only loosely defined in engineering practice.
However unless otherwise clear from the context, it is defined
herein to refer to the frequency range from about 15 MHz to about
30 GHz, more particularly about 20 MHz to about 30 GHz, and even
more particularly, from about 25 MHz to about 30 GHz. However,
other frequencies outside this range are not excluded. As used
herein, millimeter waves are defined as having a frequency of about
30 GHz to about 3,000 GHz; the corresponding wavelengths (in
vacuum) are about 10 millimeters to about 0.1 millimeters,
respectively. As used herein, infrared energy is defined as energy
having a wavelength (in vacuum) of about 0.1 millimeters up to
about 0.7 microns, where it is customary to define energy in this
part of the electromagnetic spectrum in terms of wavelength, as
opposed to frequency.
[0031] In some embodiments, the applicator further comprises a
cable, e.g., a coaxial cable. In some embodiments, the applicator
further comprises a cable, e.g., coaxial cable, and an
electromagnetic energy source. In certain embodiments, the
electromagnetic energy source is selected from the group consisting
of a magnetron and a solid state oscillator. In some embodiments,
the electromagnetic energy source is sufficiently light and compact
to make it portable by hand. FIG. 4 shows applicator 30 connected
to cable 32, and cable 32 is connected to electromagnetic energy
source 34.
[0032] Some embodiments of the methods disclosed herein include
applying electromagnetic energy to keratinized tissue when clinical
symptoms are not present, e.g., as prophylactic treatment to
prevent infection of the keratinized tissue. If pathogens are
present, they will be sterilized by the treatment, even though
clinical symptoms have not developed. This embodiment of the method
of the invention serves to prevent the development of clinical
symptoms. The exact treatment frequency may vary depending on
numerous factors including, for example, predisposition to
infection based on family history, past history of infection, past
history of related infection, such as athlete's foot, increased
risk for infection, etc. In certain examples, to prevent infection
a treatment frequency is about once monthly, biweekly, once weekly
or two or three times per week, daily, etc. Additional suitable
treatment frequencies will be readily selected by the person of
ordinary skill in the art, given the benefit of this
disclosure.
[0033] Some embodiments of the method and apparatus include
stimulation of blood perfusion in tissue in the vicinity of the
infected tissue before a treatment with electromagnetic energy by
heating the skin surface with a warm fluid or other means. When
heating with electromagnetic energy, it is important to limit the
thermal dose received by uninfected tissue. In the case of heating
a nail, for example, care should be taken to avoid the derma of the
nail bed. Moritz & Henriques (Moritz A R and Henriques F C,
"Studies of thermal injury II: The relative importance of time and
surface temperature in the causation of cutaneous burns," The
American Journal of Pathology 23: 695-720, 1947) teach that
discomfort in human subjects occurs when skin temperature is
elevated to the range 47.5-48.5.degree. C. They also teach that
hyperemia without loss of epidermis occurs in human subjects whose
skin is exposed to 51.degree. C. for 2 minutes and 49.degree. C.
for 6 minutes; these reactions were defined as below the threshold
of thermal injury. The characteristic high blood perfusion of skin
tissue affords protection from thermal damage because the
continuous transport of blood at body temperature into the
capillary bed is an effective cooling mechanism. Furthermore,
Guyton and Hall, (Guyton A C and Hall J E, Textbook of Medical
Physiology pg. 919 (Philadelphia: 1996)) teach that perfusion of
skin is a function of temperature, increasing as temperature
increases. Song (Song C W, "Role of blood flow in hyperthermia,"
In: M Urano & E B Douple, eds., Hyperthermia and Oncology, Vol.
3: Interstitial Hyperthermia--Physics, Biology, and Clinical
Aspects. (Utrecht, the Netherlands: VSP BV, 1992)) teaches that
blood perfusion in tissue increases significantly, by as much as a
factor of four, with increasing tissue temperature; the same source
teaches that the greatest increase in perfusion may occur as much
as 30 minutes after the increase in tissue temperature.
[0034] In some embodiments, the methods disclosed herein can
include the step of inducing reactive hyperemia, wherein blood
perfusion after a period of enforced low perfusion increases to a
level higher than before the intervention, as taught by Guyton and
Hall. In practice, pressure could be applied to the toe to restrict
blood perfusion before the heat treatment; alternatively, the limb
could be elevated to reduce perfusion. After the release of
pressure or removal of elevation, the resulting increased perfusion
would provide enhanced cooling during the period of microwave
heating.
[0035] In some embodiments of the methods and apparatus disclosed
herein, microwave radiometry is used to measure the temperature of
tissue heated by electromagnetic energy below the surface of the
body. Ludeke and Kohler (Ludeke K. M. and Kohler J., Journal of
Microwave Power 18(3):277-283, 1983) teach that the natural
electromagnetic emissions of an object can be correlated with its
temperature and that these emissions may come from below the
surface of the object. This method could be used to measure the
temperature, for example, below the surface of a nail plate being
treated for infection by a fungal pathogen. This temperature signal
could form part of a feedback loop that could be used to prevent
undesired temperature elevation in the nail bed below the nail
plate. FIG. 5 shows radiometry receiver 36 inside applicator 30
connected to radiometry instrument 38. Radiometry receiver 36 in
combination with radiometry instrument 38 measures the temperature
in tissue 42. Radiometry instrument 38 may be connected to
electronic controller 40 and to electromagnetic energy source 34,
which in turn may be connected to cable 32 and applicator 30. These
connected elements form a feedback loop that controls
electromagnetic power in response to the temperature measured in
tissue 42.
[0036] In certain embodiments, the method and apparatus includes
placing an electrically-conducting mask over non-infected tissues
to substantially block the absorption of microwave energy. Ramo, et
al (Fields and Waves in Communication Electronics, 3.sup.rd Ed.
(New York, 1994) teach that a metallic surface approximates a
perfect conductor and consequently reflects electric fields from
its surface. U.S. Pat. No. 5,248,478 issued Sep. 28, 1993 to
Kutner, et al. teaches the use of a metallic shield or reflector to
prevent microwave heating of contact lenses in a container used for
disinfection. U.S. Pat. No. 6,696,677 issued Feb. 24, 2004 to
Kennedy teaches the use of a microwave shield made of metallic foil
to divert microwave radiation from certain foods, i.e., reflect the
energy, during the process of microwave cooking. In some
embodiments, the method and apparatus includes placing metallic
paint over non-infected tissues to substantially block the
absorption of microwave energy. Neither Kutner nor Kennedy teaches
the use of an electrically-conducting mask or reflector to
substantially block absorption of electromagnetic energy in
selected living tissues.
[0037] In certain examples, one or more materials that can absorb
or dissipate microwave radiation may be disposed on non-infected
tissues to prevent those tissues from being exposed to microwave
energy or to reduce the amount of microwave energy that reaches
those tissues. While absorption of the microwave energy by the
materials may result in some localized heating, such heating
generally does not result in any adverse side effects. Suitable
microwave energy absorbing materials include, but are not limited
to, dyes, foams, tapes with or without metallization, and the like.
Additional suitable microwave absorbing materials will be readily
selected by the person of ordinary skill in the art, given the
benefit of this disclosure.
[0038] In certain embodiments, examples of the method and apparatus
include the application of electromagnetic energy in conjunction
with parenteral, oral, topical, or other suitable administration of
one or more other drugs or therapeutics such as the antifungal
agents: fluconazole, itraconazole, and terbinafine. Dahl (Dahl, O.,
"Interaction of heat and drugs in vitro and in vivo,"
Thermoradiotherapy and Thermochemotherapy, Vol 1: Biology,
Physiology, and Physics, Seegenschmiedt M H, Fessenden P, and
Vernon C C, Eds. (Berlin: Springer-Verlag, 1995)) teaches that
cytotoxic drugs used for cancer therapy can be potentiated by heat
treatments. In certain embodiments, the method and apparatus
include the administration of one or more suitable drugs or
therapeutics in conjunction with electromagnetic energy whose
source is sufficiently light and compact to make it portable by
hand. It will be recognized by the person of ordinary skill in the
art, given the benefit of this disclosure, that use of the methods
disclosed herein may allow for lower dosages of existing
therapeutics, such that any side effects may be minimized. For
example, an effective dose of terbinafine, when administered in
conjunction with the methods disclosed herein, may be, for example,
25% lower, 50% lower, or 75% lower (or any range in between) than
the effective amount of terbinafine required with terbinafine
treatment alone. In some examples, the treatment methods disclosed
herein assist the immune system in eradicating any remaining
infection, which allows lower amounts of therapeutics, or no
therapeutics at all, to be used to eradicate the infection.
[0039] In some embodiments, a frequency of electromagnetic energy
is chosen to reduce the penetration depth to a desired or selected
value. For example, tissue underlying the nail plate could be
heated to a toxic temperature in spite of the cooling effect of
blood perfusion by energy that penetrated significantly beyond the
nail plate. U.S. Pat. No. 6,635,055 issued Oct. 21, 2003 to Cronin
teaches that microwave radiation at 8-12 GHz is almost completely
absorbed in a layer of tissue about 5 mm thick. At lower
frequencies, the depth of penetration is characteristically
greater. Ramo et al. teach, for example, that the depth of
penetration of a plane wave of 915 MHz radiation in soft tissue
other than fat is approximately 20 millimeters. Thus, a plane wave
of microwave energy of this frequency may be useful for the
treatment of keratinized tissue that is thick, e.g. a hoof.
Accordingly, to restrict penetration, a higher frequency could be
used, as described above.
[0040] In some embodiments, the applicator comprises more than one
metallic conductor separated by a distance much less than half a
wavelength. As used herein, the term "much less than half" refers
to less than or equal to about 0.25 times a wavelength. By way of
non-limiting example, microwave energy can be coupled into
keratinized tissue by bringing metallic conductors into proximity
or contact with it. The depth of penetration of microwave energy
into tissue can be controlled by the spacing of the metallic
conductors in contact with the tissue. In this way, the depth of
penetration can be set to a value suited to the anatomical site of
treatment. Swicord and Davis (IEEE Trans. On Microwave Theory And
Techniques 29(11):1202-1208, 1981) teach that closely-spaced
metallic conductors in proximity to tissue produce a fringing
pattern of microwave fields that penetrate a lesser distance, the
total distance being determined by the spacing of metallic
conductors. As used herein, "closely-spaced" means much less than a
half-wavelength, e.g., much less than a quarter-wavelength. The
teachings of Swicord and Davishave been applied successfully, for
example, to heat the cornea of the eye without over-heating the
endothelial cells on the posterior surface of the cornea. Trembly
and Keates (Trembly B S and Keates R H, IEEE Transactions on
Biomedical Engineering 38(1):85-91, 1991) teach that in this case
the penetration of microwave energy of 915 MHz was restricted to a
few tenths of a millimeter to suit the anatomy. The same technique
would be appropriate for heating a thin layer of keratinized
tissue, such as a nail, across its narrow dimension from a position
in contact or proximity to its surface. As used herein, the term
"metallic conductor" refers to material or an object that permits
an electric current to flow easily. It is to be appreciated that in
certain embodiments, the metallic conductors can be made of copper,
brass, silver, gold, aluminum, stainless steel or any other
material that one of skill in the art, having the benefit of this
disclosure, would use.
[0041] In certain embodiments, the applicator has from about 2 to
about 40 metallic conductors. In some embodiments, the metallic
conductors of the applicator have a length from about 5 to about 40
mm and a width of about 0.25 mm to about 2 mm. In some embodiments,
the applicator has an interdigitated geometry having a spacing
between metallic conductors of about 0.25 mm to about 2 mm. In some
embodiments, the applicator has 2 conductors having a spacing of
about 0.25 mm to 2 mm which meander in the plane defined by the
surface of the tissue to be heated. In some embodiments, the
applicator has a single conductor having the shape of a horn of
diameter about 2 mm to 40 mm. By way of example, suitable metallic
conductors can be obtained from, e.g., Small Parts, Inc. (Miami
Lakes, Fla.). The term "about" as used herein refers to a variance
of 20% from the identified value, for the lower and higher values.
For example, if a numerical range is given as from about 10 to
about 20, it will be understood that the lower value may range from
8 to 12 and the higher value may range from 16 to 24. By way of
non-limiting example, a practical example of closely-spaced
metallic conductors would be an interdigitated geometry designed to
cover the surface of a nail.
[0042] In certain embodiments, the applicator further comprises an
adhesive to permit adherence to a surface. Suitable adhesives will
be readily selected by the person of ordinary skill in the art,
given the benefit of this disclosure. In some embodiments, the
metallic conductors and substrate are sufficiently thin to permit
trimming to an arbitrary shape in a plane with an instrument such
as shears. In some embodiments, the metallic conductors and
substrate are sufficiently flexible to permit conformance to a
curved anatomical site. In certain examples, the applicator may
have double-sided adhesive tape to provide adherence to a surface.
The double-sided adhesive tape can be removed easily from the
applicator and replaced with new double-sided adhesive tape to
facilitate use of the same applicator with different patients
without having to sterilize the applicator.
[0043] In some embodiments, one or more helical coil antennas are
used to heat the tissue. Ryan, T P "Comparison of six microwave
antenna for hyperthermia treatment of cancer: SAR results for
single antenna and array," International Journal of Radiation
Oncology, Biology, and Physics 21:403-413, 1991) teaches that the
helical coil applicator has a rapid decrease in energy deposition
with distance from the antenna, as compared to a conventional
dipole. U.S. Pat. No. 4,967,765 issued Nov. 6, 1990 to Turner, et
al. teaches the use of a helical coil applicator to heat the
prostate from a position within the urethra. U.S. Pat. No.
4,825,880 issued May 2, 1989 to Stauffer et al. teaches the use of
a helical coil applicator for heating cancerous tissue from within
the body. None of the citations listed immediately above teaches
the use of a helical coil antenna to heat keratinized tissue
infected with a pathogen.
[0044] In some embodiments, one or more conductors have a spiral
geometry. In some embodiments, one or more conductors have
meandering geometry. In some embodiments, pairs of conductors have
dipole geometry. In some embodiments, each conductor of the
applicator has geometry chosen from the group comprising waveguides
and horns. In some embodiments, the radiation device comprises a
horn antenna, a waveguide antenna, or any other antenna or
radiating device that one of skill in the art, having the benefit
of this disclosure, would use.
[0045] In an alternative embodiment, the metallic conductors or
radiating device may form a partially or completely closed chamber
that surrounds the tissue, e.g., a hoof, such as the configuration
of a microwave oven. For example, electromagnetic energy can be
provided to a central cavity through a cable or waveguide inlet. A
hoof or appendage to be treated can be inserted into the
applicator, and electromagnetic energy is supplied for
treatment.
[0046] The examples below are intended to further illustrate
certain preferred embodiments and are not intended to limit the
scope of the invention.
EXAMPLES
Example 1
Preliminary Testing
[0047] Two examples were performed: 1) Trichophyton species was
isolated from nail tissue and was identified at Emerson Hospital
Mycology Lab by conventional methods. The fungus was plated on BBL
Sab Dex Emmons dish (CM41, Oxoid Inc., Ogdensburg, N.Y.) and
exposed to 2450 MHz microwave energy at 1100 watts (Panasonic
Household Microwave Oven NN-S668BA) for varying lengths of time. No
growth was found at exposures greater than 10 seconds. 2) Toe nail
clippings that had previously been shown by periodic acid schiff
stain (PAS) to contain fungus were exposed to 2450 MHz at 1100
watts of microwave energy for varying lengths of time. Fungal
isolation was carried out at room temperature on BBL Sab Dex Emmons
dish (CM41, Oxoid Inc., Ogdensburg, N.Y.) with and without
chloramphenicol (0.05 g/L) and cycloheximide (5 g/L). After 21 days
of culturing, no growth was seen at exposures greater than 1
minute.
Example 2
Determination of a Kill-Dose Microwave Energy Level
[0048] The following methods were used. The dermatophyte was
obtained from the clipped toe nail sample of a human patient with
clinically diagnosed onychomycosis. Fungus was confirmed in the
sample by microscopy with the PAS stain, and cultured onto
Sabouraud's dextrose agar with/without chloramphenicol and
cycloheximide for 4 weeks, identifying the fungus as a Trichophyton
spp. Using sterile techniques the nail samples were prepared using
a #11 scalpel to scrape off the white keratin debris from the
infected nail. Samples of nail debris of length 4 mm were then
loaded into sterilized 2 mm diameter polyurethane tubing and closed
with phenolic plugs. A total of 51 samples were made.
[0049] The vial to be treated was placed within a plexiglass vial
carrier designed to position the nail sample at one of the
locations of the maximum electric field inside of a slotted line
(Hewlett Packard Model 805C). This apparatus consisted of an 11 mm
diameter cylindrical inner conductor fixed centrally between two
vertical plates that together form the outer conductor. The
electric field was greatest at the point of closest approach
between the inner and outer conductors, a gap of 4.5 mm. The
slotted line was terminated with an open circuit, producing a
standing wave pattern along the long axis of the slotted line. The
axial location of a maximum of electric field was measured with the
electric field probe integral to the slotted line. A maximum was
found at a distance equal to a half-wavelength (164 mm) from the
point of the open circuit termination, as predicted by transmission
line theory.
[0050] The slotted line was driven by a 915 MHz generator (American
Microwave Technologies Model 1120) through 6 feet of RG-214/U
cables. The generator in turn was controlled by a purpose-built
proportional-integral controller that compared the set-point of
power to the actual value measured by a dual directional coupler
(Narda Model 3020A) and power meter (Hewlett Packard Model 435B).
The generator was protected from reflected power by a circulator
(Pamtech Model 1146) terminated with a load (Narda Model 369 BNF,
175 watt rating). Samples contained in vials 1 to 25 were exposed
to 5 minutes of heating with a forward power of 68 watts. Samples
in vials 26 to 51 were used as controls.
[0051] The samples were then separately inoculated onto
Dermatophyte Test Medium (Acu-DTM, Acuderm, Inc., Ft. Lauderdale,
Fla.). They were incubated at room temperature. The test medium was
examined for color change and colony growth daily for two weeks. A
positive result was declared when the test medium changed from
yellow to red with or without concurrent colony growth. A negative
result was declared when there was no color change. Of the treated
samples, after 14 days, 1/25 showed the presence of viable
dermatophytes. Of the control samples, after 14 days, 13/25 showed
the presence of viable dermatophytes. There was no colony growth
noted without color change on the DTM medium. There was no color
change without colony growth. A chi-squared analysis of the data
was performed. Using an alpha level of 0.05 there was a significant
difference in the growth proportions across the 2 treatment
conditions. In addition, the effect size (Cramer's V) is high. At
30 days the samples were reexamined. There was no new growth among
the treated samples, and 2 additional samples among the controls
showed growth.
[0052] The results of this experiment are consistent with the use
of 68 Watts, for 5 minutes, of microwave irradiation in the slotted
line apparatus described above, as a kill-dose for a dermatophyte,
Trichophyton spp., in a keratin substrate. The main part of the
experiment was stopped after 14 days because color interpretation
of the Dermatophyte Test Medium is questionable after this due to
the possibility of false positives and fewer than 2% of cultures
require 2 weeks to show a change in color. The 30 day evaluation
was used to answer the question of whether the irradiation delayed
growth rather than provided a kill-dose. The low growth rate was
consistent with the previously described 30% positive microscopy
and culture results due to sampling errors from infected nails.
This was higher in our experiment probably because of the
particularly small sample size required by the 2 mm diameter
polyurethane tubing.
Example 3
Determination of a Kill-Dose Microwave Energy Level with a
Prototype Applicator
[0053] The methods of Example 2 were used, except that the
microwave applicator consisted of a coaxial cable with a portion of
the outer conductor removed. Vials of fungal-infected tissue were
placed in proximity to the inner conductor of the coaxial cable.
Five vials were treated at each of the following power levels: 25
watts, 40 watts, 55 watts; in every case, the duration of heating
was 5 minutes. Eleven untreated vials served as controls. Fungal
growth was observed in 7 of 11 control vials after 14 days. No
fungal growth was observed in any treated vial, regardless of power
level. Using an alpha level of 0.05 there was a significant
difference in the growth proportions across the 4 treatment
conditions.
Equivalents
[0054] While the foregoing invention has been described in some
detail for purposes of clarity and understanding, it will be
appreciated by one skilled in the art from a reading of this
disclosure that various changes, substitutions, and modifications
in form and detail can be made without departing from the true
scope of the invention and appended claims.
[0055] The issued patents, patent applications, and references that
are cited herein are hereby incorporated by reference to the same
extent as if each was specifically and individually indicated to be
incorporated by reference. In the event of inconsistencies between
any teaching of any reference cited herein and the present
specification, the latter shall prevail for purposes of the
invention.
* * * * *