U.S. patent application number 11/466047 was filed with the patent office on 2007-02-15 for enhanced noninvasive collagen remodeling.
Invention is credited to David R. Hennings, Dale E. Koop.
Application Number | 20070038201 11/466047 |
Document ID | / |
Family ID | 25465412 |
Filed Date | 2007-02-15 |
United States Patent
Application |
20070038201 |
Kind Code |
A1 |
Koop; Dale E. ; et
al. |
February 15, 2007 |
Enhanced Noninvasive Collagen Remodeling
Abstract
A method and apparatus for treatment of skin or other tissue,
using a source of thermal, electromagnetic radiation, electrical
current, ultrasonic, mechanical or other type of energy, to cause
minimally-invasive thermally-mediated effects in skin or other
tissue which stimulates a wound-healing response, in conjunction
with topical agents or other wound healing compositions, for
application on the skin or other tissue which accelerate
collagenesis, such as in response to wound healing. The dosage and
time period of application of the compositions are adjusted to
prevent external or surface tissue damage.
Inventors: |
Koop; Dale E.; (Roseville,
CA) ; Hennings; David R.; (US) |
Correspondence
Address: |
Ray K. Shahani, Esq.;Twin Oaks Office Plaza
Suite 112
477 Ninth Avenue
San Mateo
CA
94402-1854
US
|
Family ID: |
25465412 |
Appl. No.: |
11/466047 |
Filed: |
August 21, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09934356 |
Aug 21, 2001 |
7094252 |
|
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11466047 |
Aug 21, 2006 |
|
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Current U.S.
Class: |
606/9 |
Current CPC
Class: |
A61B 2017/00022
20130101; A61B 2018/00452 20130101; A61B 2017/00973 20130101; A61B
2017/00199 20130101; A61B 18/20 20130101; A61B 2018/00636 20130101;
A61B 18/203 20130101 |
Class at
Publication: |
606/009 |
International
Class: |
A61B 18/18 20060101
A61B018/18 |
Claims
1. A method for treatment of skin comprising: Treating a subsurface
layer of un-damaged skin with a source of electromagnetic energy
sufficient to cause stimulation of collagen biosynthesis without
thermal damage to the epidermis, in conjunction with using a
thermal servo feedback control system to regulate the delivery of
electromagnetic energy, thereby achieving improved collagenesis in
the skin.
2. The method of claim 1 further comprising the step of
controllably delivering pulsed cryogen spray to the skin to prevent
overheating of the skin.
3. The method of claim 1 wherein the treatment is repeated serially
with more than one day between any successive treatments.
4. A method for treatment of acne scars in skin, comprising:
Treating contiguous subsurface and surface layers of the skin with
a source of electromagnetic energy in order to stimulate collagen
biosynthesis in the skin without thermal damage to the epidermis,
in conjunction with using a thermal servo feedback control system
to regulate the delivery of electromagnetic energy, thereby
improving the appearance of the acne scars.
5. The method of claim 4 further comprising the step of
controllably delivering pulsed cryogen spray to the skin to prevent
overheating of the skin.
6. A method for treatment of photodamaged skin, comprising:
Treating the layer of skin with a source of electromagnetic energy
which stimulates biosynthesis of collagen without thermal damage to
the epidermis, in conjunction with using a thermal servo feedback
control system to regulate the delivery of electromagnetic energy,
thereby improving the appearance of the photodamaged skin.
7. The method of claim 6 further comprising the step of
controllably delivering pulsed cryogen spray to the skin to prevent
overheating of the skin.
8. A method for treatment of wrinkled skin, comprising: Treating
the layer of wrinkled skin with a source of electromagnetic energy
which stimulates biosynthesis of collagen without thermal damage to
the epidermis, in conjunction with using a thermal servo feedback
control system to regulate the delivery of electromagnetic energy,
thereby improving the appearance of the wrinkled skin.
9. The method of claim 8 further comprising the step of
controllably delivering pulsed cryogen spray to the skin to prevent
overheating of the skin.
10. A system for treatment of skin, comprising: A source of
electromagnetic energy which is sufficient to stimulate
biosynthesis of collagen in the skin without thermal damage to the
epidermis; and A thermal servo feedback control system to regulate
the delivery of electromagnetic energy, therein, thereby resulting
in improved appearance of skin.
11. The method of claim 10 further comprising the step of
controllably delivering pulsed cryogen spray to the skin to prevent
overheating of the skin.
12. A method for treatment of undamaged tissue comprising the
following steps: Causing a subdermal stimulation of collagen
biosynthesis without thermal damage to the epidermis using a source
of electromagnetic energy; and Using a thermal servo feedback
control system to regulate the delivery of electromagnetic energy,
such that collagenesis, repair and healing improvement of tissue is
accelerated.
13. The method of claim 12 further comprising the step of
controllably delivering pulsed cryogen spray to the skin to prevent
overheating of the skin.
14. A method for treating skin disorders with optical energy
comprising the step of delivering optical energy to the skin and
the step of using temperature sensing elements to provide feedback
to a controller such that the optical energy can be modulated to
maintain a predetermined skin temperature to prevent over
treatment.
15. The method of claim 14 further comprising the step of
controllably delivering pulsed cryogen spray to the skin to prevent
overheating of the skin.
16. A method for treating skin with optical energy comprising the
step of delivering optical energy to the skin and the step of using
temperature sensing elements to provide feedback to a controller
such that the optical energy can be modulated to maintain a
predetermined skin temperature to prevent over treatment.
17. The method of claim 16 further comprising the step of
controllably delivering a pulse of cryogen spray to the skin to
prevent overheating of the skin.
Description
FIELD OF THE INVENTION
[0001] This invention is related to the controlled delivery of
photothermal or other type of energy for treatment of biological or
other tissue, and more specifically, a method, system and kit for
causing a subdermal wound such that upon application of a growth
factor, collagenesis and further repair and healing improvement of
tissue is accelerated.
BACKGROUND OF THE INVENTION
[0002] Collagen is the single most abundant animal protein in
mammals, accounting for up to 30% of all proteins. The collagen
molecule, after being secreted by the fibroblast cell, assembles
into characteristic fibers responsible for the functional integrity
of tissues making up most organs in the body. The skin is the
largest organ of the body occupying the greatest surface area
within the human body. As age advances and as a result of other
noxious stimuli, such as the increased concentration of the
ultraviolet part of the electromagnetic spectrum as radiated from
the sun, structural integrity and elasticity of skin
diminishes.
[0003] Crosslinks between adjacent molecules are a prerequisite for
this integrity of the collagen fibers to withstand the physical
stresses to which they are exposed. A variety of human conditions,
normal and pathological, involve the ability of tissues to repair
and regenerate their collagenous framework. In the human, 13
collagen types have been identified. Of the different identifiable
types, type I is the most abundant in skin where it makes up 80 to
90% of the total collagen connective tissue. This type of collagen,
however, is less dynamic in the full-grown individual than its
counterparts in which collagen is involved in active remodeling. In
this case the normal collagen synthesizing activities in skin is
relatively quiescent exhibiting slow, almost negligible,
turnover.
[0004] The extra-cellular matrix of the various connective tissues,
such as skin, consists of complex macromolecules, collagen, elastin
and glycosaminoglycans (GAGs). The biosynthesis of these
macromolecules involves several specific reactions that are often
under stringent enzymatic control. The net accumulation of
connective tissues is thus, dependent upon the precise balance
between the synthesis and the degradation of the connective tissue
components.
[0005] Previous disclosures, such as U.S. Pat. No. 4,976,799 and
No. 5,137,539 have described methods and apparatus for achieving
controlled shrinkage of collagen tissue. These prior inventions
have applications to collagen shrinkage in many parts of the body
and describe specific references to the cosmetic and therapeutic
contraction of collagen connective tissue within the skin. In the
early 1980's it was found that by matching appropriate laser
exposure parameters with these conditions, one had a novel process
for the nondestructive thermal modification of collagen connective
tissue within the human body to provide beneficial changes. The
first clinical application of the process was for the
non-destructive modification of the radius of curvature of the
cornea of the eye to correct refractive errors, such as myopia,
hyperopia, astigmatism and presbyopia. New studies of this process
for the previously unobtainable tightening of the tympanic membrane
or ear drum for one type of deafness have been made.
[0006] In addition to addressing the traditional method of collagen
shrinkage wherein the ambient temperature is elevated within the
target tissue by about 23 degrees Celsius, the "thermal shrinkage
temperature" of collagen, T.sub.s, a novel method for obtaining
controlled contraction of collagen at a much lower temperature has
been developed. Evidence exists to elevate the mechanical role
played by the GAGs in the collagenous matrix. Removing or altering
these interstitial chemicals by enzymes or other reagents as
disclosed in U.S. Pat. No. 5,304,169 considerably weakens the
connective tissue integrity and influences the thermal
transformation temperature (T). Shrinkage temperature may be
defined, therefore, as the specific point at which disruptive
tendencies exceed the cohesive forces in this tissue. This
temperature, thus, makes this an actual measurement of the
stability of the collagen bearing tissue expressed in thermal
units.
[0007] The cause of wrinkles around the eyelids, mouth and lips is
multifactorial: photodamage, smoking and muscular activity such as
squinting and smiling all contribute. The end result is a general
loss of elasticity, which is a textural skin condition as opposed
to a skin redundancy or excess of skin tissue. The surgical
injection of reconstituted collagen is commonly used in order to
flatten the perioral lines. While oculoplastic surgeons may treat
this problem around the eye inappropriately by blepharoplasty, it
has been observed that even transconjunctival blepharoplasty for
removal of prolapsed retrobulbar fat fails to address the fine
periocular lines or wrinkles. Until recently, the main approach to
treating these blemishes has been chemical peeling by means of
trichloroacetic acid or phenol. Complications of chemical peels may
include hypopigmentation, scarring, cicatricial ectropion and
incomplete removal of the wrinkles.
[0008] Many patients are acutely aware of these cosmetic blemishes
as evidenced by the large quantity of money spent each year in the
U.S. and abroad upon home and spa remedies for a more youthful
appearance. With the advent of laser technology as an alternative
to chemical peels or dermabrasion, dermal ablation techniques with
both the conventional carbon dioxide lasers and the high energy,
short duration pulse waveform CO2 lasers, high tech solutions
appear to provide substantial benefits to patients.
[0009] CO2 laser resurfacing is not a new technique. CO2 lasers
have been used for several years, but regular continuous wave CO2
lasers can cause scarring due to the tissue destruction caused as
heat as conducted to adjacent tissue. Even superpulse CO2 lasers
produce excessive thermal damage. The Ultrapulse CO2 laser
introduced by Coherent, Inc. is an attempt to assuage these
drawbacks by offering a high energy, short duration pulse waveform
limiting the damage to less than 50 microns allowing a char-free,
layer by layer vaporization of the skin tissue.
[0010] All of the foregoing procedures depend for their success
upon primary damage and the reparative potential induced by the
inflammatory process in the tissue. Associated with inflammation
are, of course, the four cardinal signs of inflammation of rubor
(hyperemia), calor (thermal response), dolor (pain), and tumor or
edema or swelling. Coincident with these manifestations is the risk
of reduced resistance to infection. One must not forget that these
collateral effects accompany a cosmetic enhancement procedure and,
for the most part, are not associated with a therapeutic procedure.
Therefore, the development of a more efficacious method would be
beneficial in this regard.
[0011] Various undesirable skin conditions would be improved if the
collagen underlying the region of the condition could safely be
improved without damage to the overlying region. Wrinkles related
to photodamage and acne scars are example of such conditions.
[0012] U.S. Pat. Nos. 4,976,709, 5,137,530, 5,304,169, 5,374,265,
5,484,432 issued to Sand, disclose a method and apparatus for
controlled thermal shrinkage of collagen fibers in the cornea using
light at wavelengths between 1.8 and 2.55 microns. However strong
absorption of the laser energy by water limits the penetration
depth to the most superficial layers of skin.
[0013] The CoolTouch (trademark) 130 laser system by CoolTouch Corp
of Auburn, Calif., was first introduced at the Beverly Hills Eyelid
Symposium in 1995. It utilizes a laser at a wavelength of 1.32
microns to cause thermally mediated skin treatment. In this device
the treatment energy is targeted at the surface of the skin with in
depth optical heating of the epidermis, papillary dermis, and upper
reticular dermis. The energy is primarily absorbed in tissue water
with a skin absorption coefficient of 1.4 cm-1, corresponding to an
absorption depth of 0.71 cm. Scattering of the 1.32 micron
wavelength light by skin microstructures alters the distribution of
light from an exponential attenuation to a more complex
distribution, which has much faster attenuation approximating an
absorption depth of 0.1 cm. Most of the energy is absorbed in the
first 250 microns of tissue. To prevent overheating of the
epidermis pulsed cryogen spray precooling is used. U.S. Pat. No.
5,814,040, issued Sep. 29, 1998, describes a dynamic cooling method
utilizing pulsed cryogen spray precooling. Skin treated with this
device has improved texture and a reduction in wrinkles and
scarring due to the long term renewal of dermal collagen without
significant skin surface wounding.
[0014] U.S. Pat. No. 5,810,801 teaches a method and apparatus for
treating a wrinkle in skin by targeting tissue at a level between
100 microns and 1.2 millimeters below the surface, to thermally
injure collagen without erythema, by using light at wavelengths
between 1.3 and 1.8 microns. The parameters of the invention are
such that the radiation is maximally absorbed in the targeted
region. The invention offers a detailed description of targeting
the 100 micron to 1.2 mm region by utilization of a lens to focus
the treatment energy to a depth of 750 microns below the surface.
Because of the high scattering and absorption coefficients,
precooling is utilized to prevent excess heat build up in the
epidermis when targeting the region of 100 microns to 1.2 mm below
the surface. The wavelength range of use is 1.3 microns to 1.8
microns in order to avoid the wavelength range of Sand. However the
wavelength range of 1.4 to 1.54 microns and the range between 2.06
and 2.2 microns have identical effective attenuation coefficients
in skin. Also the range from 1.15 to 1.32 microns has a fairly
uniform effective attenuation coefficient in skin of about 6 to 7
cm.sup.-1. The effective attenuation length in skin for the range
of wavelengths of 1.3 to 1.8 microns varies from 6 cm-1 at 1.3
microns to 52 cm-1 microns, corresponding to penetration depths in
skin of 200 microns to 2 millimeters. Specific laser and cooling
parameters are selected so as to avoid erythema and achieve
improvement in wrinkles as the long term result of a new collagen
formation following treatment.
[0015] Kelly et al, report improvement in skin due to collagen
remodeling after treatments with an Nd:YAG laser at 1.32 microns
and cryogen spray precooling. In this case the method was designed
to provide a series of treatments with parameters selected to
produce erythema and mild edema, with some improvement in facial
rhytids several months following a series of treatments. However,
there is a risk of pigmentary change or transient pitted scarring
because of the high fluence level of the laser, greater than 30
joules per square centimeter in 20 millisecond exposures, and the
high level of pulse cryogen cooling.
[0016] Mucini et al. reported effective dermal remodeling using a
980 nm diode laser with a spherical handpiece which focused
irradiation into the dermis avoiding the high scattering and
absorption characteristic of longer wavelengths. The device
requires a small lens of a few millimeters in contact with skin and
results in a slow procedure when used for facial areas.
[0017] Ross et al., reported the use of an Erbium:YAG laser
operating at a wavelength of 1.54 microns fired in a multiple
pulsed mode has been described for eliciting changes in
photodamaged skin. A chilled lens in contact with skin at the
treatment site was used in an attempt to spare the epidermis.
Treatment occurred during a period of several seconds with a
sequence of cooling and heating with the laser and handpiece. At
1.54 microns the optical penetration depth 0.55 mm and the authors
reported that the surface must be chilled before the laser exposure
requiring a complex method of cooling and laser exposure. The
authors state that a more superficial thermal injury may be needed
than could be achieved, and that there are increased patient risks
because it would demand more accurate and precise control of
heating and cooling.
[0018] Bjerring et al, reported the use of a visible light laser,
operating at 585 nm wavelength, to initiate collagenesis following
interaction of laser energy with small blood vessels in skin.
[0019] Other methods of creating subepidermal wounding may utilize
electrical current, ultrasonic energy or non-coherent light
sources. In all of these methods, including those using lasers,
collagen remodeling is a long-term minimal response to the
application of energy. Since the objective is a non-invasive or
minimally invasive procedure the stimulation of collagenesis must
be below the threshold for creating an open wound, resulting in a
minimal treatment.
[0020] U.S. Pat. No. 5,599,788 describes a method of producing
recombinant transforming growth factor .beta.-induced H3 protein
and the use of this protein to accelerate wound healing. The
protein is applied directly to a wound or is used to promote
adhesion and spreading of dermal fibroblasts to a solid support
such as a nylon mesh which is then applied to the wound.
[0021] It is heretofore unknown to combine the adverse effect
caused by excessive photothermal, mechanical or other type of
energy applied to skin or other tissue coupled with a topical or
other administration of growth factor(s) or wound healing factor(s)
in order to amplify the natural stimulation of growth or
collagenesis caused by the wound.
OBJECTS AND ADVANTAGES OF THE PRESENT INVENTION
[0022] The object of this invention is to provide a method and
device for improving skin by treating layers of skin without
damaging the surface or deep skin layers. It is another object of
this invention to provide a method and device for improving acne
scars or photodamaged skin without causing a surface injury to
skin. It is another object of this invention to provide a method
and device for accelerating the collagenesis after treating skin
without damaging the surface of skin.
[0023] It is yet a further advantage and object of the present
invention to combine the adverse effect caused by excessive
photothermal, mechanical or other type of energy applied to skin or
other tissue coupled with a topical or other administration of
growth factor(s) or wound healing factor(s) in order to amplify the
natural stimulation of growth or collagenesis caused by the
wound.
[0024] The present invention circumvents the problems of the prior
art and provides a system for achieving erythema and mild edema in
an upper layer of skin without the risk of high fluence levels or
surface wounds. The invention offer advantages over existing
devices by allowing the use of lower fluence levels resulting in
faster treatments and less cost. Collagen remodeling is induced by
distributing the therapeutic energy over a series of more benign
treatments spaced weeks apart. The collagen remodeling is further
enhanced by the use of a transforming growth factor which
accelerates the wound healing response. Th growth factor is applied
topically in a media which will act on the skin.
[0025] Numerous other advantages and features of the present
invention will become readily apparent from the following detailed
description of the invention and the embodiments thereof, from the
claims and from the accompanying drawings.
SUMMARY OF THE PRESENT INVENTION
[0026] The present invention is a method and apparatus for skin or
other tissue treatment, using a source of thermal energy, which may
be electromagnetic radiation, electrical current, or ultrasonic
energy, to cause minimal-invasive thermally-mediated effects in
skin or other tissue leading to a wound-healing response, in
conjunction with topical agents which accelerate collagenesis in
response to wound healing. The dosage and time period of
application are adjusted to prevent external or surface tissue
damage.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] FIG. 1 is a cross-section view of typical skin tissue.
[0028] FIG. 2 is a graph demonstrating the temperature gradient
through a portion of the skin as a function of both the wavelength
of incident laser energy and the depth of laser radiation
penetration.
[0029] FIG. 3 is a schematic view of a microscope mounted scanner
for a temperature controlled collagen shrinkage device used in the
present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0030] The description that follows is presented to enable one
skilled in the art to make and use the present invention, and is
provided in the context of a particular application and its
requirements. Various modifications to the disclosed embodiments
will be apparent to those skilled in the art, and the general
principals discussed below may be applied to other embodiments and
applications without departing from the scope and spirit of the
invention. Therefore, the invention is not intended to be limited
to the embodiments disclosed, but the invention is to be given the
largest possible scope which is consistent with the principals and
features described herein.
[0031] It will be understood that while numerous preferred
embodiments of the present invention are presented herein, numerous
of the individual elements and functional aspects of the
embodiments are similar. Therefore, it will be understood that
structural elements of the numerous apparatus disclosed herein
having similar or identical function may have like reference
numerals associated therewith.
Definitions
[0032] An "absorption coefficient" of a substance is a measure of
the fraction of incident light that is absorbed when light is
passed through the substance. The absorption coefficient (typically
in units of cm.sup.-1) varies with the nature of the absorbing
substance and with the wavelength of the light.
[0033] "Collagen" as used herein refers to any of the several types
of collagen.
[0034] Collagen biosynthesis is said to be "inhibited" when cells
treated with the claimed methods secrete collagen at a rate that is
less than about 70% of that of untreated cells. Preferably, treated
cells secrete collagen at a rate that is less than about 50%, and
more preferably less than about 30% of the rate at which untreated
cells secrete collagen.
[0035] Collagen biosynthesis is said to be `stimulated` when cells
treated with the claimed methods secrete collagen at a rate that is
greater than about 110% of the rate at which untreated cells
synthesize collagen. Preferably, treated cells secrete collagen at
a rate that is about 150%, and more preferably greater than about
200% greater than that of untreated cells.
[0036] "Monochromatic" light is of one wavelength or a narrow range
of wavelengths. If the wavelength is in the visible range,
monochromatic light will be of a single color. As used herein,
"monochromatic" refers to light that has a bandwidth of less than
about 100 nm. More preferably, the bandwidth will be less than
about 10 nm, and most preferably less than about 1 nm.
[0037] "Non-coherent light energy" is light that is non-laser.
Unlike laser light, which is characterized by having its photon
wave motions in phase, the wave motions of the photons that make up
non-coherent light are in a randomly occurring phase order or are
otherwise out of phase.
[0038] A "wound" as used herein, refers to any damage to any tissue
in a living organism. The tissue may be an internal tissue, such as
the stomach lining or a bone, or an external tissue, such as the
skin. As such, a wound may include, but is not limited to, a
gastrointestinal tract ulcer, a broken bone, a neoplasia, and cut
or abraded skin. A wound may be in a soft tissue, such as the
spleen, or in a hard tissue, such as bone. The wound may have been
caused by any agent, including traumatic injury, infection or
surgical intervention.
[0039] A "growth factor" as used herein, includes any soluble
factor that regulates or mediates cell proliferation, cell
differentiation, tissue regeneration, cell attraction, wound repair
and/or any developmental or proliferative process. The growth
factor may be produced by any appropriate means including
extraction from natural sources, production through synthetic
chemistry, production through the use of recombinant DNA techniques
and any other techniques, including virally inactivated, growth
factor(s)-rich platelet releasate, which are known to those of
skill in the art. The term growth factor is meant to include any
precursors, mutants, derivatives, or other forms thereof which
possess similar biological activity(ies), or a subset thereof, to
those of the growth factor from which it is derived or otherwise
related.
[0040] FIG. 1 is a cross-section view of typical skin tissue. The
uppermost layer 98 of typical skin tissue is composed of dead cells
which form a tough, horny protective coating. A thin outer layer,
the epidermis 100 and a thicker inner layer, the dermis 102.
Intertwining S-like finger shaped portions 104 are at the interface
between the epidermal papillary layer 106 and the dermal papillary
layer 108, and extend downward. Beneath the dermis is the
subcutaneous tissue 110, which often contains a significant amount
of fat. It is the dermis layer which contains the major part of the
connective collagen which is to be shrunk, in a preferred
embodiment at an approximate target depth of between about 100 and
300 microns, according to the method of the present invention,
though viable collagen connective tissue also exists to a certain
degree in the lower subcutaneous layer as well. Other structures
found in typical skin include hair and an associated follicle 112,
sweat or sebaceous glands and associated pores 114, blood vessels
116 and nerves 118. Additionally, a pigment layer 120 might be
present. It will be understood that the drawing is representative
of typical skin and that the collagen matrix will take different
forms in different parts of the body. For example, in the eyelids
and cheeks the dermis and subcutaneous layers are significantly
thinner with less fat than in other areas. The target depth will be
a function of the amount of scattering in the particular skin type
and the associated absorption coefficient of the tissue.
Furthermore, in some cases the actual target depth will correspond
to one half the thickness of the subject tissue. For example, the
target depth of tissue 1/2 inch thick might be about 1/4 inch below
the surface of the skin.
A. Damage to Tissue
Optimum Wavelength: 1.3-1.4 Microns
[0041] Methods and devices for modulating collagen biosynthesis are
provided. The methods involve focusing non-coherent light energy of
a predetermined wavelength to a target site where collagen
biosynthesis can potentially occur. Depending upon the particular
wavelength employed, collagen biosynthesis is either inhibited or
stimulated. Generally, wavelengths in the red and near-infrared
portion of the electromagnetic spectrum stimulate collagen
biosynthesis, while longer wavelengths inhibit collagen
biosynthesis.
[0042] In a preferred embodiment, to inhibit collagen biosynthesis,
light energy of a wavelength greater than about 1.0 .mu.m,
preferably about 1.06 .mu.m, is delivered to the target site for a
time period sufficient to accomplish the inhibition. In a preferred
embodiment, stimulation of collagen biosynthesis occurs when light
energy at 640 nm or 900 nm is delivered to a target site for a time
period sufficient to accomplish the stimulation.
[0043] The optimal wavelength within these ranges is influenced by
whether the light energy must pass through overlying tissue before
reaching the target site. In such cases where the target site is
shielded by other tissue, the light energy is transmitted through
the shielding tissue and focused on the target site so that the
desired energy level is obtained at the target site. Because
transmission of light through tissue is highly wavelength specific,
one should choose a wavelength that is not highly absorbed by
overlying tissue.
[0044] To modulate collagen biosynthesis, an amount of light energy
of an appropriate predetermined wavelength is delivered to the
target site that is sufficient to have the desired stimulatory or
inhibitory effect. The amount of energy delivered to a target site
is a function of several factors, including the output of the light
source, the energy flux at the target site as determined by the
source output and the degree of focusing achieved by the light
delivery apparatus, and the time period for which the target site
is exposed to the light energy. Another factor, discussed below, is
the nature of any tissue overlying the target site.
[0045] The appropriate combinations of energy flux and time period
for a desired effect on collagen biosynthesis can be determined
empirically. For example, one can determine the effect on collagen
biosynthesis of irradiating cells growing in tissue, preferably in
monolayers, with light energy of a given wavelength, energy flux,
and time period.
[0046] In general, the desired energy density delivered to the
target site is between about 1.0.times.10.sup.3 and
1.6.times.10.sup.3 Joules cm.sup.-2. Preferably, the energy density
at the target site is about 1.1.times.10.sup.3 Joules cm.sup.-2.
For most applications, the amount of energy delivered to the target
site should be sufficient to modulate collagen
[0047] biosynthesis, but should not be so great as to cause a
significant decrease in cell proliferation. For example,
1.7.times.10.sup.3 Joules cm.sup.-2 of 1064 nm laser light is known
to inhibit fibroblast proliferation. Thus, an energy that is
between about 1.1.times.10.sup.3 and about 1.7.times.10.sup.3
Joules cm.sup.-2 is preferred.
[0048] To achieve the desired energy density, the light energy is
delivered to the target site for a sufficient time period. The time
period necessary depends on the energy flux delivered to the target
site by the light delivery apparatus. The light can be delivered as
a single pulse or as a multiplicity of pulses. Often, the use of
short pulses is preferred, as the shorter pulses cause less
undesirable heating of the tissues surrounding the target site than
does a single pulse of longer duration. Preferably, a higher-power
shorter-duration pulse is used, rather than a low-power
long-duration pulse. Typical pulse durations are between about 0.01
and 1.0 seconds, most preferably about 0.1 seconds.
Light Delivery Apparatus
[0049] Many types of non-laser light sources are suitable for
producing the noncoherent light that is used in the methods and
apparatus of the present invention. For example, one can employ
polychromatic light sources such as heated lamp filaments or gas
filled vacuum tubes. Commercially available light sources are
discussed in, for example, LaRocca, A., "Artificial Sources," In
Handbook of Optics, Vol. 1, Ch. 10, Bass et al., eds., McGraw-Hill,
New York, 1995, pp. 10.3-10.50, and references cited therein.
[0050] If a polychromatic light source is used, the light energy is
preferably made monochromatic or nearly monochromatic by suitable
methods known to those of skill in the art. For example, one can
direct the polychromatic light through a filter or a series of
filters that transmits only light of the desired wavelength or
range of wavelengths. Suitable filters are described in, for
example, Dobrowolski, J. A., "Optical Properties of Films and
Coatings," In Handbook of Optics, Vol. 1, Ch. 42, Bass et al.,
eds., McGraw-Hill, New York, 1995, pp. 42.3-42.130, and references
cited therein. Bandpass filters are reviewed, for example, in
Macleod, H. A., 7hin film Optical E7Iters, McGraw-Hill, New York,
1986; `Metal-dielectric Interference Filters," in Physics of 7hin
Films, Hass et al., eds., Academic Press, New York, 1977, vol. 9,
pp. 73-144; Barr, "The Design and Construction of Evaporated
Multilayer Filters for Use in Solar Radiation Technology," in
Advances in Geophysics, Drummond, ed., Academic Press, New York,
1970, pp. 391-412).
[0051] In a preferred embodiment, a monochromatic or nearly
monochromatic light source is used. By choosing a light source that
emits monochromatic or nearly monochromatic light, the need to
filter or focus the light to the desired wavelength is eliminated.
Several types of monochromatic or nearly monochromatic light source
are known to those of skill in the art. See, e.g., LaRocca, supra.,
for types and sources of monochromatic light sources.
[0052] Light-emitting diodes (LEDs) are a preferred light source
for use in the claimed invention. LEDs are described, for example,
in Haitz et al., "Light-Emitting Diodes," In Handbook of Optics,
Vol. 1, Ch. 12, Bass, M., ed., McGraw-Hill, New York, pp.
12.1-12.39. Both surface and edge emitters are commercially
available, in continuous and pulse-operated modes. Commercially
available LEDs that are useful in the claimed methods emit
wavelengths of 830, 904, 1060, 1300, and 1550 nm. In preferred
embodiments of the present invention, the 830 and 904 nm LEDs are
useful for stimulating collagen biosynthesis, while in other
preferred embodiments of the present invention, the 1060, 1300, and
1550 nm LEDs are appropriate for inhibition.
[0053] Light energy used in the claimed methods is preferably
collimated, in addition to being of a predetermined wavelength or
range of wavelengths. Collimation can be achieved by any of several
methods known to those of skill in the art. For example, passing
light through fiber optics of various core diameters will achieve
collimation. Suitable fiber optic instrumentation is available from
EG&G Opto-Electronics of Salem, Mass. Optical fibers are
described, for example, in Brown, T. G., "Optical Fibers and
Fiber-Optic Communications," In Handbook of Optics, Vol. U, Ch. 10,
Bass, M., ed., McGraw-Hill, New York, pp. 10.1 et seq.
[0054] The light energy is focused to the target site as a spot
having a diameter that is appropriate for the particular treatment
being undertaken. Where inhibition of collagen biosynthesis in a
relatively small area is used, the light is focused to a
correspondingly small spot at the target site. Typically, the light
energy is focused to a spot with a diameter in the range of about
0.25 to about 2.0 millimeters. The focusing step also concentrates
the light to an energy flux that is sufficient to achieve the
desired inhibition when delivered to the target site for an
appropriate period of time.
[0055] Methods for focusing light to achieve a desired energy flux
and spot diameter are known to those of skill in the art. For
example, a focusing lens made of glass, silica, or refractory
material such as diamond or sapphire is commonly employed. In a
preferred embodiment, the focusing lens directs the non-coherent
light energy to an optical fiber of an appropriate core diameter
and composition. For example, a 100 .mu.m diameter low-OH silica
optic fiber is appropriate. A fiber that produces a relatively low
amount of transmission loss is preferred, preferably less than
about 15% loss over a length of up to ten meters. The fiber is
typically mounted in a shaft for delivery of the non-coherent light
energy to the tissue. The output end of the shaft is preferably
fitted with an output tip that can dir maintaining the delivery end
of the fiber a desired distance away from the tissue. This distance
can be varied by substituting a longer or shorter output tip, or by
slidably adjusting the position of the output tip on the shaft.
[0056] For some applications, it is desirable to use an output tip
that directs the noncoherent focused light out of its side, rather
than through the end of the fiber. Means for accomplishing this are
known to those of skill in the art. For example, U.S. Pat. No.
5,129,895 describes the use of a reflecting surface at the end of
the fiber combined with lens action on the fiber side.
[0057] The invention also provides an apparatus for modulating
collagen biosynthesis according to the methods described herein.
The apparatus comprises a source of noncoherent light energy, a
means for collimating the light energy generated by the light
source, and a means for focusing the collimated light energy to a
target site. The apparatus delivers sufficient light energy to the
target site to modulate collagen biosynthesis.
Therapeutic Applications
[0058] The claimed methods for modulating collagen biosynthesis are
useful in treating many conditions. Depending upon the condition
being treated, either inhibition or stimulation of collagen
biosynthesis may be desired.
[0059] The invention also provides methods for stimulating collagen
biosynthesis. These methods are also useful in the clinical
setting. For example, stimulation of collagen biosynthesis is often
desirable in the early stages of wound healing. The procedures
employed are similar to those used for inhibiting collagen
biosynthesis, except for the wavelength of light delivered to the
target site. To stimulate collagen biosynthesis, one delivers light
in the red or near-infrared range of the electromagnetic spectrum
to the target site. For example, light energy at 640 nm or 900 nm
stimulates collagen biosynthesis when delivered to a target site at
specific energy densities and durations.
[0060] To enhance wound healing, collimated fight energy of an
appropriate wavelength is delivered to the wound at an energy
density sufficient to stimulate collagen biosynthesis. The light
energy can be delivered as a single pulse, or more preferably, as a
series of short pulses. The use of short pulses reduces the
likelihood of undesired heating of the tissue. Preferably, the
light energy delivered is sufficient to stimulate collagen
biosynthesis, but is insufficient to inhibit cell
proliferation.
[0061] FIG. 2 is a graph demonstrating the temperature gradient
through a portion of the skin as a function of both the wavelength
of incident laser energy and the depth of laser radiation
penetration. No external cooling is used. The graph demonstrates a
change in temperature (.DELTA.T) of about 60 degrees Celsius and
all curves are shown for the time point 1 millisecond following
exposure to the laser energy. The graph shows three lines
corresponding to laser wavelengths of 10.6 microns, 1.3-1.4 microns
and 1.06 microns.
[0062] The present invention utilizes laser energy having a
wavelength between about 1 and about 12 microns, more preferably
between about 1.2 and about 1.8 microns, and more preferably about
1.3-1.4 microns. This type of laser energy is most frequently
produced by a Nd:YAG, Nd:YAP or Nd:YALO-type laser. A laser
operating at these wavelengths may either have a high repetition
pulse rate or operate in a continuous wave mode. This laser has
been investigated in the medical community as a general surgical
and tissue welding device, but has not been used for collagen
tissue shrinkage in the past. Indeed, the prior art teaches away
from the use of laser energy at 1.3-1.4 microns for shrinking human
collagen.
[0063] The Nd:YAG, Nd:YAP and Nd:YALO-type lasers are sources of
coherent energy. This wavelength of 1.3-1.4 microns is absorbed
relatively well by water, and as a result is attractive for tissue
interaction. It is also easily transmitted through a fiber optic
delivery system as opposed to the rigid articulated arm required
for the CO.sub.2 laser. Very precise methods of controlling laser
systems and optically filtering produced light currently exist. By
selecting the appropriate combination of resonance optics and/or
anti-reflection coatings, wavelengths in the range of 1.3-1.4
microns and even 1.32-1.34 microns can be produced.
[0064] FIG. 3 is a schematic view of a microscope mounted scanner
for a temperature controlled collagen shrinkage device used in the
present invention. In this view, a laser console 60 is installed
adjacent a floor-mounted microscope 62. A fiber optic cable 64
conducts laser energy from the laser source to the scanner 66. A
laser delivery attachment 68 may be necessary to conduct the laser
energy in an appropriate beam pattern and focus. In this embodiment
of the invention, servo feedback 70 signals are also conducted
along the fiber optic back to the laser console. The servo feedback
signals could also be directed back to the laser console via an
additional fiber optic or other wiring or cabling. This servo
feedback may comprise thermal or optical data obtained via external
sensors or via internal systems, such as a fiber-tip protection
system which attenuates the laser energy transmitted, to provide
control in operation and to prevent thermal runaway in the laser
delivery device. Thus, a thermal feedback controller 72 will
regulate the laser energy being transmitted. This controller can
comprise an analog or digital PI, PD or PID-type controller, a
microprocessor and set of operating instructions, or any other
controller known to those skilled in the art. Other preferred
embodiments can also be provided with additional features. For
example, the surgeon or technician operating the laser could also
manipulate an energy adjust knob 74, a calibration knob 76 and a
footpedal 78. Thus, in a preferred embodiment, a very accurately
adjustable system is provided which allows a surgeon to deliver
laser energy via a computer controlled scanning device, according
to instructions given by the surgeon or an observer inspecting the
region of the skin where collagen is to be shrunk through a very
accurate microscope. Once a region to be treated is located, the
scanner can deliver a very precise, predetermined amount of laser
energy, in precisely chosen, predetermined regions of the skin over
specific, predetermined periods of time.
[0065] In a preferred embodiment, the invention utilizes an Nd:YAG
laser at 1320 nm wavelength, (such as the CoolTouch 130, CoolTouch
Corp., Auburn, Calif.) as the source of treatment energy. At 1320
nm the absorption depth in tissue is such that energy is deposited
throughout the upper dermis, with most absorption in the epidermis
and upper dermis, a region including the top 200 to 400 microns of
tissue. The energy falls off approximately exponentially with the
highest level of absorbed energy in the epidermis. Optical heating
of skin follows exposure to the laser energy. If the time of
exposure to the laser is very short compared to the time required
for heat to diffuse out of the area exposed, the thermal relaxation
time, than the temperature rise at any depth in the exposed tissue
will be proportional to the energy absorbed at that depth. However,
if the pulse width is comparable or longer to the thermal
relaxation time of the exposed tissue than profile of temperature
rise will not be as steep. Conduction of thermal energy occurs at a
rate proportional to the temperature gradient in the exposed
tissue. Lengthening the exposure time will reduce the maximum
temperature rise in exposed tissue.
[0066] For example at 1.3 microns the laser pulse width may be set
to 30 milliseconds and fluence to less than 30 joules per square
centimeter. This prevents excessive heat build up in the epidermis,
which is approximately the top 100 microns in skin. The papillary
dermis can then be heated to a therapeutic level without damage to
the epidermis. The epidermis will reach a temperature higher than
but close to that of the papillary dermis.
[0067] The epidermis is more resilient in handling extremes of
temperature than most other tissue in the human body. It is
therefore possible to treat the papillary dermis in conjunction
with the epidermis without scarring or blistering, by treating both
layers with laser energy and allowing a long enough exposure time
such that the thermal gradient between the epidermis and underlying
layers remains low. In this way the underlying layers can be
treated without thermal damage to the epidermis.
[0068] A wavelength of 1.3 microns is used in this embodiment to
treat the middle layers of skin. Other wavelengths such as 1.45 or
2.1 microns may by used to treat more superficial layers of skin by
this method. Visible light lasers, intense pulsed light sources,
energy delivery devices such as electrical generators, ultrasonic
transducers, and microdermabrasion devices may also be used to
initiate a wound healing response without significant surface
wounding. The use of growth factors in conjunction with these
devices allows for more superficial treatments and improved
response.
[0069] In one embodiment the invention utilizes an Nd:YAG laser at
1320 nm wavelength, (such as the CoolTouch 130, CoolTouch Corp.,
Auburn Calif.) as the source of treatment energy. At 1320 nm the
absorption depth in tissue is such that energy is deposited
throughout the upper dermis, with most absorption in the epidermis
and upper dermis, a region including the top 200 to 400 microns of
tissue. The energy falls off approximately exponentially with the
highest level of absorbed energy in the epidermis. Optical heating
of skin follows exposure to the laser energy. If the time of
exposure to the laser is very short compared to the time required
for heat to diffuse out of the area exposed, the thermal relaxation
time, than the temperature rise at any depth in the exposed tissue
will be proportional to the energy absorbed at that depth. However,
if the pulse width is comparable or longer to the thermal
relaxation time of the exposed tissue than profile of temperature
rise will not be as steep. Conduction of thermal energy occurs at a
rate proportional to the temperature gradient in the exposed
tissue. Lengthening the exposure time will reduce the maximum
temperature rise in exposed tissue.
[0070] The present invention also incorporates herein by specific
reference, in their entireties, the following issued U.S.
patents:
[0071] U.S. Pat. No. 5,885,274 issued Mar. 3, 1999 titled FLASH
LAMP FOR DERMATOLOGICAL TREATMENT, U.S. Pat. No. 5,968,034 issued
Oct. 19, 1999 titled PULSED FILAMENT LAMP FOR DERMATOLOGICAL
TREATMENT, U.S. Pat. No. 5,820,626 issued Oct. 13, 1998 titled
COOLING LASER HANDPIECE WITH REFILLABLE COOLANT RESERVOIR,U.S. Pat.
No. 5,976,123 issued Nov. 2, 1999 titled HEART STABILIZATION, U.S.
Pat. No. 6,273,885 issued Aug. 14, 2001 titled HANDHELD
PHOTOEPILATION DEVICE AND METHOD.
[0072] The present invention also incorporates herein by specific
reference, in their entireties, the following pending U.S. patent
applications: application Ser. No. 09/185,490 filed Nov. 3, 1998
titled SUBSURFACE HEATING OF TISSUE, application Ser. No.
09/364,275 filed Jul. 29, 1999 titled THERMAL QUENCHING OF
TISSUE.
B. Wound Healing and Growth Factors
[0073] When a tissue is injured, polypeptide growth factors, which
exhibit an array of biological activities, are released into the
wound where they play a crucial role in healing (see, e.g.,
Hormonal Proteins and Peptides (Li, C. H., ed.) Volume 7, Academic
Press, Inc., New York, N.Y. pp. 231-277 (1979) and Brunt et al.,
Biotechnology 6:25-30 (1988)). These activities include recruiting
cells, such as leukocytes and fibroblasts, into the injured area,
and inducing cell proliferation and differentiation. Growth factors
that may participate in wound healing include, but are not limited
to: platelet-derived growth factors (PDGFs); insulin-binding growth
factor-1 (IGF-1); insulin-binding growth factor-2 (IGF-2);
epidermal growth factor (EGF); transforming growth factor-.alpha.
(TGF-.alpha.); transforming growth factor-.beta. (TGF-.beta.);
platelet factor 4 (PF-4); and heparin binding growth factors one
and two (HBGF-1 and HBGF-2, respectively).
[0074] PDGFs are stored in the alpha granules of circulating
platelets and are released at wound sites during blood clotting
(see, e.g., Lynch et al., J. Clin. Invest. 84:640-646 (1989)).
PDGFs include: PDGF; platelet derived angiogenesis factor (PDAF);
TGF-.beta.; and PF4, which is a chemoattractant for neutrophils
(Knighton et al., in Growth Factors and Other Aspects of Wound
Healing: Biological and Clinical Implications, Alan R. Liss, Inc.,
New York, N.Y., pp. 319-329 (1988)). PDGF is a mitogen,
chemoattractant and a stimulator of protein synthesis in cells of
mesenchymal origin, including fibroblasts and smooth muscle cells.
PDGF is also a nonmitogenic chemoattractant for endothelial cells
(see, for example, Adelmann-Grill et al., Eur. J. Cell Biol.
51:322-326 (1990)).
[0075] IGF-1 acts in combination with PDGF to promote mitogenesis
and protein synthesis in mesenchymal cells in culture. Application
of either PDGF or IGF-1 alone to skin wounds does not enhance
healing, but application of both factors together appears to
promote connective tissue and epithelial tissue growth (Lynch et
al., Proc. Natl. Acad. Sci. 76:1279-1283 (1987)).
[0076] TGF-.beta. is a chemoattractant for macrophages and
monocytes. Depending upon the presence or absence of other growth
factors, TGF-.beta. may stimulate or inhibit the growth of many
cell types.
[0077] Other growth factors, such as EGF, TGF-.alpha., the HBGFs
and osteogenin are also important in wound healing. Topical
application of EGF accelerates the rate of healing of partial
thickness wounds in humans (Schultz et al., Science 235:350-352
(1987)). Osteogenin, which has been purified from demineralized
bone, appears to promote bone growth (see, e.g., Luyten et al., J.
Biol. Chem. 264:13377 (1989)). In addition, platelet-derived wound
healing formula, a platelet extract which is in the form of a salve
or ointment for topical application, has been described (see, e.g.,
Knighton et al., Ann. Surg. 204:322-330 (1986)).
[0078] The heparin binding growth factors (HBGFs), including the
fibroblast growth factors (FGFs), which include acidic HBGF (aHBGF
also known as HBFG-1 or FGF-1) and basic HBGF (bHBGF also known as
HBGF-2 or FGF-2), are potent mitogens for cells of mesodermal and
neuroectodermal lineages, including endothelial cells (see, e.g.,
Burgess et al., Ann. Rev. Biochem. 58:575-606 (1989)). In addition,
HBGF-1 is chemotactic for endothelial cells and astroglial cells.
Both HBGF-1 and HBGF-2 bind to heparin, which protects them from
proteolytic degradation. The array of biological activities
exhibited by the HBGFs suggests that they play an important role in
wound healing.
[0079] Basic fibroblast growth factor (FGF-2) is a potent
stimulator of angiogenesis and the migration and proliferation of
fibroblasts (see, for example, Gospodarowicz et al., Mol. Cell.
Endocinol. 46:187-204 (1986) and Gospodarowicz et al., Endo. Rev.
8:95-114 (1985)). Acidic fibroblast growth factor (FGF-1) has been
shown to be a potent angiogenic factor for endothelial cells
(Burgess et al., supra, 1989). Other FGF's may be chemotactic for
fibroblasts. Growth factors are, therefore, potentially useful for
specifically promoting wound healing and tissue repair.
[0080] "HBGF-1," which is also known to those of skill in the art
by alternative names, such as endothelial cell growth factor (ECGF)
and FGF-1, as used herein, refers to any biologically active form
of HBGF-1, including HBGF-1.beta., which is the precursor of
HBGF-1.alpha. and other truncated forms, such as FGF. U.S. Pat. No.
4,868,113 to Jaye et al., herein incorporated by reference, sets
forth the amino acid sequences of each form of HBGF. HBGF-1 thus
includes any biologically active peptide, including precursors,
truncated or other modified forms, or mutants thereof that exhibit
the biological activities, or a subset thereof, of HBGF-1.
[0081] Other growth factors may also be known to those of skill in
the art by alternative nomenclature. Accordingly, reference herein
to a particular growth factor by one name also includes any other
names by which the factor is known to those of skill in the art and
also includes any biologically active derivatives or precursors,
truncated mutant, or otherwise modified forms thereof.
[0082] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which the present invention belongs.
Although any methods and materials similar or equivalent to those
described can be used in the practice or testing of the present
invention, the preferred methods and materials are now described.
All publications and patent documents referenced in the present
invention are incorporated herein by reference.
[0083] While the principles of the invention have been made clear
in illustrative embodiments, there will be immediately obvious to
those skilled in the art many modifications of structure,
arrangement, proportions, the elements, materials, and components
used in the practice of the invention, and otherwise, which are
particularly adapted to specific environments and operative
requirements without departing from those principles. The appended
claims are intended to cover and embrace any and all such
modifications, with the limits only of the true purview, spirit and
scope of the invention.
* * * * *