U.S. patent application number 14/807653 was filed with the patent office on 2015-11-19 for system and method for the photodynamic treatment of burns, wounds, and related skin disorders.
This patent application is currently assigned to L'OREAL. The applicant listed for this patent is L'OREAL. Invention is credited to David H. Mcdaniel.
Application Number | 20150328479 14/807653 |
Document ID | / |
Family ID | 34115488 |
Filed Date | 2015-11-19 |
United States Patent
Application |
20150328479 |
Kind Code |
A1 |
Mcdaniel; David H. |
November 19, 2015 |
SYSTEM AND METHOD FOR THE PHOTODYNAMIC TREATMENT OF BURNS, WOUNDS,
AND RELATED SKIN DISORDERS
Abstract
A method including photomodulating mammalian tissue with more
than one light source of narrowband, multi chromatic
electromagnetic radiation, wherein at least one light source emits
radiation at a wavelength corresponding to yellow light and at
least one light source emits radiation corresponding to infra-red
light, wherein the ratio of the intensity of yellow light to
infra-red light is about 4:1.
Inventors: |
Mcdaniel; David H.;
(Virginia Beach, VA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
L'OREAL |
Paris |
|
FR |
|
|
Assignee: |
L'OREAL
Paris
FR
|
Family ID: |
34115488 |
Appl. No.: |
14/807653 |
Filed: |
July 23, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12550464 |
Aug 31, 2009 |
9144690 |
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14807653 |
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10903483 |
Aug 2, 2004 |
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12550464 |
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60491277 |
Jul 31, 2003 |
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Current U.S.
Class: |
607/88 |
Current CPC
Class: |
A61N 2005/0659 20130101;
A61N 5/0616 20130101; A61N 2005/0667 20130101; A61N 2005/0663
20130101; A61N 2005/0652 20130101; A61N 2005/0662 20130101 |
International
Class: |
A61N 5/06 20060101
A61N005/06 |
Claims
1. (canceled)
2. A device, comprising: more than one light source of narrowband,
multi chromatic electromagnetic radiation, wherein at least one
light source emits radiation at a wavelength corresponding to
yellow light and at least one light source emits radiation
corresponding to infra-red light, and wherein the device emits
electromagnetic radiation at a fluence of less than 4
J/cm.sup.2.
3. The device of claim 2, wherein at least one light source emits
radiation having a dominant emissive wavelength of 580 nm to 600 nm
and at least one light source emits radiation having a dominant
emissive wavelength of 850 nm to 950 nm.
4. The device of claim 3, wherein the at least one light source
emits radiation having a dominant emissive wavelength of 590 nm at
an energy output of 4 mW/cm.sup.2 and at least one light source
emits radiation having a dominant emissive wavelength of 850 nm at
an energy output of 1 mW/cm.sup.2.
5. The device of claim 2, comprising at least one optical,
mechanical, or electrical filter for varying the ratio of infra-red
light intensity with respect to yellow light intensity.
6. The method of claim 2, wherein the ratio of the intensity of
yellow light to infra-red light is 4:1.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of and claims
the benefit of priority under 35 U.S.C. .sctn.120 from U.S.
application Ser. No. 12/550,464, filed Aug. 31, 2009, which is a
continuation application of U.S. application Ser. No. 10/903,483,
filed Aug. 2, 2004, now abandoned, which is a non-provisional
application of U.S. Provisional Application No. 60/491,277, filed
Jul. 31, 2003, the contents of each of which is hereby incorporated
by reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to method and devices for the
photodynamic regulation of cell proliferation and gene expression.
In particular, the invention relates to the reducing, reversing,
and/or diminishing the effects of sunburn, thermal burns, chemical
burns, radiation burns, various types of wounds, such as traumatic,
surgical, laser, chemical peel, cosmetic surgery, warfare agents or
injuries, freezing, hypoxia, vascular insufficiency, bruising,
chronic ulcers, etc., allergic reactions or contact dermatitis, and
various inflammatory diseases.
[0004] 2. Description of the Background
[0005] Chronological aging, "photo-aging", i.e., the aging of skin
caused by exposure to natural and synthetic light sources, disease,
and trauma all bring about changes in the appearance of human and
mammalian skin as well as changes in the structure and function of
the skin. All living cells, tissues and organs also undergo changes
associated with chronological aging, bruising, photo-aging,
disease, and trauma. Since the human skin is an organ that is
highly visible, the changes associated with these conditions are
readily apparent and visible. These changes are reflections of the
underlying structural and functional changes.
[0006] The most widely appreciated form of skin aging is that which
is produced by over exposure and repeated chronic exposure to
sunlight and is generally termed photoaging. More specifically
certain portions of the ultraviolet A (UVA) and ultraviolet B (UVB)
and have been determined to be the principal causative factors of
what are associated with photoaging.
[0007] For many years it was thought that photoaging occurred
through a different mechanism of action or and was somehow
different than chronological aging. However, more recently it
appears that photoaging and chronological aging may share similar,
if not identical pathways.
[0008] Solar radiation is composed of ultraviolet (LTV), visible
and infrared, light. Current conventions divide IJV radiation into
UVA (320-400 nm), UUB (290-320 nm) and UVC (<290 nm). UVC
radiation is blocked by ozone in the stratosphere and does not
reach the earth's surface, but can be generated by germicidal lamps
and other machinery. UVA and UVB sunlight do reach the earth and
are believed to be the principal agents of photoaging. UVA
radiation is further subdivided into UVA 1 and UVA 2. While UVB has
been believed to be the primary agent for photoaging, it is now
appreciated that certain wavelength ranges within the UVA rays also
contribute to changes associated with photoaging.
[0009] Acute environmental injuries include sunburn from UV light
and other thermal, chemical, and other types of burns or burn-like
injuries. These type of injuries produce not only damaged cells,
but dying cells. Damaged cells may either repair the damage and
return to normal, repair the damage imperfectly and produce an
abnormal or sub-optimally functioning cell, or the cells may die.
In the case of sunburn chronic sun-damage accumulates damaged and
imperfectly repaired cells to produce what might be termed `solar
scars` but we more commonly think of these as `wrinkles`. That is a
wrinkle is really the result of accumulation of imperfectly
repaired cell damage. Likewise the brown `liver` or `age spots`
that are common as one ages and photoages are similarly damage to
the pigment cells or melanocytes.
[0010] Acute UV injury or sunburn produces dying cells in the upper
skin layer or epidermis called `sunburn cells`. Counting sunburn
cells is a classic scientific method to quantify the severity of
damage to these keratinocyte cells. Therapies which reduce the
number of sunburn cells are considered beneficial to diminishing
the severity of the injury or repairing or reversing the injury.
More generally speaking damaged cells which might recover or die
are termed `apoptotic` cells and those cells which are irreversibly
damaged and will die are termed `necrotic` cells. Treatments which
can turn necrotic cells into living cells would be considered
treatments which `rescue` or `revive` the cells which are destined
for death. Such treatments and therapies would have great
importance in treating not only acute sunburn, but sub-acute sun
damage that leads to accumulated chronic damage. The ability to
`rescue` dying cells in wounds, burns, etc would have a powerful
impact on healing time, scarring or lack thereof, infection risk,
and even survival of entire organs or organisms. The pertinent arts
have, heretofore, been unable to produce a system or method for
reviving or rescuing necrotic cells or those in advanced stages of
necrosis.
[0011] UVA and UVB light exposure to human skin triggers a series
of molecular events including the induction of reactive oxygen
species (ROS) in the skin. Through a series of cell signaling
events collagen production is down regulated and various enzymes
known to degrade structural proteins in the skin up-regulated. The
net result of this is a decrease in collagen and the production of
wound. The skin's reaction to UVA or UVB (or combined) wounding is
to repair the wound through the skins wound healing mechanism.
Typically these wound repair mechanisms are imperfect which is
considered by many to be a solar scar. After many years of the UVA
or UVB wounding of the skin, chronic solar scarring develops which
manifests itself in the visible phenotypic changes termed
photoaging, which might also be considered the visible outward
evidence of solar scars.
[0012] Photoaging of the skin may occur through acute injury at
higher levels, such as what one associates with sunburn. This
triggers an inflammatory process in the skin and the associated
cellular mechanisms. There is also a more chronic low-level type of
injury that does not produce a sunburn reaction, but which produces
the changes of chronic photoaging. Other processes, which are known
to decrease collagen production and increase collagen-dissolving
enzymes, such as tobacco smoking, also are associated with changes
that visibly appear, similar to the photoaging from UVA/UVB light.
This can be seen strikingly in photographs of identical twins
wherein only one twin smoked tobacco for many years.
[0013] UVB radiation in sufficient doses produces reddening or sun
burning of the skin. The threshold level is typically described as
minimal erythema' dose (MED), typically produced by 290-300 nm UVB
wavelengths. As the wavelengths increase they become much less
likely to produce the redness and burning reactions and indeed
wavelengths of 320 nm are about 100 times as powerful as
wavelengths of 340 nm approximately 100 times less powerful than
the 290-300 nm range of producing erythema and sunburns. The total
UVB exposure is more related to the appearance of photoaging and
sunburns are more likely to trigger malignant changes in the skin
such as malignant melanoma. In contrast, UVA radiation can produce
redness, but also produced tanning and these are the wavelengths
typically used for the so-called tanning beds. UVA radiation is a
longer wavelength and is proportionately greater in the early
morning and late afternoon and the UUB rays, which are typically
most predominant and intense at the midday summer sun time exposure
period, UVA radiation may also penetrate certain sun blocks mid
certain sunscreens and also window glass on automobiles, thus
accounting for the frequently observed greater wrinkling, brown
pigmentation and redness and overall aged appearance on the left
side of the face than the right in patients who occupationally or
recreationally spend considerable time driving a left hand drive
motor vehicle.
[0014] In sunny countries with fair complexioned populations, such
as Australia, where right hand drive motor vehicles are used, these
changes are seen typically seen on the right side of the face. The
patterns of photoaging are determined by which areas of the body
are anatomically are more chronically exposed to sunlight. Thus,
the face, neck, back of hands, upper chest, lower arms, lower legs
and depending on hair styling and density, ears and balding areas
manifest the greatest photoaging changes.
[0015] The chronological changes and photoaging changes typically
are manifest by fine lines and wrinkling of the skin. A coarser,
crepey texture to the skin, skin laxity and skin sagging, uneven
pigmentation, brown splotchy pigment, loss of skin tone, texture
and radiancy, bruising and sallowness. The skin is composed of
several layers, the outermost layer is called the stratamocornium
(SC), next layer is the epidermis (EPI), and underneath the
epidermis lies the dermis (DER). The outer SC serves primarily a
barrier function to protect the skin from environmental exposure
and also to help minimize water loss from the skin. The epidermis
serves many important and diverse roles as does the dermis. The
dermis contains the principal structural proteins of the skin.
These proteins are collagen, elastin and ground substance. They are
manufactured by the fibroblast cells within the dermis. Fibroblast
cells control the activity to produce these proteins as regulated
by a complex and relatively well defined series of cell receptors
and cell signaling mechanisms.
[0016] The proliferation of these cells is also an important
activity. For example, the dermis also contains blood vessels,
nerve fibers, oil and sweat glands, hair follicles and many other
important components. There is a remarkably complex inner
communication through cell signaling in the cells of the skin.
Fibroblasts produced what are termed pro-collagen fibers, which are
then insymmetrically assembled into collagen fibers, and form
bundles within the dermis. Other molecules, such as decorin affect
the function of the collagen. There are various sub-types of
collagen fibers such as Collagen I, Ill, etc., within the body.
Collagen I comprises approximately 85% of the skin and Collagen III
approximately 10%. However, in photoaged skin the amount of
Collagen I decreases so the ratio of Collagen III/I is altered.
[0017] There are also a variety of enzymes termed matrix
metalloproteinases (MMP) which play important roles in aging skin.
Fibroblasts also have important functions in wound healing with the
removal of damaged structural ECM and the repair and production of
(ECM). The Collagen I is degraded principally by MMP 1
(collagenase). There are a variety of MMP enzymes, which degrade
one or more of the structural proteins in the skin. While these
degrading MMP enzymes serve an important role in removing damaged
skin (for example, in wound healing), their activation and
synthesis in increased quantities in normal skin helps contribute
to the changes seen in both chronological and photoaging. Likewise,
if the production of Collagen I is decreased or diminished this
results in changes which are associated with chronologically or
photoaged skin. Aging or senescent fibroblasts may exhibit
decreased synthesis of Collagen I and increased synthesis of MMP 1.
Similar changes are seen with UVA/UVB exposure. Other environmental
agents may produce similar changes.
[0018] Certain drugs, therapies, chemicals, active agents have been
demonstrated to reversing the appearance of or phenotype of a
chronologically aging or photoaging skin. Some topically applied
agents serve as a physical or optical barrier either by reflection
or absorption of ultraviolet light thus protecting the skin. There
are also enzymes that have been to shown actually repair the DNA
dimers which are produced from UV damage. Other topically applied
or oral or systemically agents have been shown to improve the
appearance of the skin. One of the classic and well-known agents is
a topical Vitamin A derivatives termed Retinoids. Numerous studies
have demonstrated the ability to improve the appearance or
phenotype of photoaged skin with the use of all-trans retinoic acid
(RA). Many of the pathways involve the mechanism of action of RA
and also Retinol (RO), Much of the mechanism of action in the cell
signaling pathways through which RA appears to produce anti-aging
effects.
[0019] One of the goals of some current anti-aging therapies is to
increase production of collagen in the ECM and the dermis of the
skin. Some believe collagen I is the more desirable form of
collagen to increase. There is some support for this since
photoaged skin has less desirable visco elastic properties and this
is thought in part to be due to the increased proportion of
collagen Ill to collagen I. Other anti-aging approaches indicate
that reducing the activity or production of the degrading enzymes
in the ECM will similarly produce an anti-aging effect in the
appearance of the skin. Doing a combination of both is even more
beneficial. An analogy one might make is the production of new
collagen I and that of freshly newly fallen snow. The amount of
accumulation of the fresh snowfall is dependent both on the amount
of snow that is fallen as well as the amount of the freshly fallen
snow which then melts. Thus one could envision an anti-aging
therapy which stimulated new collagen production (newly fallen
snow). When a piece of black asphalt in a parking lot abuts a piece
of warmer black asphalt adjoins a colder piece of concrete or
frozen ground, while the amount of new snowfall is equal in both
areas, the amount of accumulated snow is less was melted by the
asphalt. If an anti-aging therapy stimulates collagen I production,
but does not diminish MMP 1 activity, the net increase in collagen
I will be smaller than if the MMP 1 activity is also decreased.
[0020] Historically there have been many approaches to restoring a
youthful appearance to human skin for achieving anti-aging or age
reversal therapies. Most methods utilize some form of triggering
the body's own wound healing mechanism. The more destructive and
traumatic methods use chemicals to peel off the stratum cornium
epidermis and often a portion of the dermis or they mechanically
abraded by sand papering or dermabrating or more recently
high-energy thermal lasers have been used to vaporize or coagulate
the skin. These methods have a prolonged and painful wounding
period and require wound care and patients typically must limit
their daily social and business activities during the wound-healing
phase. Subsequently the skin undergoes months or years an on going
wound healing and wound remodeling process whereby damage is
repaired and new structural proteins in skin are generated. These
treatments typically amount to trying to produce a controlled entry
to the skin and proving the wound care environment that minimizes
the risk of scarring. These methods are notoriously known for
producing many problems and sometimes even disfiguring scarring or
catastrophic pigment changes in the skin. However, properly
performed and with good wound care, many people achieved
significant and sometimes dramatic anti-aging effects. Other
gentler methods have become more popular in recent years which
involve the classic plastic surgery lifting procedures and newer
procedures termed non-ablative where the outer stratum eornium and
epidermis are not removed or blated from the skin, but are by
various means and methods protected and left in tact. Non-ablative
methods have typically been thermal in nature and through various
means of laser light, intense pulsed light, radio frequency or
microwave energy delivery then produced a thermal injury to the
dermis. The theory behind these therapies is that this injury will
result in a net increase in the desirable structural proteins,
while not triggering, worsening, scarring or other complications.
Results are occasionally traumatic but have been extremely variable
with this therapy. The variability in individuals wound healing
repair mechanism and the overall health of their body and skin and
many other factors contribute to this variability.
[0021] There are various topical agents that have been developed
for anti-aging purposes such as Retinoic acid, topical Vitamin C,
topical Vitamin B and other antioxidant and other antiwrinkle
creams and lotions. Many of these are well defined. Additional
topical compositions, cosmeceuticals, etc. are disclosed in
applicant's copending application serial number U.S. Ser. No.
09/899,894, entitled "Method and Apparatus for the Photomodulation
of Living Cells", filed Jun. 29, 2001, which is hereby incorporated
by reference in its entirety. Further, methods for enhancing the
penetration of such composition into the skin using ultrasound
radiation are described in U.S. Pat. No. 6,030,374, and U.S. Pat.
No. 6,398,753, each of which is hereby incorporated by reference in
its entirety. Use of such compositions for wound treatment, acne
reduction, and other dermatological conditions is described in
applicant's copending application Ser. No. 09/933,870, filed Aug.
22, 2001, which is also incorporated by reference herein in its
entirety. Additional discussion of the related art is described in
applications copending application Ser. No. 10/119,772, filed Apr.
11, 2002, and 60/461,512, filed Apr. 10, 2003, which are also
incorporated by reference herein in their entirety.
[0022] There is a need to improve the appearance of chronologically
aged, photoaged, or environmentally damaged skin, as well as skin
that has been damaged by disease or trauma, but without producing
the risk, complications, recovery time, pain, discomfort, wound
care or other side effects traditionally associated with surgical,
chemical, electromagnetic radiation and other types of
therapies.
SUMMARY OF THE INVENTION
[0023] As embodied and broadly described herein, the present
invention is directed to method and devices for improving the
appearance of photoaged or damaged skin. Methods and devices
involve the regulation of cell proliferation and gene expression of
skin and other cells through photodynamic means such as
photomodulation.
[0024] One embodiment of the invention relates to reducing the
undesirable effects and enhancing the beneficial effects of
narrowband and wideband multichromatic electromagnetic radiation,
as well as monochromatic radiation, emitted by sources including,
but not limited to lasers (monochromatic and filtered, narrowband
multichromatic), LED's (narrowband multichromatic), radio
frequency, electromagnetic therapy or non ablative thermally
mediated surgical procedures, etc. For example, LED photomodulation
and other similar non-LED therapies may be used to enhance the
desired effects or inhibit the undesirable one. This may be
accomplished via means such as thermal injury to the skin which
forces the expression of MMP and causing an increase structural
proteins like collagen. LED light sources may also boost collagen
while decreasing the upregulated MMP to produce a beneficial net
effect. Such means generally quench the inflammatory processes that
thermal therapies typically produce.
[0025] One embodiment of the invention is directed to methods for
both inhibiting, as well as reversing the appearance of photoaging
(beauty maintenance or skin fitness) or chronological or
environmentally damaged induced aging of human skin by application
of photomodulation by, for example LED or other electromagnetic
radiation treatment. Preferably, the invention is directed to the
regulation of cell proliferation of cells of the skin, and/or the
regulation of gene expression in such cells.
[0026] Another embodiment of the invention is directed to the
various genotypes that characterize different phenotypes of aging
skin and also a database comprising a collection or library of such
phenotypes. The data base may comprise a plurality of genotypes
identified from a variety of different individuals with the same
disorder, or a variety of individuals with different disorders.
[0027] Another embodiment of the invention is directed to
photomodulation by light or electromagnetic radiation so as to
effect cell proliferation and/or gene expression. Examples of
different types of electromagnetic radiation include ultrasound,
radiowaves, micro rays, magnetic fields, any electrical stimulation
that produces changes in the genotype or phenotype of aging skin,
and combinations thereof.
[0028] Other embodiments and advantages of the invention are set
forth in part in the description, which follows, and in part, may
be obvious from this description, or may be learned from the
practice of the invention.
BRIEF DESCRIPTION OF THE DRAWING FIGURES
[0029] FIG. 1 is a chart which illustrates the RT-PCR expression of
MMP-1 in cultured human fibroblasts.
[0030] FIG. 2 is a chart which illustrates the RT-PCR expression of
MMP-1 in cultured human fibroblasts under a variety of light
exposure conditions.
[0031] FIG. 3 is a chart which illustrates the RT-PCR expression of
MMP-I in cultured human fibroblasts at varying energy fluences.
[0032] FIG. 4 is a chart which illustrates the RT-PCR expression of
cytochrome c oxidase 2 in cultured human fibroblasts after exposure
to narrowband, multichromatic electromagnetic radiation.
[0033] FIG. 5 is a chart which illustrates the RT-PCR expression of
collagen I in cultured human fibroblasts after exposure to
narrowband, multichromatic electromagnetic radiation.
[0034] FIG. 6 is another chart which illustrates the RT-PCR
expression of collagen I in cultured human fibroblasts after
exposure to narrowband, multichromatic electromagnetic
radiation.
[0035] FIG. 7 is a chart which illustrates the RT-PCR expression of
MMP-1, collagen I, and cytochrome c oxidase 2 in cultured human
fibroblasts after exposure to narrowband, multichromatic
electromagnetic radiation.
[0036] FIG. 8 is another chart which illustrates the RT-PCR
expression of collagen I in cultured human fibroblasts after
exposure to narrowband, multichromatic electromagnetic
radiation.
[0037] FIG. 9 is another chart which illustrates the RT-PCR
expression of collagen I in cultured human fibroblasts after
exposure to narrowband, multichromatic electromagnetic
radiation.
[0038] FIG. 10 is a chart which illustrates the RT-PCR expression
of cytochrome b in cultured human fibroblasts after exposure to
narrowband, multichromatic electromagnetic radiation.
[0039] FIG. 11 is a chart which illustrates the RT-PCR expression
of cytochrome b oxidase I in cultured human fibroblasts after
exposure to narrowband, multichromatic electromagnetic
radiation.
[0040] FIG. 12 is a chart which illustrates the RT-PCR expression
of atpase6 in cultured human fibroblasts after exposure to
narrowband, multichromatic electromagnetic radiation.
[0041] FIG. 13 is a chart which illustrates the RT-PCR expression
of cytochrome c oxidase Ill in cultured human fibroblasts after
exposure to narrowband, multichromatic electromagnetic
radiation.
[0042] FIG. 14 is a chart which illustrates the RT-PCR expression
of p53 in cultured human fibroblasts after exposure to narrowband,
multichromatic electromagnetic radiation.
[0043] FIG. 15 is a chart which illustrates the RT-PCR expression
of MMP-1 in cultured human fibroblasts after exposure to
narrowband, multichromatic electromagnetic radiation with varying
energy fluence.
[0044] FIG. 16 is a chart which illustrates the RT-PCR expression
of collagen I in cultured human fibroblasts after exposure to
narrowband, multichromatic electromagnetic radiation.
[0045] FIG. 17 is a another chart which illustrates the RT-PCR
expression of collagen I in cultured human fibroblasts after
exposure to narrowband, multichromatic electromagnetic radiation
employing various light cycle regimen and filters.
[0046] FIG. 18 is a another chart which illustrates the RT-PCR
expression of collagen I in cultured human fibroblasts after
exposure to narrowband, multichromatic electromagnetic radiation
employing various light cycle regimen and filters.
[0047] FIG. 19 is another chart which illustrates the RT-PCR
expression of MMP-1 in cultured human fibroblasts after exposure to
narrowband, multichromatic electromagnetic radiation employing
various light cycle regimen and filters.
[0048] FIG. 20 is another chart which illustrates the RT-PCR
expression of MMP-1 in cultured human fibroblasts after exposure to
narrowband, multichromatic electromagnetic radiation employing
various light cycle regimen and filters.
[0049] FIG. 21 is a chart which illustrates the RT-PCR EGF
expression in cultured human fibroblasts after exposure to
electromagnetic radiation simulator solar radiation.
[0050] FIG. 22 is a chart which illustrates the RT-PCR expression
of collagen I in cultured human fibroblasts after exposure to
electromagnetic radiation simulator solar radiation.
[0051] FIG. 23 is a chart which illustrates the RT-PCR expression
of cJun in cultured human fibroblasts after exposure to
electromagnetic radiation simulator solar radiation.
[0052] FIG. 24 is a chart which illustrates the RT-PCR expression
of MMP-1 in cultured human fibroblasts after exposure to
electromagnetic radiation simulator solar radiation.
[0053] FIG. 25(a) illustrates the specific extinction coefficients
of various cytochromes at various wavelengths.
[0054] FIG. 25(b) illustrates specific extinction coefficients of
the cytochromes of FIG. 25(a) from 700 nm to 1000 nm.
[0055] FIG. 26 illustrates specific extinction coefficients vs.
wavelength.
[0056] FIG. 27 shows the emission or spectral output of the LED
with dominant visible and secondary infrared (IR) peaks and their
relative intensity and shape.
[0057] FIG. 28 shows the same LED emission with a selective
infrared filter in place which reduces both the visible and IR
output, but alters the relative ratio of visible to IR light as
well as altering the shape of the IR spectral output curve.
[0058] FIG. 29 shows the emission or spectral output of the LED
with dominant visible and secondary infrared (IR) peaks and their
relative intensity and shape.
[0059] FIG. 30 shows the same LED emission with a selective
infrared filter in place which reduces both the visible and IR
output, but alters the relative ratio of visible to IR light as
well as altering the shape of the IR spectral output curve.
DETAILED DESCRIPTION OF THE INVENTION
[0060] As embodied and broadly described herein, the present
invention is directed to method and devices for the regulation of
cell proliferation and gene expression and, in particular, the
inhibition of photoaging of the skin, and the revival of necrotic
cells. As well, the invention is directed toward a system and
method for rejuvenating cells in various stages of necrosis.
[0061] Photoaging of the skin occurs through many mechanisms,
including, for example, environmental factors such as tobacco
smoke, exposure to the sun, and poor health, to name a few. These
events can triggers an inflammatory process in the skin and the
associated cellular mechanisms. There is also a more chronic
low-level type of injury that does not produce a sunburn reaction,
but which produces the changes of chronic photoaging. Chronological
aging of the skin and photoaging and other environmentally induced
changes share many or in some cases, all of the same pathways as UV
induced photoaging of the skin. These pathways involve up and/or
down regulation of cell proliferation and also alterations in the
level of expression of many different types of genes.
[0062] It was surprisingly discovered that, this combination of
regulation of cell proliferation and regulation of gene expression,
is responsible for photoaging of the skin and other cells and
tissues, and thus, photoaging could be reversed or at least
ameliorated by affecting these same processes. Accordingly, one
embodiment of the invention is directed to identifying and
correlating the phenotypic and genotypic expression characteristics
of photoaging and other skin and cell-associated disorders. Once
identified, correlated maps can be compiled and collected into a
data base to allow for the rapid and efficient identification of
similar disorders and conditions for the purpose of tailoring
appropriate treatment. Further, once identified, treatment and
appropriate intervention and prevention methods can be used to halt
or even reverse the appearance and genotypic characteristics of
photoaging. Thus, the invention is not directed to artificially
hiding or covering up aspects associated with aging, but actually
reversing the processes and mechanisms associated with
aging-related phenomena.
[0063] A further embodiment of the invention is directed to
applying these same mechanisms and tools to other cells such as
stem cells (completely undifferentiated cells) and progenitor cells
(partially differentiated cells). By altering the cell cycle, cell
proliferation, and/or gene expression characteristics of these
cells along defined parameters, it is possible to determine
differentiation pathways and to create or recreate cells, tissues
and other cell structures for disease therapy and prevention, and
wound healing.
[0064] Methods to modulate cell proliferation and gene expression
include exposure to electromagnetic radiation in an amount or dose
that is sufficient to stimulate the desired effect (e.g. see U.S.
Pat. Nos. 6,398,753, 5,837,224, and 6,130,254; and U.S. Patent
Application Nos. 2002/0028185, 2001/0053347, 2003/0004556,
2003/0004499, and 2002/0123746, all of which are specifically and
entirely incorporated by reference). For example, exposure of skin
to LED can stimulate or inhibit the expression of various gene
products. These same methods can be used to cause stimulation or
inhibition of cell proliferation and cell cycle modulation in these
cell populations. Further, photomodulation can be used in
combination with certain oral agents (for systemic affects) or
topical agents (for localized affects) (e.g. vitamin A, retin A,
retinol), for a desired effect unachievable with either stimulant
used individually.
[0065] The types of cells that can be affected include, but are not
limited to skin cells (reversal of photoaging), nerve cells
(disease prevention and treatment), stem cells (tissue
reconstruction), cells of hair follicles (hair growth or
inhibition), cells of the immune system including cells intimately
involved with the process of inflammation (due to disease,
infection, or congenital disorder), wound repair, and combinations
thereof. Modulation can be achieved by exposing cells to
electromagnetic radiation (e.g. photomodulation) such as,
preferably, visible light, (e.g. purple, blue, green, yellow,
orange, red), infrared radiation, ultraviolet light (UVA, UVB,
UVA1, UVA2, or combinations thereof), or combinations of any.
Preferred exposure strengths and exposure times are as set forth in
the attachments hereto, but may include pulsed exposures,
continuous and periodic exposures.
Modulation of Gene Expression
[0066] Ultraviolet light injury triggers reactive oxygen species
and a series of cell signaling events called kinase cascades. One
of the final common pathway in the up and down regulation of
fibroblast activity is through AP-1 which up regulates and
increases the production of various MMP's including MMP 1
(collagenase 1 or interstitial collagenase synthesis), MMP 9
(gelatinases B) and MMP 3 (stromelysins 1). The production of these
MMP enzymes results in the breakdown of collagen, elastin and ECM
in the dermis of the skin. Simultaneously the actual production of
collagen I and other structural proteins may be diminished or down
regulated thus further accelerating the process.
[0067] The aging of living cells, tissues and organs may be related
to free radical exposure and oxidative stress. To apply this model
to aging skin, chronological aging results from a decrease
antioxidant defense mechanisms while UV photoaging and other
environmental stresses can be thought of as increasing oxidative
stress. The net result of decreased antioxidant defense or
increased oxidative stress is increase production of (ROS) or free
radicals.
Modulation of Gene Activity
[0068] Increased ROS production in the skin stimulates cell
signaling or signals transduction pathways, which produce altered
gene activity. Damage to structural proteins (e.g. damage,
disruption and fragmentation of collagen caused by UV light) alters
proteins, structure and function which in turn changes cell
signaling and may alter gene activity. Another possible outcome of
increased ROS production is the production of DNA mutations, which
then alters gene structure and thus may alter the normal structure
and function of cells. Much of the variation in the human state, as
far as disease and response to environmental insults may be
mediated by relatively small differences in the genetic make-up
from one individual to the next. Single nucleotide polymorphisms
(SNPs) are currently being very actively investigated as a means of
identifying and potentially predicting the differences in
biological responses of humans and other animals. For example,
characterization of SNPs may allow prediction of whether a patient
is more or less likely to develop a specific disease or tumor and
thus take known preventative measures. Another possible application
is the use of SNPs to screen individuals before placing them on a
prescription drug to identify those individuals who might be more
likely to develop serious side effects and thus avoid the use of
that drug. Another potential novel use of SNPs is to identify the
haplotype or patterns of SNPs, which are associate with, for
example, chronological aging of the skin. Some individuals and
families have reduced risk of skin cancers or simply look younger
than their peers of the same age group and like backgrounds. A
profile of SNPs can be developed that characterizes common factors
associated with the phenotypic changes of aging skin (defined the
SNP genotypic pattern that puts an individual at a greater risk of
accelerate aging from increased oxidative stress from environmental
agents). This allows for a treatment plan, which would have greater
anti-aging benefits.
[0069] TGF-B is a major cytokine for cell signaling and inhibits
the growth of epidermal keratinocytes and stimulates the growth of
thermal fibroblasts. It also induces synthesis and secretion of the
major collagen elastin and inhibits the expression of MMP 1 and MMP
3. There are multiple TGF-B's, TGF-B 1, TBR I, TBR II, many of
which are down regulated in aging skin cells. TGF-B is also
activity altered in aging skin by binding with Decerin and when
this combines with collagen affects the tinsel strength of skin as
well as controlling the rate of collagen fiber formation. c Jun
MRNA is doubled in activity and age human skin compared to young
skin but c-fos was unchanged. MMP 2 is not regulated through AP 1.
ERK activity is reduced in aging skin, but JNK activity is
increased 3-4 times in aging skin. Environmental insults-damage can
vary anatomically over a person's body. These methods allow for
rejuvenating human skin including the steps of simultaneously
preventing collagen degradation while also stimulating the
formation of new collagen in aging human skin.
[0070] Increased MMP's result in reduced levels of ERK, cyclin D2
and type I and III pro collagen. This is part of the core genotype,
phenotype stimulating a number of keratinocytes as well as
decreasing c-gen activity and increasing ERK activity.
[0071] A system of sunscreens, topical oil and antioxidants,
topical oil and photomodulated ECM stimulation and MMP and MMP
inhibition and various combinations and mixtures of the above.
Inhibiting c-gen formation also inhibits formation AP-I and thus
diminishes MMP's, inducing the proliferation of keratinocytes and
fibroblasts.
Modulation of Mitochondrial Activity
[0072] Mitochondria and ATP production mechanisms (e.g. cytochrome
expression) can be modulated by electromagnetic radiation. LED
light activates cell surface receptors via redox mediated in
activation or a receptor type protein tyrosine phosphatase (RTPT).
SAP (stress activated pathways) verses mitogen activated pathways
compare and contrast SAP increase MMP and decreases pro collagen 1
and 2 if c Jun goes up. Primarily has to do with the ECM production
whereas the MAP pathways activate ERK induced cyclins and promote
cell growth so that PSAT's tend to increase or decrease protein
production whereas the MAPS increase or decrease cell growth.
Ras/MAP/AP-1 pathway plays a key role in response to wounding.
FGFR1 contains sites in the promoter region and IL1 antagonist
promoter. Antioxidant compounds also have anti-erythema sunscreen
effect although they may not inhibit the increased MMP after UV
exposure, lycopene is one of these. LED photomodulation can also be
used to diminish sunburn activity and MMP levels were maxed about
24 hours later. Use a solar simulator to cause a one MED minimal
erythema dose on the arm in two places on volunteers and treat one
a couple times a day with the GW device and to reduce redness with
the chromometer. Biopsy will show what happens when you treat them
with GW after UV Inhibiting cytocrome P-450 breakdown of retinoids
increases retinoid strength concentration.
[0073] While not wishing to be constrained to a particular theory
of operation, the invention includes the surprising discovery that
multiple receptor-mediated pathways may be photomodulated in human
or mammalian skin that lead to an expression of the genotype
associated with a younger or more youthful or less aged skin both
in appearance and structurally and functionally.
[0074] Reference to infrared-a radiation induced MMP 1. Infrared is
capable of producing MMP 1 by way of up regulation or activation of
MAPK signaling pathway that is the activation of ERK 1/2 that the
promoter region of the MMP 1 gene was activated by IRA without the
production of heat, but that TIMP 1 was not increased. MMP-8 or
elastase is increased with inflammatory reaction, which also
involves AP I. And when NF-KB is increased it activates more of
IL-1 and TNFa that discontinues the presence of continued
inflammation.
[0075] Fibroblasts sensor matrix surround them and when in contact
with a matrix they tend to be less active produce little collagen,
but when the presence of collagen breaks down products such as
gelatin, they tend to produce more collagen if the inflammation
persists. The collagen not only proliferates, but produces less
scarring.
[0076] Topical compounds that inhibit cytokines are indirect MMP
inhibitors because if they block the pathway the signals MMP the
essentially block this. The same is true for MMP regulation.
Regarding nutraceuticals, Vitamin C can be topically applied to
assemble stable collagen molecules. Collagen I and collagen III can
be stimulated by topical of Vitamin C, whereas elastin, Fibrilin
1/2 are not affected nor is MMP 1, 2, and 9 affected. TIMP was
increased, TIMP 2 was unchanged.
Modulation for Wound Healing and Therapy
[0077] Proteolytic degradation of ECM is an essential feature of
repair and remodeling during continuous wound healing. Wound repair
consists of narcotic or damaged tissue, cell and/or tissue
migration, angiogenisis, remodeling of newly synthesized ECM, and
cell growth factor regulations. During wound repair MMP 1 and MMP 3
increase as well as MMP 2 and 9. MMP 13, in particular, for chronic
wounds, but also acute. TIMP is also altered. MMP 1, 3, 9 are
increased with UVB; increased elastin and fibrilian verscian;
result in the formation of non functional elastin fibers and reduce
skin elasticity and aging or photoaged skin. Collagen I is reduced,
and UVA shows increased expression of MMP 1, 2, 3.
[0078] Disease states-systemic sclaraderma skin fibroblasts
produced less MMP 1 and MMP 3 and more TIMP 1 compared to normal.
Skin cancers BCC produce more MMP 1, 2, 9 and 11. More signs of
photoaging, bruising, skin hypopigmented areas, fibrosis. Methods
and inventions for preventing the photoaging or chronological or
environmental aging of unaged skin include retinoids that retard
the effects of photoaging topical antioxidants to reduce presence
of ROS in the skin. Environmental stresses include oxidants, heat,
UV light. Thus, LED phototherapy is both an ECM protein/collagen
stimulator, and an MMP inhibitor. Dose dependent UVB induction of
AP 1 and NF-KB, these induced MMP 2 and MMP 9. The formation of
collagen bundles is responsible for the strength, resiliency and
elasticity of the skin.
[0079] In one embodiment of the invention single or multiple light
sources may be used, to produce either a single dominant emissive
wavelength, i.e., a narrowband multichromatic radiation, or
multiple wavelengths (either monochromatic, narrowband
multichromatic, wideband multichromatic, or combinations thereof).
The single or multiple combinations may be applied either
simultaneously or sequentially.
[0080] For example a device emitting narrowband, multichromatic
electromagnetic radiation with a dominant emissive wavelength of
about 590 nm (+/- about 10 nm) and also some light in the 850 nm
range and, optionally, a small amount in the 1060 nm range. It has
been discovered that the combination of the visible 590 and the
infrared 850 nm is bioactive. A special IR filter may also be added
to reduce the IR component of the radiation that the target skin or
tissue is exposed to, as this is believed to unsymmetrically dampen
the shape of the IR/850 curve. Treatment examples of such a device
are shown in the attached drawing figures and illustrate that at
850 nm, there is believed to be a `dose dependent` effect on
fibroblasts. Further, at a power level of about 1 mW/cm.sup.2,
photomodulation occurs for anti aging phenotype effect (those
skilled in the art will recognize that power meters cannot measure
this precisely, so there may be some variation/error in meter
methods). Generally, where a treatment that does not cause thermal
injury is desired, an energy fluence of less than about 4
J/cm.sup.2 is preferable.
[0081] The ratio of yellow light to IR radiation in the radiation
used for treatment has been found to have an effect on the overall
performance of the present system. Relative amounts of each type of
radiation are believed to be important, more so than the actual
radiation level (provided that ablation does not occur). At about 4
mW/cm.sup.2 for 590 nm and about 1 mW/cm.sup.2 for the 850 nm
(i.e., a 4:1 ratio of yellow to IR) has been found to produce good
results. Mother factor to consider is the shape of the amplitude
vs. wavelength curve for the IR component of the system.
[0082] The `code` refers to the pulse scheme for various treatment
regimen. This includes various factors such as pulse length,
interpulse delay, and pulse repetition. For example a treatment may
comprise a pulse code of 250 msec "on" time, 100 msec "off" time
(or dark period), and 100 pulses. This produces a total energy
fluence, in J/cm2, of 25 seconds times the power output level of
the emitters. This permits a comparison of pulsed versus continuous
wave treatment (the "code" for continuous wave treatment would be 1
pulse, an "on" time of whatever the treatment length is chosen to
be, and an "off" time of 0 sec.) Examples showing various codes,
ratios, and power levels and the resulting effect on the photoaging
effect on certain genes, and other data, are shown in the attached
data tables and drawing figures.
[0083] The present invention is also related to a method and
apparatus for treating sunburn and other sun-related photoeffects
on human or mammalian skin. One approach is to use Retin A for
prior to sun exposure and research is being conducted using
vitamins C, E, and other antioxidants topically. Another approach
being tried is the use of the antioxidant Lycopene, administered
orally, to quench some of inflammation from sunburn. The present
invention shows great improvement of such treatment methods,
however.
[0084] One may think of wrinkles, sun damage, and other sun-related
photo effects as `solar scars`. They are cumulative injuries that
result from repeated or long-term exposure to the sun. The human
body employs and imperfect wound repair mechanism, thus the solar
simulator of the present invention is, in some ways, a model for
other wound healings. The present invention employs a treatment
that simulates sunlight broken down into its component parts. The
UVA 1 portion is used in some embodiments, but there is UVB and
combinations of UVA and UVR that are more oncogenic. For example,
UV, and in particular UVA 1, causes skin sagging and photoaging,
changes to the dermal matrix and structural proteins, and
upregulates MMPs. UV radiation also causes the upregulation of
inflammatory pathways such as IL1, IL6 and NFkB. These pathways are
known to affect aging and other sun-related skin disorders and
environmental damage, such as smoking, pollution, drugs, diseases,
thermal injuries, other wounds.
[0085] The present invention is believed to inhibit or reverse the
effects of photoaging and other skin disorders by reversing the
direction of gene up/down regulation from the unfavorable and
destructive directions caused by the effects of the solar simulator
UVA1 for things like collagen, MMP1, cJun which is important
related to MMP1, IL/interleukins in inflammatory pathway, and
cytochromes. The attached examples describe the use of the present
system for illustrative treatments.
[0086] The systems and methods of the present invention may be used
in combination with various wound dressings like bandage strips
modified to have a transparent covering, so that the desired
spectra of photomodulation by LED or other light is transmitted to
the wounded area of the skin or target tissue. One embodiment
includes `trap door` to permit the periodic inhibition of light
transmission. The opening or translucent/transparent portion of the
bandage may comprise an IR filter, as well. In instances where it
is undesirable to include an opening as part of the bandage or
wound dressing, the size of LED's and other light sources makes it
possible to include a light source within the bandage. Such a
source could be powered from a small battery and include means for
having the light source automatically or manually apply treatment
at regular intervals and according to a variety of preset codes
(for example, a dressed chemical burn may require a different code
than a cut or electrical burn). As well, various topical
compositions for enhancing the penetration of the light through the
skin or target tissue can be included in the dressing or bandage or
applied to the skin or target tissue prior to covering the affected
skin with the bandage or dressing.
[0087] A light source within the bandage may also be coded to
`release` or to `activate` substances or delivery vehicles for
substances so that oxygen, antibacterial, antiviral, anti fungal,
etc., or other agents released. Combinations of such compositions
may be used as well.
[0088] Another application would allow for the treatment of blood
outside of the body (extracorporeally, in a phoresis device for
example). The blood may be run through banks of arrays of LED, or
other light or EMR, and then photomodulated either directly or by
an agent that was photoactivatable, or both, to stimulate the
immune system, treat disease, etc.
[0089] The present system and method may also be used for retinal
and other eye treatments, alone or along with antioxidant
eyedrop-type medications, bioengineered peptides, and growth
factors. Antioxidant eyedrops include, but are not limited to
glutathione, vitamin C, vitamin E, catalase, ubiquinone, idebenone,
etc.
[0090] Other applications of the present invention include nerve
regeneration, hormone manipulation (thyroid disease is common and
is particularly contemplated due to the proximity of the thyroid to
the skin). As well, photomodulating adipocytes for fat reduction,
cellulite, etc. may be accomplished using light sources in the
range of about 850-950 nm and 1000-1100 nm.
[0091] The following examples illustrate embodiments of the
invention, but should not be viewed as limiting the scope of the
invention.
EXAMPLES
[0092] Attached hereto are graphs, tables of data, and examples
that further illustrate the various embodiments of the invention,
as well as lists of gene products which can be regulated by methods
of the invention. In the appendix, the results of two experiments
which illustrate the invention are shown.
[0093] Other embodiments and uses of the invention will be apparent
to those skilled in the art from consideration of the specification
and practice of the invention disclosed herein. All references
cited herein, including all publications, U.S. and foreign patents
and patent applications, are specifically and entirely incorporated
by reference. It is intended that the specification and examples be
considered exemplary only.
* * * * *