WO2015031189A1 - Traitement de surfaces de peau ciblées à administration ciblée de nanoparticules - Google Patents

Traitement de surfaces de peau ciblées à administration ciblée de nanoparticules Download PDF

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Publication number
WO2015031189A1
WO2015031189A1 PCT/US2014/052266 US2014052266W WO2015031189A1 WO 2015031189 A1 WO2015031189 A1 WO 2015031189A1 US 2014052266 W US2014052266 W US 2014052266W WO 2015031189 A1 WO2015031189 A1 WO 2015031189A1
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Prior art keywords
skin
nanoparticles
plasmonic nanoparticles
plasmonic
kit
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Application number
PCT/US2014/052266
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English (en)
Inventor
Todd James Harris
Alice Ann Chen KIM
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Sienna Labs, Inc.
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Publication date
Priority claimed from US14/321,509 external-priority patent/US9572880B2/en
Application filed by Sienna Labs, Inc. filed Critical Sienna Labs, Inc.
Publication of WO2015031189A1 publication Critical patent/WO2015031189A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0092—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0241—Containing particulates characterized by their shape and/or structure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/008—Preparations for oily skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/41—Particular ingredients further characterized by their size
    • A61K2800/413—Nanosized, i.e. having sizes below 100 nm
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/81—Preparation or application process involves irradiation

Definitions

  • the field of the invention comprises nanoparticles and/or photoactive compounds for use in cosmetic, diagnostic and/or therapeutic procedures, including ultrasonic delivery systems and methods for delivering the particles and/or compounds to a target tissue.
  • Ultrasound is low frequency ultrasound delivered by, for example, a transducer or sonotrode.
  • the invention relates to using laser or light energy combined with nanoparticles and/or photoactive compounds to modify, smooth, and/or resurface the skin (including tissue under the skin surface) of humans. Description of the Related Art
  • Laser treatments of the skin have been highly advocated for therapeutic and cosmetic utility.
  • potential uses for laser skin therapy include laser ablation of cancerous cells in cancer patients and laser ablation of damaged tissue in burn victims.
  • Cosmetic applications for laser skin therapy are much more numerous, and include hair removal/reduction, treatment of dyschromia, shrinking of the skin following operations such as liposuction, acne treatment, chemical or physical abrasion of unwanted markings on the skin, surgical treatments including nose reduction and face- and neck-lifts, and other aesthetic skin remodeling purposes.
  • the invention relates to using laser or light energy combined with nanoparticles and/or photoactive compounds to treat the skin (including tissue under the skin surface) using ultrasound to facilitate the delivery of the nanoparticles and/or photoactive compounds.
  • the invention is able to modify, smooth, and/or resurface the skin (including tissue under the skin surface) of humans.
  • Several embodiments of the present invention also relate to methods for focusing electromagnetic energy with particles and/or photoactive compounds to selectively heat target regions of skin with a discrete, often minute, size and shape for the treatment of acne, especially acne scars, while not damaging surrounding skin tissue.
  • the particles can be microparticles and/or nanoparticles.
  • compositions and methods useful in the targeted thermomodulation of target cell populations and target tissues for the purposes of cosmetic treatments and the treatment and prevention of chronic and acute diseases and disorders and enhanced delivery systems and methods (e.g., using ultrasound) for delivering the particles and/or compounds to a target tissue.
  • a method of delivering a composition to a target tissue under a skin surface with a delivery device includes applying a composition to a skin surface, and distributing the composition from the skin surface to a target tissue under the skin surface with a delivery device.
  • the delivery device is an ultrasound device.
  • the composition comprises a plurality of unassembled plasmonic nanoparticles.
  • the unassembled plasmonic nanoparticles comprise a conductive metal portion.
  • the conductive metal portion comprises at least one of gold or silver.
  • the unassembled plasmonic nanoparticles have a size in a range of 10 nm to 300 nm.
  • the unassembled plasmonic nanoparticles comprise a coating that coats the conductive metal portion, wherein the coating facilitates selective removal from the skin surface.
  • the coating comprises at least one of silica or polyethylene glycol (PEG).
  • the unassembled plasmonic nanoparticles have a concentration of 10 9 to 1023 particles per ml of the composition, wherein the concentration is sufficient to, after exposure to irradiation, induce thermal damage in a sebaceous gland.
  • the method includes selectively removing the composition from the skin surface, while leaving the composition localized within the sebaceous gland.
  • the method includes irradiating the composition with an infrared light source thereby inducing a plurality of surface plasmons in the unassembled plasmonic nanoparticles.
  • the plurality of surface plasmons generates localized heat in the target tissue.
  • the mechanical vibration device is a low frequency ultrasound device.
  • the method includes pre-treating the skin surface prior to irradiating the composition, wherein pre- treating the skin surface comprises hair removal.
  • the unassembled plasmonic nanoparticles comprise an optical density of 10 O.D. to 5,000 O.D. at an infrared light range.
  • the unassembled plasmonic nanoparticles comprise a solid, conducting silver core and a silica coating.
  • the conductive metal portion is a silver nanoplate, and the coating is less conductive than the conductive metal portion.
  • the conductive metal portion is a nanoplate, and the nanoplate has a peak absorption wavelength in a range of 750 nm to 1200 nm.
  • the coating comprises silica, wherein generation of localized heat is sufficient to affect at least one of a sebocyte and sebum.
  • a method of delivering a composition to a sebaceous gland includes topically applying a solution of unassembled plasmonic nanoparticles to a skin surface, and targeting a sebaceous gland by redistributing the solution of unassembled plasmonic nanoparticles from the skin surface to the sebaceous gland with a delivery device.
  • the delivery device is a mechanical vibration device, wherein the mechanical vibration device comprises at least one of the group consisting of an ultrasound device and a massage device.
  • the unassembled plasmonic nanoparticles have a dimension in a range of 10 nm to 300 nm.
  • the unassembled plasmonic nanoparticles have a concentration of 10 9 to 1023 particles per ml of the solution.
  • the unassembled plasmonic nanoparticles comprise a conductive metal portion.
  • the conductive metal portion comprises at least one of gold or silver.
  • the unassembled plasmonic nanoparticles comprise a coating that coats the conductive metal portion, wherein the coating facilitates selective removal from the skin surface.
  • the coating comprises at least one of silica or polyethylene glycol (PEG).
  • the method includes selectively removing the solution from the skin surface, while leaving the solution localized within the sebaceous gland.
  • the method includes irradiating the solution of unassembled plasmonic nanoparticles with an energy wavelength in a range of 750 nm to 1200 nm to induce a plurality of surface plasmons in the unassembled plasmonic nanoparticles, thereby treating acne at the sebaceous gland.
  • the mechanical vibration device is configured for bubble formation or liquid microstreaming.
  • the method includes pre-treating the skin surface to increase delivery of the unassembled plasmonic nanoparticles to the sebaceous gland with at least one of the group consisting of shaving, waxing, peeling, cyanoacrylate surface peeling, a calcium thioglycolate treatment, a surface exfoliation, a mechanical exfoliation, a salt glow, a microdermabrasion, a chemical exfoliation, a chemical exfoliation with an enzyme, a chemical exfoliation with alphahydroxy acid, and a chemical exfoliation with betahydroxy acid.
  • the concentration of the unassembled plasmonic nanoparticles is 10 9 to 10 16 particles per ml of the solution.
  • the coating is less conductive than the conductive metal portion.
  • the unassembled plasmonic nanoparticles have an optical density of 10 O.D. to 5,000 O.D. within an infrared light range.
  • the coating is semiconductive, wherein the conductive metal portion is inside the coating, and wherein the coating is less conductive than the conductive metal portion.
  • the conductive metal portion is a nanoplate, and wherein the coating is less conductive than the conductive metal portion.
  • a method of delivering a composition of unassembled plasmonic nanoparticles to a pilosebaceous unit includes applying a solution of unassembled plasmonic nanoparticles to a skin surface, and distributing the solution of unassembled plasmonic nanoparticles with a mechanical vibration device from the skin surface to a pilosebaceous unit thereby targeting the pilosebaceous unit.
  • the mechanical vibration device comprises at least one of the group consisting of an ultrasound device, a sonic force device, a massage device, a high pressure air flow device, a high pressure liquid flow device, and a vacuum device, and a dermabrasion device.
  • the pilosebaceous unit comprises one or more structures consisting of: a hair shaft, a hair follicle, a sebaceous gland, and a hair follicle infundibulum.
  • the unassembled plasmonic nanoparticles comprise a conductive metal portion.
  • the conductive metal portion comprises at least one of gold or silver.
  • the unassembled plasmonic nanoparticles have a peak absorption wavelength of between 750 nm and 1200 nm.
  • the unassembled plasmonic nanoparticles have a concentration of 10 9 to 1023 particles per ml of the solution.
  • the unassembled plasmonic nanoparticles comprise a coating that coats the conductive metal portion.
  • the coating comprises at least one of silica or polyethylene glycol (PEG).
  • the method includes selectively removing the solution from the skin surface while leaving the solution localized within the portion of the sebaceous gland.
  • the method includes irradiating the solution with an energy to induce the unassembled plasmonic nanoparticles to generate localized thermal damage in the sebaceous gland.
  • the method includes pre-treating the skin surface to increase delivery of the unassembled plasmonic nanoparticles to the pilosebaceous unit with at least one of the group consisting of shaving, waxing, peeling, cyanoacrylate surface peeling, a calcium thioglycolate treatment, a surface exfoliation, a mechanical exfoliation, a salt glow, a microdermabrasion, a chemical exfoliation, a chemical exfoliation with an enzyme, a chemical exfoliation with alphahydroxy acid, and a chemical exfoliation with betahydroxy acid.
  • the method includes irradiating the solution of unassembled plasmonic nanoparticles comprises exposing the solution of unassembled plasmonic nanoparticles to the energy at a wavelength of between 750 nm and 1200 nm to induce a plurality of surface plasmons in the unassembled plasmonic nanoparticles, thereby treating acne at the sebaceous gland.
  • the mechanical vibration device comprises at least a low frequency ultrasound device.
  • the method includes irradiating the solution of unassembled plasmonic nanoparticles with the energy comprises an infrared light source wavelength of between 750 nm and 1200 nm to induce a plurality of surface plasmons in the unassembled plasmonic nanoparticles, thereby treating acne at the sebaceous gland.
  • the unassembled plasmonic nanoparticles are nanoplates.
  • the unassembled plasmonic nanoparticles have an optical density of 10 O.D. to 5,000 O.D. within an infrared light range and the concentration is 10 9 to 1018 particles per ml of the solution.
  • the method includes irradiating the solution of unassembled plasmonic nanoparticles with the energy comprises an infrared wavelength of between 750 nm and 1200 nm to induce a plurality of surface plasmons in the unassembled plasmonic nanoparticles, thereby heating the pilosebaceous unit.
  • selectively removing the composition from the skin surface comprises using water or alcohol to remove the composition from the skin surface while leaving the composition localized within the pilosebaceous unit.
  • Several embodiments of the present invention provide safe, tolerable, and efficacious treatments for acne and acne scarring that achieve prolonged improvement of the skin.
  • Other light based treatments for acne including photodynamic therapy (PDT) and long wave length lasers (e.g. 1450nm), tend to need high energy illumination and may lack target specificity, which can lead to intolerable off-target side-effects including sensitivity to light, pain, inflammation, hyper/hypo-pigmentation, and permanent scarring.
  • PDT photodynamic therapy
  • long wave length lasers e.g. 1450nm
  • Many traditional light based procedures for treating acne scars including ablative and non-ablative skin resurfacing, often involve aggressive treatment settings that lead to long healing times and risk of side-effect (e.g., hyperpigmentation, scarring).
  • Several embodiments of the present invention are particularly effective for box car scars, ice pick scars, and other pitted scars, where excision is otherwise considered among the only reliable methods for treatment.
  • Human skin is vulnerable to damage, scarring, and an overall decline in skin smoothness or texture from disease, trauma, environmental exposure, and aging. Consumer demand for aesthetic skin enhancement that has minimal risk and provides rapid recovery has resulted in efforts to provide methods of non-surgical skin rejuvenation including skin resurfacing (e.g., lasabration, laser peel and laser vaporization).
  • skin resurfacing e.g., lasabration, laser peel and laser vaporization
  • many skin resurfacing and other techniques resulting in the removal of epidermal layers fail to address deeper, dermal-layer scars and skin lesions.
  • Skin resurfacing generally involves controlled removal and, optionally, regeneration of the skin either from ablative or non-ablative damage. In general, these and related aesthetic procedures use electro-magnetic energy and/or heat to induce thermal injury in areas of the skin, and are often considered minimally invasive. Much of the prior work in skin resurfacing involves either non-fractional skin resurfacing or fractional skin resurfacing.
  • Non-fractional skin resurfacing uses non-fractional high-energy pulsed and/or scanned C0 2 or Er:YAG lasers, the energy from which when directed to the skin remove skin material in a controlled manner.
  • Several embodiments of the present invention are particularly advantageous because some or all of the following advantages are present: (i) prolonged and unpleasant postoperative recovery period characterized by edema, oozing, and burning discomfort are avoided, (ii) substantial patient pain and discomfort during the procedure, generally requiring a significant amount of analgesia (local anesthetic for nerve blockade or general anesthesia) are not needed; (iii) reduced incidence of complications including persistent erythema, hyperpigmentation, hypopigmentation, scarring, and infection (e.g., infection with Herpes simplex virus); (iv) ability to selectively and uniformly target energy to small target regions, e.g., lesions or scars with dimensions of a few mm ; (v) reduced incidence of physical impediments ("shadows”) that
  • a derivative technique from the ablative use of non-fractional lasers for skin resurfacing is to induce selective thermal damage to the sub-epidermal layer (particularly the dermal layer) with no disruption of the superficial epidermal layer integrity.
  • Such techniques have been termed non-ablative resurfacing, non-ablative subsurfacing, or non-ablative skin remodeling, and have been used as an alternative procedure.
  • Techniques generally utilize non-ablative lasers, flashlamps, or radio frequency currents.
  • overall efficacy is typically limited because of epidermal sparing.
  • Several embodiments of the invention are advantageous because irregular patterns of energy deposition are reduced or absent, thereby reducing or avoiding visible spots or edges.
  • fractional resurfacing has emerged as a technique attempting to address some of the limitations in patient discomfort and recovery time from non-fractional approaches.
  • thermally ablated microscopic zones of epidermis and dermis (referred to as "micro thermal zones") are spaced in a grid over the skin surface in a generally controlled, geometric pattern; the non-ablated zones in the uninjured surrounding tissue serves as a reservoir of cells that accelerate and promote safe and rapid healing.
  • the affected zones can compromise approximately 15-70% of the skin surface area per treatment session and can be randomly selected by the orientation of the geometric pattern.
  • a small target region such as a scar region that does not exceed about 25mm (e.g., a scar region that is within about 1-10 mm 2 , 10-15mni 2 , 15-25 mm 2 , and ranges therein) can be treated;
  • skin outside of target regions do not need to be unnecessarily treated and the selective targeting of small regions can be achieved with respect to scars or other lesions (whether atrophic or not) where new collagen formation and re-epithelialization would provide the highest benefit;
  • several embodiments provide a balance between aggressive treatments with high skin surface coverage that are characterized by long healing time and less aggressive treatments that have no effect; and
  • several embodiments apply electromagnetic energy to selectively and uniformly heat small target regions that are near or below the spot size of the energy (e.g., light), while sparing other tissue.
  • UV/blue light is approved by the FDA for the treatment of mild to moderate acne only, due to its antiinflammatory effects mediated on skin cells (keratinocytes), potentially through the action of endogenous porphyrin photosensitizers within follicles.
  • Exogenous porphyrin precursors such as 5-aminoluveulinic acid (5 -ALA) have been formulated for topical or oral delivery and shown to accumulate within sebaceous follicles, absorb photons from red light exposure and form reactive oxygen species that directly damage cellular membranes and proteins.
  • 5 -ALA 5-aminoluveulinic acid
  • Several embodiments of the invention are useful for hair removal and/or reduction.
  • Light-based hair removal systems suffer from particularly low rates of efficacy at removing light hair (vellus, blonde, gray, red hair). Multiple (even 6 or more) treatments are insufficient to achieve a therapeutic result in blonde- gray- or red-haired patients, even with the use of topically applied chromophores such as carbon.
  • thermoablative technology as described in several embodiments of the invention herein, has untapped potential in the fields of wound healing, tissue remodeling, vascular repair, and acne treatment.
  • many embodiments of the invention are used for treating acne and the scars that result from acne.
  • Acne vulgaris results from obstruction of the pilosebaceous unit, consisting of the hair shaft, hair follicle, sebaceous gland and erector pili muscle, which leads to accumulation of sebum oil produced from the sebaceous gland and the subsequent colonization of bacteria within the follicle.
  • Microcomedones formed as a result of accumulated sebum progress to non-inflamed skin blemishes (white/blackheads), or to skin blemishes which recruit inflammatory cells and lead to the formation of papules, nodules and pus-filled cysts.
  • reduction of microorganisms, via the photoactive particles (e.g., plasmonic nanoparticles) described herein include, but is not limited to, inactivation of bacteria or other microorganisms, reduction in the number, growth, viability, and/or function etc. of bacteria or other microorganisms.
  • This reduction can be accomplished by, for example, the heat generated by several of the embodiments described herein and/or the enhanced delivery of drugs and other substances.
  • This reduction can be accomplished in target regions, including atrophic regions and small target regions as described herein.
  • compositions of matter comprising a cosmetically acceptable carrier and a plurality of photoactive particles (e.g., plasmonic nanoparticles) in an amount effective to induce thermomodulation in a target tissue region with which the composition is topically contacted.
  • a cosmetically acceptable carrier e.g., a cosmetically acceptable carrier
  • a plurality of photoactive particles e.g., plasmonic nanoparticles
  • the composition comprises, or consists essentially of photoactive particles (e.g., plasmonic nanoparticles) that are activated by exposure to energy delivered from a surface plasmon resonance excitation sources (e.g., nonlinear excitation surface plasmon resonance source) to the target tissue region.
  • plasmonic nanoparticles can act as antennas, providing a "nonlinear excitation" at peak resonance or, in other words, an enhanced extinction cross section for a given physical cross-section of material when compared to non-plasmonic photoactive materials of the same dimension.
  • plasmonic materials are able pull more energy from delocalized electromagnetic waves surrounding the material at peak resonance than non-plasmonic photoactive material of the same dimension.
  • compositions comprising, or consisting essentially of, at least one photoactive particles (e.g., plasmonic nanoparticle) that comprises a metal, metallic composite, metal oxide, metallic salt, electric conductor, electric superconductor, electric semiconductor, dielectric, quantum dot or composite from a combination thereof.
  • photoactive particles e.g., plasmonic nanoparticle
  • a composition wherein a substantial amount of the photoactive particles (e.g., plasmonic particles) present in the composition comprise geometrically-tuned nanostructures.
  • photoactive particles comprise any geometric shape currently known or to be created that absorb light and generate plasmon resonance at a desired wavelength, including nanoplates, solid nanoshells, hollow nanoshells, partial nanoshells, nanorods, nanorice, nanospheres, nanofibers, nano wires, nanopyramids, nanoprisms, nanostars, nanocrescents, nanorings, or a combination thereof.
  • compositions wherein the photoactive particles comprise silver, gold, nickel, copper, titanium, silicon, galadium, palladium, platinum, or chromium, as well as including metal alloys, composites, and amalgams.
  • a cosmetically acceptable carrier that comprises, or consists essentially of, an additive, a colorant, an emulsifier, a fragrance, a humectant, a polymerizable monomer, a stabilizer, a solvent, or a surfactant.
  • a composition wherein the surfactant is selected from the group consisting of: sodium laureth 2-sulfate, sodium dodecyl sulfate, ammonium lauryl sulfate, sodium octech-l/deceth-1 sulfate, lipids, proteins, peptides or derivatives thereof.
  • a surfactant is present in an amount between about 0.1 and about 10.0% weight-to-weight of the carrier.
  • the solvent is selected from the group consisting of water, propylene glycol, alcohol, hydrocarbon, chloroform, acid, base, acetone, diethyl-ether, dimethyl sulfoxide, dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane, and ethylacetate.
  • the composition comprises, or consists essentially of, photoactive particles (e.g., plasmonic particles) that have an optical density of at least about 1 O.D. at one or more (e.g., 50 O.D. - 10,000 O.D.) peak resonance wavelengths at, for example, infrared.
  • photoactive particles e.g., plasmonic particles
  • plasmonic particles comprise a hydrophilic or aliphatic coating, wherein the coating does not substantially adsorb to skin of a mammalian subject, and wherein the coating comprises polyethylene glycol, silica, silica-oxide, polyvinylpyrrolidone, polystyrene, polyquaternium(s), a protein or a peptide.
  • thermomodulation comprises damage, ablation, thermoablation, lysis, denaturation, deactivation, activation, induction of inflammation, activation of heat shock proteins, perturbation of cell-signaling or disruption to the cell microenvironment in the target tissue region.
  • target tissue region comprises a sebaceous gland, a component of a sebaceous gland, a sebocyte, a component of a sebocyte, sebum, or hair follicle infundibulum.
  • the target tissue region comprises a bulge, a bulb, a stem cell, a stem cell niche, a dermal papilla, a cortex, a cuticle, a hair sheath, a medulla, an arrector pili muscle, a Huxley layer, or a Henle layer.
  • a method for performing targeted ablation of a tissue to treat a mammalian subject in need thereof comprising the steps of i) topically administering to a skin surface of the subject a composition of photoactive particles (e.g., plasmonic particles) ii) providing penetration means to redistribute the plasmonic particles from the skin surface to a component of dermal tissue; and iii) causing irradiation of the skin surface by light.
  • photoactive particles e.g., plasmonic particles
  • the light source comprises excitation of mercury, xenon, deuterium, or a metal-halide, phosphorescence, incandescence, luminescence, light emitting diode, or sunlight.
  • the penetration means comprises high frequency ultrasound, low frequency ultrasound (e.g., frequencies of 1 kHz to 500 kHz, e.g., 1 kHz - 100 kHz, 5 kHz - 45 kHz, 20 kHz - 50 kHz, 30 kHz - 40 kHz, 30 kHz, 40 kHz, and any ranges or frequencies therein), massage (e.g., hand massage, vibration, mechanical vibration, and/or at frequencies of less than lkHz, 1 Hz - 900 Hz, 5 - 500 Hz, 10 - 100 Hz, 1 - 80Hz, 50 - 250 Hz, and any frequencies therein), iontophoresis, high pressure air flow, high pressure liquid flow, vacuum, pre-treatment with fractionated photothermolysis or dermabrasion, or a combination thereof, and/or pre- treatment with heat, massage, ultrasound or a combination thereof.
  • high frequency ultrasound e.g., frequencies of 1 kHz to 500 kHz, e.
  • the irradiation comprises light having a wavelength of light between about 200 nm and about 10,000 nm (e.g., 700 nm to 1,200 nm, 600 nm to 1,500 nm, 500 nm to 2,000 nm), a fluence of about 0.1 to about 100 joules/cm
  • a pulse width of about 1 femptosecond to about 1 second e.g., 100 microsecond to 500 millisecond, 100 microsecond to 1000 microseconds, 1 millisecond to 10 millisecond, 10 millisecond to 100 millisecond, 100 millisecond to 500 millisecond
  • a repetition frequency of about 1 Hz to about 1 THz e.g., 1 Hz to 10 Hz, 1 Hz to 1 MHz, 1 Hz to 1 GHz.
  • compositions comprising a cosmetically acceptable carrier, an effective amount of sodium dodecyl sulfate, and a plurality of photoactive particles (e.g., plasmonic nanoparticles) in an amount effective to induce thermal damage in a target tissue region with which the composition is topically contacted, wherein the nanoparticles have an optical density of at least about 1 O.D.
  • a cosmetically acceptable carrier an effective amount of sodium dodecyl sulfate
  • a plurality of photoactive particles e.g., plasmonic nanoparticles
  • plasmonic particles comprise a silica coating from about 5 to about 35 nanometers
  • the acceptable carrier comprises water and propylene glycol.
  • systems for laser ablation of hair or treatment of acne comprising a composition and a source of plasmonic energy suitable for application to the human skin.
  • the invention comprises a method for reducing dermal scar tissue (e.g., in a human subject) comprising: i) identifying a target region of skin tissue on a human subject, wherein the target region comprises an epidermal surface and dermal scar tissue, wherein the target region does not exceed about 25mm ; (ii) contacting the epidermal surface of the target region with a non-dispersive composition comprising a photoactive material; and (iii) delivering to the target region energy in the 700nm to about 1200nm range in an amount sufficient to heat at least a portion of the dermal scar tissue to a temperature of at least 40 degrees Celsius for a period of time sufficient to reduce the dermal scar tissue.
  • the temperature may be in the range of about 40 to 45, 40 to 50, 40 to 55, 40 to 60, 40 to 65, 40 to 70, 40 to 75, 40 to 80 or 40 to above 80.
  • the time period may be in the range of 1 femptosecond to about 1 second (e.g., 100 microsecond to 1000 microseconds, 1 millisecond to 10 millisecond, 10 millisecond to 100 millisecond, 100 millisecond to 500 millisecond).
  • the invention comprises a method for reducing dermal scar tissue (e.g., in a human subject) comprising: (i) identifying a target region of skin tissue on a human subject, wherein the target region comprises an epidermal surface and dermal scar tissue comprising a pathophysiological collagen deposition, dermal matrix, or epidermal surface, wherein the target region does not exceed about 25mm ; (ii) contacting the epidermal surface of the target region with a non-dispersive composition comprising a photoactive material; and (iii) delivering to the target region energy in the 700nm to about 1200nm range in an amount sufficient to heat at least a portion of the dermal scar tissue to a temperature sufficient to cause damage and regeneration, thereby reducing the dermal scar tissue.
  • the target region e.g., atrophic scar
  • the region may be sized in at least one dimension as follows: 0.1 mm to 5 mm 2 , 5 mm 2 - 10 mm 2 , 10 mm2 - 15 mm 2 , 15 mm2 - 25 mm 2 , 0.1mm2 -25mm2 overlapping ranges therein. These dimensions can apply, for example, to the surface area of the region (the inner surface area of an atrophic scar).
  • the target region e.g., atrophic scar
  • the target region e.g., atrophic scar
  • the target region is at least 0.25mm mean thickness (e.g., 0.01 - .25mm).
  • the methods can be performed in any order, with any step repeated one or more times.
  • the contacting and/or delivering steps can be repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 24, or more times.
  • the methods for treating the target regions are repeated one or more times on one or more additional target regions.
  • the procedure may be performed/repeated 1-24 times (e.g., 2, 3, 4, 5, 10 or more times).
  • a single target region may be treated, or alternatively, multiple target regions may be treated sequentially or simultaneously.
  • the dermal scar tissue comprises a scar resulting from an acne vulgaris infection.
  • the dermal scar tissue may be atrophic (e.g., recessed).
  • the target region of skin tissue is located on the face or neck of a human subject.
  • the photoactive material comprises carbon. In several embodiments, the photoactive material comprises graphite. In several embodiments, the photoactive material comprises a plasmonic nanoparticle. In several embodiments, the photoactive material comprises a silver plasmonic nanoparticle. In several embodiments, the photoactive material comprises a silica-coated silver plasmonic nanoparticle. In several embodiments, the photoactive material is present at a concentration of from about 0.01% to about 10% volume to volume ratio, or greater than 10% volume to volume ratio (e.g., 0.01%- 0.1%, 0.1%-1%, 1%-10%. In several embodiments, the photoactive material does not substantially penetrate the epidermal surface.
  • the energy comprises a spot diameter anywhere in the range of about 0.5mm to about 20mm at the epidermal surface.
  • the non-dispersive composition comprises a volume of about 10 microliters with a diameter of less than about 5mm at the epidermal surface for at least one minute after contacting of the non-dispersive composition with the epidermal surface. In several embodiments, the non-dispersive composition comprises a volume of about 0.01 microliters with a diameter of less than about 5mm at the epidermal surface for at least one minute after contacting of the non-dispersive composition with the epidermal surface.
  • the non-dispersive composition comprises a volume of 0.001 - 50 microliters (e.g., 0.001 - 0.01, 0.01 - 0.05, 0.01 - 0.10, 0.01 - 0.50, 0.01 - 1.0, 0.01 - 5.0, 0.01 - 10, 0.01 - 25, 0.01 - 45, 0.01 - 50, 0.001, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 1.0, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 25, 30, 40, and/or 50 microliters).
  • the non-dispersive composition does not laterally migrate along the epidermal surface at a rate greater than about 1mm per minute.
  • the non-dispersive composition comprises at least one of water, a humectant, a surfactant, a thickener, a dye, an antiseptic, an anti-inflammatory agent, an anti-oxidant, a vitamin, a fragrance, an oil, or a topical anesthetic.
  • the non-dispersive composition is contacted with the epidermal surface with a volume of about 1 to about 50 microliters of the non-dispersive composition.
  • the methods further comprise the step of contacting the epidermal surface of the target region with an adhesive compound prior to contacting the epidermal surface with the non-dispersive composition, wherein the adhesive compound increases retention of the photoactive material at the target region.
  • the invention comprises a means for delivering photoactive particles into small target regions.
  • the means for delivering includes an apparatus for delivering a formulation into a target region (e.g., an acne scar or other atrophic scar) of a human subject.
  • a formulation into a target region (e.g., an acne scar or other atrophic scar) of a human subject.
  • formulation and composition can be used interchangeably.
  • the apparatus comprises a supply of a liquid formulation comprising an photoactive material, which, when put in substantial physical contact with a target area of a skin surface of a human subject, with the target area comprising an acne scar or portion thereof, is capable of penetrating the skin surface at the target area to denature at least one pathophysiological collagen deposition present in the acne scar, by delivering sufficient thermal energy to the targeted area such that the temperature of the collagen deposition in the target area is elevated above the denaturation temperature of the collagen deposition.
  • a liquid formulation comprising an photoactive material
  • the apparatus enables the liquid formulation, when the liquid formulation is put in contact with the target area, to be substantially retained in the target area, wherein the apparatus delivers the liquid formulation onto the target area in a volume of from about 0.01ml to about 1ml. In several embodiments, the apparatus enables the liquid formulation, when the liquid formulation is put in contact with the target area, to be substantially retained in the target area, wherein the apparatus delivers the liquid formulation onto the target area in a volume of from about 0.01 microliters to about 1ml (e.g., 0.01 - 1 microliters, 0.01 - 10 microliters, 0.01 - 20 microliters, 0.01 - 50 microliters, 0.01 - 100 microliters, 0.01 - 500 microliters).
  • the invention comprises a system for affecting collagen (e.g., denaturing collagen) present in a target region such as an atrophic region (e.g., acne scar) comprising: (i) an apparatus for delivering a formulation, and (ii) a light source.
  • the apparatus contains a supply of a liquid formulation comprising an photoactive material, which, when put in substantial physical contact with a target area of a skin surface of a human subject, the target area comprising an acne scar or portion thereof, is capable of penetrating the skin surface at the target area to denature at least one pathophysiological collagen deposition present in the acne scar, by delivering sufficient thermal energy to the targeted area such that the temperature of the collagen deposition in the target area is elevated above the denaturation temperature of the collagen deposition.
  • a liquid formulation comprising an photoactive material
  • the apparatus enables the liquid formulation, when the liquid formulation is put in contact with the target area, to be substantially retained in the target area, wherein the apparatus delivers the liquid formulation onto the target area in a volume of from about 0.01 ml to about 1 ml.
  • the apparatus enables the liquid formulation, when the liquid formulation is put in contact with the target area, to be substantially retained in the target area, wherein the apparatus delivers the liquid formulation onto the target area in a volume of from about 0.01 microliters to about 1ml (e.g., 0.01 - 1 microliters, 0.01 - 10 microliters, 0.01 - 20 microliters, 0.01 - 50 microliters, 0.01 - 100 microliters, 0.01 - 500 microliters).
  • the a means for delivering photoactive particles into small target regions includes apparatus comprising a needle-nose applicator, a fine tip applicator, a pipette, a dropper, a brush, an applicator, a module, a capsule, a syringe, and/or a sprayer (e.g., a micro-sprayer such an airbrush).
  • the apparatus is capable of delivering a volume of from about 1 to about 50 microliters (e.g., 1 - 10, 10 - 25, 25 - 50 microliters) of the formulation on the target area such that the surface area of the target area contacted by the formulation is less than about 25mm .
  • the formulation is liquid in many embodiments (and includes gelatinous formulations), but also includes solid forms, such as grains, granules, and/or fine powders.
  • the light source comprises an infrared laser or intense pulsed light (IPL).
  • the invention comprises a kit for treating the skin.
  • the kit includes some or all of the following: a formulation of photoactive particles (such as nanoparticles and/or chromophores), means for delivering the formulation to the skin (e.g., to atrophic regions or other target regions), a light source, and instructions for use.
  • an energy source such as light source
  • a means of removing the formulation of photoactive particles from the skin or modifying the distribution of the formulation on the skin is provided.
  • drugs or other substances to be delivered to the dermis and epidermis are provided which can either enhance the effects of the treatment, or decrease the side effects caused by partial damage of the epidermis and/or dermis, or both.
  • a method of delivering a cosmetic composition to a target tissue under a skin surface with a delivery device including: applying a composition to a skin surface, distributing the composition from the skin surface to a target tissue under the skin surface with a delivery device, wherein the delivery device is a low frequency ultrasound device including a sonotrode.
  • the low frequency ultrasound device includes a frequency in a range of 1 kHz to 500 kHz.
  • said composition includes a plurality of plasmonic nanoparticles.
  • the plasmonic nanoparticles comprise a conductive metal portion.
  • the conductive metal portion includes at least one of gold, silver, nickel, copper, platinum, titanium, chromium, and palladium, or a metal alloy, composite or amalgam thereof.
  • the plasmonic nanoparticles comprise a coating that coats the conductive metal portion, wherein said coating facilitates selective removal from the skin surface.
  • the method includes selectively removing the composition from the skin surface, while leaving the composition localized within the sebaceous gland.
  • the method includes irradiating the composition with an infrared light source thereby inducing a surface plasmon in said plasmonic nanoparticles.
  • inducing the plurality of surface plasmons generates localized heat in the target tissue.
  • the low frequency ultrasound device frequency is in a range of 1 kHz - 100 kHz.
  • the infrared light source includes a fluence of 1 to 60 joules/cm . In one embodiment, the infrared light source includes a pulse width of 100 microseconds to 1000 microseconds. In one embodiment, the infrared light source includes a repetition frequency of 1 Hz to 1 GHz. In one embodiment, the method includes mechanical vibration at 1 Hz - 900 Hz. In one embodiment, low frequency ultrasound is applied at a frequency in the range of 20 kHz - 50 kHz. In one embodiment, the coating includes silica or polyquaternium. In one embodiment, generation of localized heat is sufficient to affect at least one of a sebocyte and sebum.
  • the nanoparticle is any one of a nanoplate, a partial nanoshell, a nanocrescent, and a nanoring.
  • the plasmonic nanoparticles are unassembled.
  • the plasmonic nanoparticles have a size in a range of 10 nm to 300 nm.
  • the coating includes at least one of silica or polyethylene glycol (PEG).
  • the plasmonic nanoparticles have a concentration of 10 9 to 10 16 particles per ml of the composition, wherein said concentration is sufficient to, after exposure to irradiation, induce thermal damage in a sebaceous gland.
  • the conductive metal portion is silver.
  • a method of delivering a cosmetic composition to a sebaceous gland including topically applying a solution of plasmonic nanoparticles to a skin surface, targeting a sebaceous gland by redistributing the solution of plasmonic nanoparticles from the skin surface to the sebaceous gland with a delivery device; wherein the delivery device is a low frequency ultrasound device including a sonotrode; wherein the low frequency ultrasound device includes a frequency in a range of 1 kHz to 500 kHz, wherein the plasmonic nanoparticles comprise a conductive metal portion, wherein the conductive metal portion includes at least one of gold, silver, nickel, copper, platinum, titanium, chromium, and palladium, or a metal alloy, composite or amalgam thereof, wherein the plasmonic nanoparticles comprise a coating that coats the conductive metal portion, wherein said coating facilitates selective removal from the skin surface; selectively removing the solution from the skin surface, while leaving the solution localized within the sebaceous
  • the method includes vibrating the solution with a mechanical vibration device configured for bubble formation or liquid microstreaming. In one embodiment, the method includes vibrating the solution with mechanical vibration at a frequency in the range of 1 Hz - 900 Hz. In one embodiment, low frequency ultrasound is applied at a frequency in the range of 20 kHz - 50 kHz. In one embodiment, the coating includes silica or polyquaternium. In one embodiment, inducing a plurality of surface plasmons in said plasmonic nanoparticles generates localized heat sufficient to affect at least one of a sebocyte and sebum. In one embodiment, the nanoparticle is any one of a nanoplate, a partial nanoshell, a nanocrescent, and a nanoring.
  • the method includes pre-treating the skin surface to increase delivery of the plasmonic nanoparticles to the sebaceous gland with at least one of the group consisting of shaving, waxing, peeling, cyanoacrylate surface peeling, a calcium thioglycolate treatment, a surface exfoliation, a mechanical exfoliation, a salt glow, a microdermabrasion, a chemical exfoliation, a chemical exfoliation with an enzyme, a chemical exfoliation with alphahydroxy acid, and a chemical exfoliation with betahydroxy acid.
  • the concentration of the plasmonic nanoparticles is 10 9 to 10 16 particles per ml of the solution.
  • the plasmonic nanoparticles have an optical density of 10 O.D.
  • the coating is semiconductive, wherein the conductive metal portion is inside the coating, and wherein the coating is less conductive than the conductive metal portion. In one embodiment, the conductive metal portion is a nanoplate, and wherein the coating is less conductive than the conductive metal portion.
  • the low frequency ultrasound device frequency is in a range of 1 kHz - 100 kHz.
  • the infrared light source includes a fluence of 1 to 60 joules/cm2. In one embodiment, the infrared light source includes a pulse width of 100 microseconds to 1000 microseconds. In one embodiment, the infrared light source includes a repetition frequency of 1 Hz to 1 GHz.
  • the plasmonic nanoparticles have a dimension in a range of 10 nm to 300 nm. In one embodiment, the plasmonic nanoparticles have a concentration of 10 9 to 10 15 particles per ml of the solution. In one embodiment, the coating includes at least one of silica or polyethylene glycol (PEG).
  • a method of delivering a composition of plasmonic nanoparticles to a pilosebaceous unit including: applying a solution of plasmonic nanoparticles to a skin surface, distributing the solution of plasmonic nanoparticles with a mechanical vibration device from the skin surface to a pilosebaceous unit thereby targeting the pilosebaceous unit, wherein the mechanical vibration device includes at least one of the group consisting of a low frequency ultrasound device, a sonic force device, a massage device, a high pressure air flow device, a high pressure liquid flow device, and a vacuum device, and a dermabrasion device, vibrating the solution with mechanical vibration at a frequency in the range of 1 Hz - 50 kHz, wherein the pilosebaceous unit includes one or more structures consisting of: a hair shaft, a hair follicle, a sebaceous gland, and a hair follicle infundibulum; wherein the plasmonic nanoparticles comprise
  • the method includes pre-treating the skin surface to increase delivery of the plasmonic nanoparticles to the pilosebaceous unit with at least one of the group consisting of shaving, waxing, peeling, cyanoacrylate surface peeling, a calcium thioglycolate treatment, a surface exfoliation, a mechanical exfoliation, a salt glow, a microdermabrasion, a chemical exfoliation, a chemical exfoliation with an enzyme, a chemical exfoliation with alphahydroxy acid, and a chemical exfoliation with betahydroxy acid.
  • irradiating the solution of plasmonic nanoparticles includes exposing the solution of plasmonic nanoparticles to the energy at a wavelength of between 750 nm and 1200 nm to induce a plurality of surface plasmons in said plasmonic nanoparticles, thereby treating acne at said sebaceous gland.
  • the mechanical vibration device includes at least a low frequency ultrasound device; wherein irradiating the solution of plasmonic nanoparticles with the energy includes an infrared light source wavelength of between 750 nm and 1200 nm to induce a plurality of surface plasmons in said plasmonic nanoparticles, thereby treating acne at said sebaceous gland.
  • the plasmonic nanoparticles are nanoplates,wherein the plasmonic nanoparticles have an optical density of 10 O.D. to 5,000 O.D. within an infrared light range and the concentration is 10 9 to 1023 particles per ml of the solution; and wherein irradiating the solution of plasmonic nanoparticles with the energy includes an infrared wavelength of between 750 nm and 1200 nm to induce a plurality of surface plasmons in said plasmonic nanoparticles, thereby heating said pilosebaceous unit.
  • selectively removing the composition from the skin surface includes using water or alcohol to remove the composition from the skin surface while leaving the composition localized within the pilosebaceous unit.
  • the conductive metal portion includes at least one of gold or silver.
  • the plasmonic nanoparticles have a peak absorption wavelength of between 750 nm and 1200 nm.
  • the plasmonic nanoparticles have a concentration of 10 9 to 10 16 particles per ml of the solution.
  • the coating includes at least one of silica or polyethylene glycol (PEG).
  • a method for reducing dermal scar tissue includes identifying a target region of skin tissue on a human subject, wherein the target region includes an epidermal surface and dermal scar tissue, wherein the target region does not exceed about 25 mm , contacting the epidermal surface of the target region with a non- dispersive composition including a photoactive material; and delivering to the target region energy in the 700 nm to about 1200 nm range in an amount sufficient to heat at least a portion of the dermal scar tissue to a temperature of at least 40 degrees Celsius for a period of time sufficient to reduce the dermal scar tissue.
  • the temperature is in the range of 40 to 80 degrees Celsius.
  • delivering energy is in a time period in the range of 100 microsecond to 1000 microseconds.
  • a method for reducing dermal scar tissue includes identifying a target region of skin tissue on a human subject, wherein the target region includes an epidermal surface and a skin inconsistency, wherein the target region does not exceed about 25 mm , contacting the epidermal surface of the target region with a non- dispersive composition including a photoactive material; and delivering to the target region energy in the 700 nm to about 1200 nm range in an amount sufficient to heat at least a portion of the skin inconsistency to a temperature of at least 40 degrees Celsius for a period of time sufficient to reduce the skin inconsistency.
  • the temperature is in the range of 40 to 80 degrees Celsius.
  • delivering energy is in a time period in the range of 100 microsecond to 1000 microseconds.
  • a method for reducing dermal scar tissue includes identifying a target region of skin tissue on a human subject, wherein the target region includes an epidermal surface and dermal scar tissue including a pathophysiological collagen deposition, dermal matrix, or epidermal surface, wherein the target region does not exceed about 25 mm ; contacting the epidermal surface of the target region with a non-dispersive composition including a photoactive material; and delivering to the target region energy in the 700 nm to about 1200 nm range in an amount sufficient to heat at least a portion of the dermal scar tissue to a temperature sufficient to cause damage and regeneration, thereby reducing the dermal scar tissue.
  • the target region is a surface area of the region is in the range 0.1mm 2 to 25mm 2. In one embodiment, the target region has at least one dimension in the range 0.01 mm to 10 mm. In one embodiment, the target region is a surface area of the region is in the range 0.1 mm 2 to 25 mm 2 includes a mean thickness of 0.01 mm to 0.25 mm.
  • the dermal scar tissue includes a scar resulting from an acne vulgaris infection. The dermal scar tissue may be atrophic (e.g., recessed). The target region of skin tissue is located on the face or neck of a human subject.
  • the non-dispersive composition includes a volume of 0.01 microliters to 10 microliters with a diameter of less than about 5mm at the epidermal surface for at least one minute after contacting of the non-dispersive composition with the epidermal surface. In one embodiment, the non-dispersive composition does not laterally migrate along the epidermal surface at a rate greater than about 1mm per minute. In one embodiment, the non-dispersive composition includes at least one of water, a humectant, a surfactant, a thickener, a dye, an antiseptic, an anti-inflammatory agent, an anti-oxidant, a vitamin, a fragrance, an oil, or a topical anesthetic.
  • the non-dispersive composition is contacted with the epidermal surface with a volume of 0.01 to about 50 microliters of the non-dispersive composition.
  • the method includes contacting the epidermal surface of the target region with an adhesive compound prior to contacting the epidermal surface with the non-dispersive composition, wherein the adhesive compound increases retention of the photoactive material at the target region.
  • the target region includes any one of the group consisting of freckles, sun spots, age spots, actinic keratosis, sebhorreic keratosis, onychomycosis, sebhorreic dermatitis, atopic dermatitis, contact dermatitis, herpes simplex, Human papillomavirus (HPV), and dermatophytosis.
  • HPV Human papillomavirus
  • a system for delivering photoactive particles into a small target region includes a light source, and a material delivery apparatus including: a supply of a liquid formulation including an photoactive material, and a delivery apparatus configured to deliver the liquid formulation onto a target area in a volume of 0.01 microliters to 10 microliters.
  • the system is configured for delivering the liquid formulation in a volume of 1 to about 50 microliters on the target area such that the surface area of the target area contacted by the formulation is less than about 25mm .
  • the light source is configured to heat the liquid formation to a temperature of at least 40 degrees Celsius. In one embodiment, the light source is configured to heat the liquid formation to a temperature range of 40 to 80 degrees Celsius.
  • the light source is configured to deliver light energy in a time period in the range of 100 microsecond to 1000 microseconds.
  • the target region is a surface area of the target area is in the range 0.1mm 2 to 25mm 2.
  • the target area has at least one dimension in the range 0.01 mm to 10 mm.
  • the delivery apparatus is configured to deliver the liquid formulation to a surface area in the range 0.1 mm2 to 25 mm2 including a mean thickness of 0.01 mm to 0.25 mm.
  • the delivery apparatus is a needle-nose applicator.
  • the delivery apparatus is a fine tip applicator.
  • the delivery apparatus is a pipette.
  • the delivery apparatus is a dropper.
  • the delivery apparatus is a brush. In one embodiment, the delivery apparatus is an applicator. In one embodiment, the delivery apparatus is a module. In one embodiment, the delivery apparatus is a capsule. In one embodiment, the delivery apparatus is a syringe. In one embodiment, the delivery apparatus is a sprayer. In one embodiment, the target area includes a scar resulting from an acne vulgaris infection. In one embodiment, the use of a system is for the cosmetic treatment of skin. In one embodiment, the use of a system is for the cosmetic treatment of a freckle. In one embodiment, the use of a system is for the cosmetic treatment of a sun spot. In one embodiment, the use of a system is for the cosmetic treatment of an age spot.
  • the use of a system is for the cosmetic treatment of actinic keratosis. In one embodiment, the use of a system is for the cosmetic treatment of sebhorreic keratosis. In one embodiment, the use of a system is for the cosmetic treatment of onychomycosis, sebhorreic dermatitis. In one embodiment, the use of a system is for the cosmetic treatment of atopic dermatitis. In one embodiment, the use of a system is for the cosmetic treatment of contact dermatitis. In one embodiment, the use of a system is for the cosmetic treatment of herpes simplex. In one embodiment, the use of a system is for the cosmetic treatment of Human papillomavirus (HPV).
  • HPV Human papillomavirus
  • the use of a system is for the cosmetic treatment of dermatophytosis. In one embodiment, the use of a system is for the cosmetic treatment of an atrophic scar. In one embodiment, the use of a system is for the cosmetic treatment of a dermal inconsistency. In one embodiment, the use of a system is for the cosmetic treatment of a face. In one embodiment, the use of a system is for the cosmetic treatment of a neck.
  • a kit for treatment of skin includes a formulation of photoactive nanoparticles, means for delivering the formulation to the skin, wherein the skin includes an atrophic scar, and a light source.
  • the kit includes instructions for use of the kit.
  • the kit includes a means of removing the formulation of photoactive nanoparticles from the skin.
  • the kit includes a means of modifying the distribution of the formulation on the skin.
  • the formulation includes drugs to be delivered to a dermis and an epidermis, wherein the drugs enhance the effects of the treatment.
  • the formulation includes drugs to be delivered to a dermis and an epidermis, wherein the drugs or decrease the side effects caused by partial damage of the epidermis or the dermis. In one embodiment, the formulation includes drugs to be delivered to a dermis and an epidermis, wherein the drugs or decrease the side effects caused by partial damage of the epidermis and the dermis.
  • a kit for treatment of skin includes a formulation of photoactive nanoparticles, means for delivering the formulation to the skin, wherein the skin includes a skin inconsistency, and a light source.
  • the kit includes instructions for use of the kit.
  • the kit includes a means of removing the formulation of photoactive nanoparticles from the skin.
  • the kit includes a means of modifying the distribution of the formulation on the skin.
  • the formulation includes drugs to be delivered to a dermis and an epidermis, wherein the drugs enhance the effects of the treatment.
  • the formulation includes drugs to be delivered to a dermis and an epidermis, wherein the drugs or decrease the side effects caused by partial damage of the epidermis or the dermis. In one embodiment, the formulation includes drugs to be delivered to a dermis and an epidermis, wherein the drugs or decrease the side effects caused by partial damage of the epidermis and the dermis.
  • a kit for treatment of skin includes an infrared light source, a supply of a liquid formulation including an photoactive material, and a delivery apparatus configured to deliver the liquid formulation onto a target area in a volume of 0.01 microliters to 10 microliters.
  • a kit for treatment of skin includes a supply of a liquid formulation including an photoactive material, a light source, a delivery apparatus configured to deliver the liquid formulation onto a target area, and a low frequency ultrasound device.
  • the low frequency ultrasound device is a sonotrode.
  • the photoactive material includes plasmonic nanoparticles.
  • the photoactive material includes plasmonic nanoparticles comprise a conductive metal portion including at least one of gold, silver, nickel, copper, platinum, titanium, chromium, and palladium, or a metal alloy, composite or amalgam thereof.
  • the low frequency ultrasound device delivers energy at a frequency in a range of 1 kHz - 100 kHz.
  • the light source includes a fluence of 1 to 60 joules/cm .
  • the light source includes a pulse width of 100 microseconds to 1000 microseconds.
  • the light source includes a repetition frequency of 1 Hz to 1 GHz.
  • the kits provides mechanical vibration at 1 Hz - 900 Hz.
  • low frequency ultrasound is applied at a frequency in the range of 20 kHz - 50 kHz.
  • the coating includes silica or polyquaternium.
  • the light generates localized heat sufficient to affect at least one of a sebocyte and sebum.
  • the photoactive material is any one of a nanoplate, a partial nanoshell, a nanocrescent, and a nanoring.
  • FIG. 1 is illustrative of schematics depicting certain embodiments of the use of formulations for hair removal and acne treatment.
  • the plasmonic nanoparticle formulation (black) is 1. applied topically to human skin, 2. delivered deep into the follicle and washed from the skin surface, 3. irradiated with a clinical laser at a wavelength resonant to the peak absorption wavelength of the plasmonic particle, and 4. shed from the follicle along with the damaged hair follicle;
  • the plasmonic nanoparticle formulation (black) is 1. applied topically to human skin, 2. delivered specifically into the sebaceous gland and washed from the skin surface, 3. irradiated with a clinical laser at a wavelength resonant to the peak absorption wavelength of the plasmonic particle, and 4. shed from the target site where the accumulated sebum and sebum-producing capabilities of the sebaceous gland are destroyed.
  • Figure 2 is illustrative of a temperature profile of certain embodiments of the formulations of plasmonic nanoparticles (SL-001, triangles) provided herein compared to certain embodiments of clinical dyes carbon lotion (circles), meladine spray (diamonds), and indocyanine green (squares), after exposure to 1064 nm, 20 J/cm 55 ms laser pulses.
  • Figure 3 is illustrative of hair follicle penetration of fluorescently-labeled nanoparticles determined using porcine skin explants and confocal imaging of certain embodiments of the subject matter described herein. Depicted is (A) schematic of treated porcine skin, sectioned and imaged at an angle to the follicle, in two serial 60 ⁇ planes: 'plane (showing follicle infundibulum) and 'plane 2' (showing deep follicle); (B) representative confocal images show red fluorescent nanoparticles (548 nm) within superficial and deep follicle, but not in underlying dermis; and (C) red fluorescent nanoparticles retained in the deep follicle (-400 ⁇ ) at high magnification. Green is tissue autofluorescence.
  • Figure 4 is illustrative of a hair follicle penetration of plasmonic nanoparticles determined using porcine skin explants and dark field imaging. Shown is (A) schematic of treated porcine skin, sectioned and imaged horizontal to the follicle; (B) bright blue plasmonic particles are visible in a 1.2 mm deep section, and are differentiated from (C) untreated (negative control) porcine skin, where no pigments are visible.
  • Figure 5 depicts clinical observations in live human skin treated with Laser
  • massage e.g., hand massage, vibration, mechanical vibration
  • non-specific clinical burns were observed in B compared to A, due to significant photothermal heating of residual, uncoated particles on the skin surface.
  • FIG. 6 is a photograph showing nanoparticle-targeted photothermal damage in live human skin treated with a plasmonic nanoparticle formulation and clinical laser.
  • a formulation of 1020 nm resonant, silica-coated (200 nm-diameter) plasmonic nanoparticles in 20% propylene glycol and 3 minute massage was contacted with live human skin. The procedure was repeated 3 times, and skin surface wiped with 3 applications of alternating water and ethanol to remove residual particles.
  • the treated skin was irradiated with 1064 nm laser pulses (40 J/cm , 55 ms, 3 passes). Following laser irradiation, clinical observation of perifollicular erythema and edema was visible at hair follicles where nanoparticles were targeted, but not visible in surrounding or non-particle-treated tissues.
  • Figure 7 is illustrative of a plasmonic nanoparticle formulation delivery to human skin sebaceous gland.
  • A Confocal microscope image of a human skin biopsy and section, immunostained for Collagen IV basement membrane (blue) and PGP 9.5 nerve marker (green), shows hair follicle (HF) and sebaceous gland (SG) microanatomy. Red is silica nanoparticles (200nm).
  • B Schematic and dark field microscope image of excised human skin treated with plasmonic nanoparticle formulation, then sectioned and imaged horizontal to the follicle. Bright blue plasmonic particles are visible up to 400 ⁇ deep and within the human sebaceous gland.
  • Figure 8 is illustrative of cosmetic formulations of plasmonic nanoparticles for sebaceous gland targeting that include surfactants.
  • Silica-coated nanoparticles 200 nm diameter, 100 O.D.
  • SDS sodium dodecyl sulfate
  • SLES sodium laureth-2 sulfate
  • A Formulations of plasmonic particles in 1% SDS/20% PG penetrated sebaceous gland down to 400 um as in Figure 7.
  • Figure 9 is an image depicting impact of massage vs. ultrasound on nanoparticle targeting to the human follicle and sebaceous gland.
  • Silica-coated nanoparticles 200 nm diameter, 100 O.D.
  • SDS/20 propylene glycol were formulated in 1% SDS/20 propylene glycol and applied to human skin with massage or ultrasound.
  • Dark field images of horizontal planar sections taken at low (20x) and high (50x) magnification show (A) little to no accumulation of plasmonic particles into follicle infundibulum after massage alone, compared to (B) follicle infundibulum expansion and significant plasmonic particle accumulation after ultrasound alone.
  • low frequency ultrasound can be applied at frequencies of 1 kHz to 500 kHz, e.g., 1 kHz - 100 kHz, 5 kHz - 45 kHz, 20 kHz - 50 kHz, 30 kHz - 40 kHz, 30 kHz, 40 kHz, and any ranges or frequencies therein.
  • massage e.g., hand massage, vibration, mechanical vibration
  • Figure 10 depicts an embodiment of the plasmonic nanoparticle cosmetic formulations for sebaceous gland targeting. Plasmonic nanoparticles comprising different shapes and coatings were formulated in 1% SDS/20% propylene glycol and applied to human skin with massage + ultrasound, and skin was sectioned in horizontal planes for dark field microscopy.
  • PEG Polyethylene glycol
  • Figure 11A is illustrative of temperature profiles of certain embodiments of plasmonic nanoparticle formulations compared to other commercial and research chromophores as a function of number of pulses from a 20 J/cm 1064 nm laser (55 ms pulses).
  • Figure 11B is illustrative of temperature profiles of certain embodiments of plasmonic nanoparticle formulations compared to other commercial and research chromophores as a function of number of pulses from a 20 J/cm 810 nm laser (30 ms pulses).
  • Figures 12 A and 12B are images of embodiments of nanoparticle formulations in porcine skin.
  • Figures 13 A and 13B are images of biopsies taken from in vivo-treated human skin, which were sectioned and immunostained for skin markers, with various embodiments of nanoparticles.
  • Figure 14 includes images of an embodiment of a treatment of atrophic scars with a laser and photoactive material delivered to small target regions of dermal scar tissue.
  • Figure 15 is a schematic side view of a composition being distributed from a skin surface to a target in the tissue with a delivery device according to an embodiment of the invention.
  • Figure 16 is a schematic of an experimental process for measuring the distribution of a composition with various embodiments of delivery devices in tissue.
  • Figure 17 is a table summarizing experimental data measuring the performance of three embodiments of delivery devices to deliver a single embodiment of the composition to various depths in tissue.
  • Figure 18 illustrates images of the delivery of a composition in skin models with various embodiments of delivery devices.
  • Figure 19 is illustrative of a graph of experimental measurements of percentage of composition delivery to an area at a depth in tissue with various delivery devices according to embodiments of the invention.
  • Figure 20 is illustrative of a graph of experimental measurements of percentage of composition delivery to an area at a depth in tissue with various delivery devices according to embodiments of the invention.
  • Figure 21 is illustrative of images taken of tissue sections at approximately
  • composition delivery within tissue samples using various embodiments of delivery devices.
  • a vibration device Vibraderm
  • acoustic horn/sonotrode ultrasound energy there is a markedly increase in the total amount of composition delivered (100) and number of follicles that the composition is delivered to over the other delivery embodiments alone.
  • vibration device Vibraderm
  • 30-40 kHz ultrasound flat transducer
  • Figure 22 is illustrative of images taken of tissue sections at approximately
  • composition delivery within tissue samples using various embodiments of delivery devices 1060 microns deep of composition delivery within tissue samples using various embodiments of delivery devices.
  • delivery device embodiment of a vibration device plus acoustic horn/sonotrode ultrasound energy there is a markedly increase in the total amount of composition delivered (100) and number of follicles that the composition is delivered to over the other delivery embodiments alone.
  • this depth of approximately 1060 microns the amount delivery of the composition by the other delivery device embodiments has significantly decreased.
  • An object of the subject matter described herein is to provide compositions, methods and systems for noninvasive and minimally-invasive treatment of skin and underlying tissues, or other accessible tissue spaces with the use of photoactive compounds (including but not limited to photoactive particles such as nanoparticle, plasmonic nanoparticles, etc.).
  • the invention describes the development and utilization of compositions containing photoactive materials (e.g., nanoparticles and other materials) for the treatment of small target regions of skin including acne scars and other skin conditions.
  • compositions are generally applied topically, through an apparatus that provides the composition in a form suitable for contact with and retention at a target region of skin in a manner that encompasses irradiating the skin with light (e.g., electromagnetic radiation) having a wavelength sufficient to ablate or otherwise damage the target region of skin and cause remodeling of the skin tissue.
  • light e.g., electromagnetic radiation
  • the treatment includes, but is not limited to, hair removal, hair growth and regrowth, and skin rejuvenation or resurfacing, acne removal or reduction, wrinkle reduction, pore reduction, ablation of cellulite and other dermal lipid depositions, wart and fungus removal, thinning or removal of scars including hypertrophic scars and keloids, abnormal pigmentation (such as port wine stains), tattoo removal, and skin inconsistencies (e.g. dermal inconsistencies, e.g., in texture, color, tone, skin brightness (e.g., skin lightening or skin whitening), elasticity, hydration, and including sun spots, age spots, freckles, and other inconsistencies).
  • hair removal hair growth and regrowth, and skin rejuvenation or resurfacing
  • acne removal or reduction wrinkle reduction, pore reduction, ablation of cellulite and other dermal lipid depositions
  • wart and fungus removal thinning or removal of scars including hypertrophic scars and keloids
  • abnormal pigmentation such
  • Other therapeutic or preventative methods include but are not limited to treatment of hyperhidrosis, anhidrosis, Frey's Syndrome (gustatory sweating), Horner's Syndrome, and Ross Syndrome, actinic keratosis, sebhorreic keratosis, keratosis follicularis, dermatitis, vitiligo, pityriasis, psoriasis, lichen planus, eczema, alopecia, psoriasis, malignant or non-malignant skin tumors, onychomycosis, sebhorreic dermatitis, atopic dermatitis, contact dermatitis, herpes simplex, Human papillomavirus (HPV), and dermatophytosis.
  • hyperhidrosis anhidrosis
  • Frey's Syndrome gustatory sweating
  • Horner's Syndrome and Ross Syndrome
  • actinic keratosis sebhorreic ker
  • administering include providing or causing the provision of a material to a subject, such as by a topical, subdermal, subcutaneous, intradermal, enteral, parenteral, rectal, nasal, intravenous, intramuscularly, intraperitoneal, or other route.
  • a "carrier suitable for administration" to a subject is any material that is physiologically compatible with a topical or route of administration to a desired vertebrate subject.
  • Carriers can include solid-based, dry materials for formulation; or the carrier can include liquid or gel-based materials for formulations into liquid or gel forms.
  • the specific type of carrier, as well as the final formulation depends, in part, upon the selected route(s) of administration and the type of product.
  • a “comparable amount” is an amount that is measurably similar to a given reference or standard.
  • compositions include any products or compounds associated with or contained within it.
  • an “effective dose”, “effective amount” or “therapeutic amount” is an amount sufficient to elicit the desired pharmacological, cosmetic or therapeutic effects, thus resulting in effective prevention or treatment of a disease or disorder, or providing a benefit in a vertebrate subject.
  • a “therapeutic effect” or “therapeutically desirable effect” refers to a change in a domain or region being treated such that it exhibits signs of being effected in the manner desired, e.g., cancer treatment causes the destruction of tumor cells or halts the growth of tumor cells, acne treatment causes a decrease in the number and/or severity of blemishes, hair removal treatment leads to evident hair loss, or wrinkle reduction treatment causes wrinkles to disappear.
  • An "isolated" biological component (such as a nucleic acid molecule, protein, or cell) has been substantially separated or purified away from other biological components in which the component was produced, including any other proteins, lipids, carbohydrates, and other components.
  • a “nanoparticle”, as used herein, refers generally to a particle having at least one of its dimensions from about 0.1 nm to about 9000 nm. (e.g., 1 nm - 500 nm, 10 nm - 300 nm, 100 nm - 500 nm.).
  • a "subject” or “patient” as used herein is any vertebrate species.
  • a “substantially pure” or “substantially isolated” compound is substantially free of one or more other compounds.
  • a "target tissue” includes a region of an organism to which a physical or chemical force or change is desired.
  • various embodiments of target tissues for acne treatment include a sebaceous gland
  • various embodiments of target tissues for hair removal include a pilosebaceous unit, a hair infundibulum, a hair follicle, or a non-follicular epidermis.
  • Target tissues for sweat or hyperhidrosis include a sweat gland.
  • a "region" of a target tissue includes one or more components of the tissue.
  • target tissue regions include the stem cell niche, bulge, sebaceous gland, dermal papilla, cortex, cuticle, inner root sheath, outer root sheath, medulla, Huxley layer, Henle layer or arrector pili muscle.
  • a "domain" of a target tissue region includes basement membrane, extracellular matrix, cell-surface proteins, unbound proteins/analytes, glycomatrices, glycoproteins, or lipid bilayer.
  • a compound that is "substantially free" of some additional contents is largely or wholly without said contents.
  • a "plasmonic nanoparticle” is a nanometer-sized metallic structure within which localized surface plasmons are excited by light. These surface plasmons are surface electromagnetic waves that propagate in a direction parallel to the metal/dielectric interface (e.g., metal/air or metal/water).
  • a "light-absorbing nanomaterial” includes a nanomaterial capable of demonstrating a quantum size effect.
  • compositions that contain plasmonic nanoparticles to induce selective thermomodulation in a target tissue.
  • a composition comprises plasmonic nanoparticles.
  • compositions contain from about 2 to about 1x10 18 or up to 10 23 nanoparticles (e.g., 10 9 to about 10 16 nanoparticles), such as 10 2 , 10 3 , 10 4 , 10 5 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , 10 12 , 10 13 , 10 14 , 10 15 , 10 16 , 10 17 , or 10 18 particles, including such as ranges between about 10 9 to 10 23 , 10 9 to 10 18 , 10 9 to 10 16 , 10 9 to 10 15 , 10 9 to 10 14 , 10 9 to 10 13 , 10 9 to 10 12 , 10 9 to 10 11 , 10 10 9 to 10 11 particles per ml.
  • nanoparticles e.g., 10 9 to about 10 16 nanoparticles
  • the range is between about 10 5 to 1018 per ml of composition or solution. In one embodiment, the range is between about 10 9 to 10 16 per ml of composition or solution
  • the numbers of particles may include the number, or any range of any numbers disclosed. In some embodiments, a concentration of particles is expressed as the number of particles per milliliter of, for example, the solution. In one embodiment, the compositions contain about 10 11 to 1013 particles so that the amount of particles localized to an effective 1ml treatment volumes is from 10 9 to 10 11 . In various embodiments, the compositions contain nanoparticles in a concentration of from about 1 O.D. to about 10,000 O.D.
  • compositions contain particle concentrations with optical densities of, for example, 10 O.D. -5000 O.D. more specifically 100 O.D. -1000 O.D., or optical densities greater than 1,000 O.D.
  • compositions contain particle concentrations with optical densities (O.D.) of 10 O.D. -1000 O.D., or optical densities greater than 1,000 O.D.
  • the optical density of a composition is any of 100 O.D., plus or minus 10%, plus or minus 5%, and/or plus or minus 1%.
  • the optical density of a composition is 100 O.D. to 10,000 O.D. e.g., 1000 O.D., plus or minus 10%, plus or minus 5%, and/or plus or minus 1%. In some embodiments these correspond to concentrations of about 1-10% w/w (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10%, or ranges within these numbers) or more of nanoparticles. Determination of O.D. units in a composition is determined using devices and analyses known in the art.
  • Nanoparticles may be homogenous or heterogeneous in size and other characteristics.
  • the size of the nanoparticle is generally about 0.1 nm to about 50,000 nm (e.g., about 0.1 nm to about 5,000 nm) in at least one dimension.
  • Some variation in the size of a population of nanoparticles is to be expected. For example, the variation might be less than 0.01%, 0.1%, 0.5%, 1%, 5%, 10%, 15%, 25%, 50%, 75%, 100%, 200% or greater than 200%, or any range between any numbers therein (e.g., 0.01% - 200%, 0.1% - 10%, 15% - 75%, 0.1% - 100%, etc.).
  • a particle size in the range of from about 10 nm to about 100 nm is provided.
  • a particle size in the range of from about 100 nm to about 1000 nm is provided. Modulation of particle size present in the composition is also a useful means of concentrating the composition in a target domain.
  • nanoparticles having a size range of from about 10 nm to about 100 nm can be used as component of a larger molecular structure, generally in the range of from about 100 nm to about 1000 nm.
  • the plasmonic nanoparticle can be surface coated to increase its size, embedded into an acceptable carrier, or it can be cross-linked or aggregated to other particles, or to other materials, that generate a larger particle.
  • the nanoparticle surface can be coated with a matrix (e.g. silica) of 10-100 nm thickness or more in order to increase that dimension or particle to 50- 100 nm or more.
  • This increased dimension size can increase the delivery of all nanoparticles to a target region (e.g., hair follicle) and limit delivery to non-target region (e.g. dermis).
  • the invention comprises a composition comprising at least about 1 O.D. (e.g., at least 10 O.D.) of coated plasmonic nanoparticles (e.g., comprising silica or polyethylene glycol (PEG)) having a mean length in at least one dimension greater than about 30 nanometers, wherein the coated nanoparticles are formulated in an acceptable carrier to be effective in induction of selective thermoablation in a target tissue region with which the composition is contacted, wherein the affinity of the coated nanoparticles for the target tissue region is substantially greater than the affinity of the coated nanoparticles for a non-target tissue region.
  • coated plasmonic nanoparticles e.g., comprising silica or polyethylene glycol (PEG) having a mean length in at least one dimension greater than about 30 nanometers
  • Nanoparticle surfaces can be functionalized with thiolated moieties having negative, positive, or neutral charges (e.g. carboxylic acid, amine, hydroxyls) at various ratios.
  • anion-mediated surface coating e.g.
  • surfactant coating e.g., sodium dodecyl sulfate, sodium laureth 2-sulfate, ammonium lauryl sulfate, sodium octech-l/deceth-1 sulfate, lecithin and other surfactants including cetyl trimethylammonium bromide (CTAB), lipids, peptides), or protein/peptide coatings (e.g. albumin, ovalbumin, egg protein, milk protein, other food, plant, animal, bacteria, yeast, or recombinantly-derived protein) can be employed.
  • CTAB cetyl trimethylammonium bromide
  • protein/peptide coatings e.g. albumin, ovalbumin, egg protein, milk protein, other food, plant, animal, bacteria, yeast, or recombinantly-derived protein
  • Block-copolymers are also useful.
  • the particle surface is unmodified. Modulation of hydrophilicity versus hydrophobicity is performed by modifying nanoparticle surfaces with chemistries known in the art, including thiols, dithiolane, silanes, isothiocyanates, short polymers (e.g., PEG), or functionalized hydrocarbons.
  • Polymer chains e.g., biopolymers such as proteins, polysaccharides, lipids, and hybrids thereof; synthetic polymers such as polyethyleneglycol, PLGA, and others; and biopolymer-synthetic hybrids
  • biopolymers such as proteins, polysaccharides, lipids, and hybrids thereof
  • synthetic polymers such as polyethyleneglycol, PLGA, and others
  • biopolymer-synthetic hybrids of different lengths and packing density are useful to vary the adsorption layer/slippage plane of particles.
  • nanoparticles have optical absorption qualities of about 10 nm to about 10,000 nm, e.g., 100-500 nm, 500-750 nm, 600- 900 nm, 700-1,000 nm, 800-1,200 nm, or 500-2,000 nm.
  • the nanoparticles have optical absorption useful to excitation by standard laser devices or other light sources. For example, nanoparticles absorb at wavelengths of about 755 nm (alexandrite lasers), in the range of about 800-810 nm (diode lasers), or about 1064nm (Nd: YAG lasers). Similarly, the nanoparticles absorb intense pulsed light (IPL), e.g., at a range of about 500 nm to about 1200 nm.
  • IPL intense pulsed light
  • the nanoparticles can contain a collection of unassembled nanoparticles.
  • unassembled nanoparticles it is meant that nanoparticles in such a collection are not bound to each other through a physical force or chemical bond either directly (particle-particle) or indirectly through some intermediary (e.g. particle-cell- particle, particle-protein-particle, particle-analyte-particle).
  • the nanoparticle compositions are assembled into ordered arrays. In particular, such ordered arrays can include any three dimensional array.
  • nanoparticles are assembled, e.g., 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 86, 90, 95, 99% or greater than 99% of the nanoparticles are assembled in an ordered array.
  • the nanoparticles are assembled by a van der Walls attraction, a London force, a hydrogen bond, a dipole-dipole interaction, or a covalent bond, or a combination thereof.
  • Ordered array can take the form of a macrostructure from individual parts that may be patterned or unpatterned in the form of spheres, colloids, beads, ovals, squares, rectangles, fibers, wires, rods, shells, thin films, or planar surface. In contrast, a "disordered array” lacks substantial macrostructure.
  • Geometrically tuned nanostructures In various embodiments, the particles are formable in all shapes currently known or to be created that absorb light and generate a plasmon resonance at a peak-wavelength or composition of wavelengths from 200 nm to 10,000 nm.
  • the nanoparticles are shaped as spheres, ovals, cylinders, squares, rectangles, rods, stars, tubes, pyramids, stars, prisms, triangles, branches, plates or comprised of a planar surface.
  • the plasmonic particles comprise nanoplates, solid nanoshells, hollow nanoshells nanorods, nanorice, nanospheres, nanofibers, nanowires, nanopyramids, nanoprisms, or a combination thereof.
  • Plasmonic particles present in the composition comprise a substantial amount of geometrically-tuned nanostructures defined as 5, 10, 15, 25, 50, 75, 80, 85, 90, 95, 98, 99, 99.9 or greater than 99.9% of particles.
  • the nanoparticle is a metal (e.g., gold, silver), metallic composite (e.g., silver and silica, gold and silica), metal oxide (e.g. iron oxide, titanium oxide), metallic salt (e.g., potassium oxalate, strontium chloride), intermetallic (e.g., titanium aluminide, alnico), electric conductor (e.g., copper, aluminum) , electric superconductor (e.g., yttrium barium copper oxide, bismuth strontium calcium copper oxide), electric semiconductor (e.g., silicon, germanium), dielectric (e.g., silica, plastic), or quantum dot (e.g., zinc sulfide, cadmium selenium) .
  • metal oxide e.g. iron oxide, titanium oxide
  • metallic salt e.g., potassium oxalate, strontium chloride
  • intermetallic e.g., titanium aluminide, alnico
  • electric conductor
  • the materials are gold, silver, nickel, platinum, titanium, palladium, silicon, galadium.
  • the nanoparticle contains a composite including multiple metals (e.g., alloy), a metal and a dielectric, a metal and a semiconductor, or a metal, semiconductor and dielectric.
  • the composition contains coated particles.
  • Biological material Material that is sourced from albumin, ovalbumin, egg living matter protein, milk protein, other food, plant, animal, bacteria, yeast, or recombinantly- derived protein; peptides; enzymes, lipids, fatty acids, sugars
  • Biocide material Material that is active in killing, Synthetic or natural
  • Dielectric materials An insulator that may be Silicon, doped
  • Chemorecognitive Material that is able to interact Receptor, receptor ligand, material with a moiety for binding, chemical molecule
  • Polymer/dendrimer Long chain molecule linear or PLGA, PEG, PEO,
  • polystyrene branched, block or co-block polystyrene, carboxylate styrene, rubbers, nylons, silicones, polysaccharides
  • Hydrogel Polymer with high hydrophilicity Synthetic 2-hydroxyethyl and water "ordering" capacity metacrylate (HEMA)-based, polyethylene glycol (PEG)- based, PLGA, PEG- diacrylate; Natural ionic gels, alginate, gelatin, hyaluronic acids, fibrin
  • polystyrene cellulose polystyrene cellulose, pplyquaterniums, lipids, surfactants, carbopol.
  • the composition may contain a peptide, a nucleic acid, a protein, or an antibody.
  • a protein, antibody, peptide, or nucleic acid that binds a protein of a follicular stem cell (e.g., keratin 15), a protein, glycomatrix, or lipid on the surface of a cell or stem cell, a protein, peptide, glycomatrix of the extracellular matrix or basement membrane.
  • the coated nanoparticles may contain charged moieties whereby those charges mediate enhanced or diminished binding to components within or outside the hair follicle via electrostatic or chemical interactions.
  • Hydrophilic moieties Moieties that are water-loving PEG, PEO, PLGA
  • Agnostic moieties Moieties that bind a target cell, Antibodies, peptides,
  • Antagonistic moieties Moieties that block the binding to Antibodies, peptides,
  • Reactive moieties Moieties that react with biological Aldehydes
  • target tissues for topical and dermatological applications include the surface of the skin, the epidermis and the dermis.
  • Diseases or conditions suitable for treatment with topical and dermatological applications include acne, warts, fungal infections, psoriasis, scar removal, hair removal, hair growth, reduction of hypertrophic scars or keloids, skin inconsistencies (e.g. dermal inconsistencies, e.g., texture, color, tone, skin brightness (e.g., skin lightening or skin whitening), elasticity, hydration), and malignant or non-malignant skin tumors.
  • skin inconsistencies e.g. dermal inconsistencies, e.g., texture, color, tone, skin brightness (e.g., skin lightening or skin whitening), elasticity, hydration
  • malignant or non-malignant skin tumors e.g. dermal inconsistencies, e.g., texture, color, tone, skin brightness (e.g., skin lightening or skin whitening
  • acne vulgaris includes acne vulgaris as well as other forms of acne and related cutaneous conditions, including acne aestivalis, acne conglobata, acne cosmetic, acne fulminans, acne keloidalisnuchae, acne mechanica, acne miliarisnecrotica, acne necrotica, chloracne, drug-induced acne, excoriated acne, halogen acne, lupus miliaris disseminates faciei, pomade acne, tar acne, and tropical acne.
  • target tissues for subdermal applications include the adipose tissue and connective tissue below the integumentary system.
  • Diseases or conditions suitable for treatment with subdermatological applications include wrinkles and tattoos.
  • Other applications with photoactive particles include skin rejuvenation and/or resurfacing, the removal or reduction of stretch marks and fat ablation.
  • a specific region of the target tissue that can be treated with the photoactive particles (e.g., plasmonic nanoparticles) descried herein is a hair follicle, a sebaceous gland, a merocrine sweat gland, an apocrine sweat gland, or an arrector pili muscle, within which a specific domain is targeted.
  • the bulge region of the hair follicle is targeted.
  • the nanoparticles are useful to thermally ablate hair follicle stem cells for hair removal, regions containing hair follicle stem cells are of particular interest for targeting.
  • the target tissue region may include a stem cell niche, bulge, sebaceous gland, dermal papilla, cortex, cuticle, inner root sheath, outer root sheath, medulla, Huxley layer, Henle layer or arrector pili muscle.
  • Each of these regions may contain cells, stem cells, basement membrane, extracellular matrix, growth factors, analytes, or other biologic components that mediate hair follicle rejuvenation. Disruption or destruction of these components would have a therapeutic effect, e.g. slow or stop the processes that mediate hair regrowth, prevent the secretion of sebum from the sebaceous gland, damage or deter tumor cells, reduce the appearance of wrinkles.
  • Structures can also be targeted that are in close proximity to a desired target for ablation, especially when capable of conducting heat effectively.
  • compositions containing nanoparticles that preferentially localize to a domain of a target tissue region of a mammalian subject to whom the composition is administered.
  • nanoparticles e.g., plasmonic or non-plasmonic nanoparticles
  • the nanoparticles are operably linked to the domain via a biologic moiety, in order to effectively target the nanoparticles to the target tissue domain.
  • the moiety contains a component of a stem cell, a progenitor cell, an extracellular matrix component, a basement membrane component, a hair shaft component, a follicular epithelial component, or a non-follicular epidermal component.
  • Biological moieties include proteins such as cell surface receptors, glycoproteins or extracellular matrix proteins, as well as carbohydrates, analytes, or nucleic acids (DNA, RNA) as well as membrane components (lipid bilayer components, microsomes).
  • nanoparticles e.g., plasmonic or non-plasmonic nanoparticles
  • present in the composition preferentially delocalize away from a domain of a target tissue region.
  • Derealization domains include specific regions of a tissue into which nanoparticles do not substantially aggregate, or alternatively, are removed from the domain more effectively.
  • the derealization domain is a non-follicular epidermis, dermis, a component of a hair follicle (e.g., a hair stem cell, a stem cell niche, a bulge, a sebaceous gland, a dermal papilla, a cortex, a cuticle, an inner root sheath, an outer root sheath, a medulla, a Huxley layer, a Henle layer, an arrector pili muscle), a hair follicle infundibulum, a sebaceous gland, a component of a sebaceous gland, a sebocyte, a component of a sebocyte, or sebum
  • a hair follicle e.g., a hair stem cell, a stem cell niche, a bulge, a sebaceous gland, a dermal papilla, a cortex, a cuticle, an inner root sheath, an outer root sheath,
  • Energy sources Provided herein are various embodiments of energy sources to, for example, apply to or otherwise activate the photoactive particles. These include, but are not limited to, surface plasmon resonance excitation sources (e.g., nonlinear excitation surface plasmon resonance sources), various light sources and optical sources.
  • Various embodiments of light sources include a laser (ion laser, semiconductor laser, Q-switched laser, free-running laser, or fiber laser), light emitting diode, lamp, the sun, a fluorescent light source or an electroluminescent light source.
  • the energy source is capable of emitting radiation at a wavelength from about 100, 200, 300, 400, 500, 1000, 2000, 5000 nm to about 10,000 nm or more.
  • the surface plasmon resonance excitation sources (e.g., nonlinear excitation surface plasmon resonance source) is capable of emitting electromagnetic radiation, ultrasound, thermal energy, electrical energy, magnetic energy, or electrostatic energy.
  • the energy is radiation at an intensity from about 0.00005 mW/cm 2 to about 1000 TW/cm 2.
  • the optimum intensity is chosen to induce high thermal gradients from plasmonic nanoparticles in regions from about 10 microns to hundreds of microns in the surrounding tissue, but has minimal residual effect on heating tissue in which particles do not reside within a radius of about 100 microns or more from the nanoparticle.
  • a differential heat gradient between the target tissue region and other tissue regions is greater than 2-fold, 3-fold, 5-fold, 10-fold, 15-fold, 20-fold, 50-fold, 100-fold, or greater than 100 fold.
  • plasmonic nanoparticles can act as antennas, providing a nonlinear excitation at peak resonance or, in other words, an enhanced extinction cross section for a given physical cross-section of material when compared to non-plasmonic photoactive materials of the same dimension.
  • plasmonic materials may be able to pull more energy from delocalized electromagnetic waves surrounding the material at peak resonance than non-plasmonic photoactive material of the same dimension.
  • the energy can be tuned by monitoring thermal heat gradients on the surface of the skin with a thermal/infrared camera.
  • the methods and systems of the present disclosure provide superior efficacy when a surface plasmon is generated on the nanoparticles by the action of the radiation.
  • the plasmon is generated in a one- photon mode or, alternatively, a two-photon mode, a multi-photon mode, a step-wise mode, or an up-conversion mode.
  • physical means of delivery of the light energy (e.g., laser, flash lamp, intense pulse, etc.) to the surface plasmon resonance excitation (e.g., nonlinear excitation surface plasmon resonance source) to the target tissue region include a fiber, waveguide, a contact tip, a microlens array, a digital micromirror array (DMA), or a combination thereof.
  • the light energy e.g., laser, flash lamp, intense pulse, etc.
  • the surface plasmon resonance excitation e.g., nonlinear excitation surface plasmon resonance source
  • DMA digital micromirror array
  • optical sources include a CW optical source or a pulsed optical source, which may be a single wavelength polarized (or, alternatively, unpolarized) optical source capable of emitting radiation at a frequency from about 200 nm to about 10,000 nm.
  • the optical source is a multiple wavelength polarized (or, alternatively, unpolarized) optical source capable of emitting radiation at a wavelength from about 200 nm to about 10,000 nm.
  • the pulsed optical source is generally capable of emitting pulsed radiation at a frequency from about 1 Hz to about 1 THz.
  • the pulsed optical source is capable of a pulse less than a millisecond, microsecond, nanosecond, picoseconds, or femtosecond in duration.
  • a source emitting radiation at a wavelength of 755 nm is operated in pulse mode such that the emitted radiation is pulsed at a duration of 0.25-300 milliseconds (ms) per pulse, with a pulse frequency of 1-10 Hz.
  • radiation emitted at a wavelength of 810 nm is pulsed at 5-100 ms with a frequency of 1- 10Hz.
  • a source emitting radiation at a wavelength of 1064 nm is pulsed at 0.25-300 ms at a frequency of 1-lOHz.
  • a source emitting intense pulsed light at a wavelength of 530-1200 nm is pulsed at 0.5-300 ms at a frequency of 1- 10Hz.
  • the optical source may be coupled to a skin surface cooling device to reduce heating of particles or structures on the skin surface and focus heating to components within follicles or tissue structures at deeper layers.
  • pulse widths range from 0.1ms to lm, lms-lOms, lOms-lOOms, lOOms-lOOOms, greater than 1000ms.
  • Nanoparticle-containing compositions In order to provide optimal dermal penetration into the target tissue, photoactive particles (e.g., plasmonic nanoparticles) in certain embodiments are formulated in various compositions. In one embodiment, the nanoparticles are formulated in compositions containing 1-10% v/v surfactants (e.g. sodium dodecyl sulfate, sodium laureth 2-sulfate, ammonium lauryl sulfate, sodium octech-l/deceth- 1 sulfate).
  • 1-10% v/v surfactants e.g. sodium dodecyl sulfate, sodium laureth 2-sulfate, ammonium lauryl sulfate, sodium octech-l/deceth- 1 sulfate.
  • Nanoparticle-containing compositions may also include emulsions at various concentrations (1-20% w/v) in aqueous solutions, silicone/oil solvents, polypropylene gel, propylene glycol or creams (e.g. comprising alcohols, oils, paraffins, colloidal silicas).
  • the formulation contains a degradable or non-degradable polymer, e.g., synthetic polylactide/co-glycolide co-polymer, porous lauryllactame/caprolactame nylon co-polymer, hydroxyethylcellulose, polyelectrolyte monolayers, or alternatively, in natural hydrogels such as hyaluronic acid, gelatin and others.
  • a hydrogel PLGA, PEG-acrylate is included in the formulation.
  • a matrix component such as silica, polystyrene or polyethylene glycol is provided in the formulation.
  • Other formulations include components of surfactants, a lipid bilayer, a liposome, microsome, polymersomes, or a polymer microcapsules.
  • a nanoparticle may comprise a larger micron-sized particle.
  • an effective dose of the nanoparticle-containing compositions includes an amount of particles required, in some aspects, to generate an effective heat gradient in a target tissue region, such that a portion of the target tissue region is acted upon by thermal energy from excited nanoparticles.
  • a "minimal effective dose” is the smallest number or lowest concentration of nanoparticles in a composition that are effective to achieve the desired biological, physical and/or therapeutic effect(s).
  • the photoactive particles e.g., plasmonic nanoparticles
  • the photoactive particles have an optical density of 10 O.D.-1.000 O.D. (e.g., 10 - 100 O.D, 50 - 200 O.D, 20 - 300 O.D.) at one or a plurality of peak resonance wavelengths.
  • Cosmetically acceptable carriers are cosmetic or pharmaceutical compositions with a plurality of photoactive particles (e.g., plasmonic nanoparticles) and a cosmetically or pharmaceutically acceptable carrier.
  • the carrier and composition must be suitable for topical administration to the skin of a mammalian subject, such that the photoactive particles (e.g., plasmonic nanoparticles) are present in an effective amount for selective thermomodulation of a component of the skin.
  • the nanoparticles are formulated with a carrier containing 1-10% v/v surfactants (e.g.
  • the carrier contains a polar or non-polar solvent.
  • suitable solvents include alcohols (e.g., n-Butanol, isopropanol, n-Propanol, Ethanol, Methanol), hydrocarbons (e.g., pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-Dioxane), chloroform, Diethyl-ether, water, water with propylene glycol, acids (e.g., acetic acid, formic acid), bases, acetone, isooctanes, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), acetonitrile (MeCN), tetrahydrofuran (THF), dichloromethane (DCM), ethylacetate, tetramethylammonium hydroxide, isopropanol, and others.
  • alcohols e.g., n-Butanol, isopropanol
  • a stabilizing agent such as antioxidants, preventing unwanted oxidation of materials, sequestrants, forming chelate complexes and inactivating traces of metal ions that would otherwise act as catalysts, emulsifiers, ionic or non-ionic surfactants, cholesterol or phospholipids, for stabilization of emulsions (e.g. egg yolk lecithin, sodium stearoyllactylate, sodium bis(2-ethylhexyl-sulfosuccinate (AOT)), ultraviolet stabilizers, protecting materials, especially plastics, from harmful effects of ultraviolet radiation is provided.
  • a composition with a cosmetically acceptable carrier is generated such that the nanoparticles are substantially in a suspension.
  • emulsion emulsion, polymer, hydrogel, matrix, lipid bilayer, liposome, microsome, polymersome, or polymer microcapsule.
  • inclusion of a detectable colorant e.g., a pigment
  • a fragrance e.g., a fragrance
  • a moisturizer e.g., a moisturizer
  • a skin protectant e.g., a skin protectant
  • the formulation has a viscosity of above, below or within 0.1-10,000 (e.g., 5e - ⁇ 4 x 103 , 1,000), as measured in millipascal-seconds (mPa-s).
  • compositions contain particle concentrations with optical densities of 10 O.D.-1000 O.D. (e.g., 10 - 100 O.D, 50 - 200 O.D, 20 - 300 O.D.), or optical densities greater than 1,000 O.D. (e.g., 1,200 - 1,500, 2,000) In some embodiments these correspond to concentrations of about 0.1-10% w/w or more of nanoparticles.
  • nanoparticle formulations e.g., photoactive nanoparticles, such as plasmonic nanoparticles
  • skin and hair follicles can be pre-treated to increase the delivery of nanoparticles to a target region.
  • hair shafts are cut or removed via shaving, waxing, sugaring, cyanoacrylate surface peels, calcium thioglycolate treatment, or other techniques to remove the hair shaft and/or hair follicle plugs and create a void wherein nanoparticles can accumulate.
  • Orifices of active or inactive follicles can be blocked by plugs formed of corneocytes and/or other material (e.g. cell debris, soot, hydrocarbons, cosmetics).
  • pre-treatment with surface exfoliation including mechanical exfoliation (e.g., salt glow or microdermabrasion) and chemical exfoliation (e.g., enzymes, alphahydroxy acids, or betahydroxy acids) removes plugs from the orifice of follicles to increase the targeting of nanoparticle formulations to target regions within the hair follicle.
  • mechanical exfoliation e.g., salt glow or microdermabrasion
  • chemical exfoliation e.g., enzymes, alphahydroxy acids, or betahydroxy acids
  • the nanoparticle formulations are formulated for application by a sponge applicator, cloth applicator, direct contact via a hand or gloved hand, spray, aerosol, vacuum suction, high pressure air flow, or high pressure liquid flow, roller, brush, planar surface, semi-planar surface, wax, ultrasound and other sonic forces (e.g., low frequency ultrasound via a transducer, acoustic horn, or sonotrode), mechanical vibrations, physical manipulation, hair shaft manipulation (including pulling, massaging), physical force, electrophoresis, iontophoresis, thermal manipulation, and other treatments.
  • a sponge applicator cloth applicator
  • direct contact via a hand or gloved hand spray, aerosol, vacuum suction, high pressure air flow, or high pressure liquid flow
  • roller, brush planar surface, semi-planar surface, wax
  • ultrasound and other sonic forces e.g., low frequency ultrasound via a transducer, acoustic horn, or sonotrode
  • mechanical vibrations e.g.,
  • massage e.g., hand massage, vibration, mechanical vibration
  • nanoparticle formulation treatments are performed alone, in combination, sequentially or repeated 1-24 times.
  • the nanoparticles e.g., photoactive nanoparticles, such as plasmonic nanoparticles
  • the nanoparticles are selectively removable from components of the skin other than the first component, such removal accomplished with acetone, alcohol, water, air, peeling of the skin, chemical peeling, waxing, or reduction of the plasmonic compound. Further, in some embodiments the nanoparticles have a coat layer to increase solubility of the nanoparticles in the carrier and/or reduce "stickiness" and accumulation in non-target areas.
  • an exterior surface of the nanoparticle is modified, such as to include a layer of a polymer, polar monomer, non-polar monomer, biologic compound, a metal (e.g., metallic thin film, metallic composite, metal oxide, or metallic salt), a dielectric, or a semiconductor.
  • the exterior surface modification is polar, non-polar, charged, ionic, basic, acidic, reactive, hydrophobic, hydrophilic, agonistic, or antagonistic.
  • the nanoparticle surface can be coated with a matrix (e.g.
  • silica of 10-100 nm thickness or more in order to increase that dimension or particle to 50-100 nm or more.
  • This increased dimension size can increase the delivery of all nanoparticles to a target region (e.g., hair follicle) and limit delivery to non-target region (e.g. dermis).
  • compositions of the instant disclosure are topically administered.
  • low frequency ultrasound can be applied at frequencies of 1 kHz to 500 kHz, e.g., 1 kHz - 100 kHz, 5 kHz - 45 kHz, 20 kHz - 50 kHz, 30 kHz - 40 kHz, 30 kHz, 40 kHz, and any ranges or frequencies therein.
  • massage e.g., hand massage, vibration, mechanical vibration
  • a delivery device 200 is used to deliver, distribute, redeliver, redistribute, penetrate, drive, disperse, direct, and/or enhance movement of a composition 100 to a target location.
  • the delivery device 200 is a mechanical vibration device.
  • the delivery device 200 is a mechanical vibration device configured for mechanical mixing.
  • a mechanical vibration device vibrates at frequencies of less than 1kHz, 1 Hz - 900 Hz, 5 - 500 Hz, 10 - 100 Hz, 1 - 80Hz, 50 - 250 Hz, and any frequencies therein.
  • a mechanical vibration device vibrates, laterally, longitudinally, or radially.
  • a mechanical vibration device vibrates longitudinally. In one embodiment, a mechanical vibration device vibrates horizontally. In one embodiment, a mechanical vibration device vibrates radially. In one embodiment, a mechanical vibration device vibrates with a mix of one or more motions, longitudinal, horizontal, and/or radial. In one embodiment, a mechanical vibration device vibrates longitudinally at 80 Hz. In one embodiment, the delivery device 200 is a mechanical vibration device with 80 Hz longitudinal vibration. In one embodiment, the delivery device 200 is a Vibraderm with 80 Hz longitudinal vibration, configured to deliver a composition 100 to a depth of 1000 microns. [00127] In some embodiments, the delivery device 200 is an ultrasound device. In some embodiments, the delivery device 200 is an ultrasound device with focused ultrasound energy.
  • the delivery device 200 is an ultrasound device with unfocused ultrasound energy. In some embodiments, the delivery device 200 is an ultrasound device that produces cavitation. In some embodiments, the delivery device 200 is an ultrasound device with pulsed energy. In some embodiments, the delivery device 200 is an ultrasound device with non-pulsed energy. In some embodiments, the delivery device 200 is an ultrasound device with surface localized energy such as that which can be generated by a Sonotrode.
  • a sonotrode may refer to an acoustic horn, acoustic waveguide, ultrasonic probe, or ultrasonic horn.
  • a sonotrode consists of a metal shaft, rod, horn, cone, taper, barbell, wedge, or other shape capable of translating and/or augment the amplitude produced by a low frequency ultrasonic transducer.
  • the main function of a sonotrode is to deliver ultrasonic energy from a transducer into a gas, liquid, solid or tissue.
  • delivery device 200 is a sonotrode that is attached to an ultrasonic transducer or a stack of ultrasonic transducers.
  • the sonotrode delivery device 200 is designed to operate at frequencies between 15 kHz -100 kHz, e.g., 15 kHz -85 kHz, 15 kHz -75 kHz, 15 kHz - 65 kHz, 15 kHz - 55 kHz, 15 kHz - 45 kHz, 15 kHz - 35 kHz, 15 kHz - 25 kHz, 25 kHz - 60 kHz, 20 kHz - 60 kHz, 20 kHz - 50 kHz, 20 kHz - 40 kHz, and any frequencies therein.
  • the sonotrode is used to deliver ultrasonic energy into the composition, tissue, and/or surface of the tissue or any combination of the composition, tissue, and surface of the tissue.
  • the power and amplitude of the sonotrode generates acoustic cavitation in the surrounding medium (e.g., composition, tissue, and/or surface of the tissue or any combination of the composition, tissue, and surface of the tissue).
  • the action of sonotrode generates heat, mixing, jetting, and streaming at or near the surface of the sonotrode in the surrounding medium.
  • the acoustic waveguide within the sonotrode may also produce evanescent waves responsible for localized effects in the surrounding medium.
  • One or more of the actions of the sonotrode are responsible for driving the delivery of the composition into the targeted area of the skin.
  • Localized surface effects of the sonotrode include cavitation, jetting, mixing, and streaming.
  • the delivery device 200 is a high frequency ultrasound device. In some embodiments, the delivery device 200 is a low frequency ultrasound device. In several embodiments of the invention, low frequency ultrasound can be applied at frequencies of 1 kHz to 500 kHz, e.g., 1 kHz - 100 kHz, 5 kHz - 45 kHz, 20 kHz - 50 kHz, 30 kHz - 40 kHz, 30 kHz, 40 kHz, and any ranges or frequencies therein.) In one embodiment, the delivery device 200 operates at a frequency of 20-50 kHz and more specifically 32.4 kHz with an axial amplitude between 1 micron - 30 microns, e.g., 1 micron- 20 microns, 1 micron- 15 microns, 5 microns - 15 microns, 5 microns - 12 microns, 7 microns, 8 microns, 9 microns, 10 microns, 11 microns, 12 microns
  • the delivery device 200 operates at a frequency of 32.4 kHz with an axial amplitude between 1 micron - 20 microns and a radial amplitude between 0 microns - 5 microns, e.g., 0 microns, 1 micron, 2 microns, 3 microns, 4 microns, 5 microns, and any radial amplitude therein.
  • the delivery device 200 operates at a frequency of 32.4 kHz with an axial amplitude between 1 micron - 20 microns, radial amplitude between 0 microns - 5 microns, and is driven by an ultrasonic transducer with powers between 3W - 20W, e.g., with surface localized energy configured to induce cavitation, configured to deliver a composition 100 to a depth of at least 1500 microns.
  • the delivery device 200 is a low frequency ultrasound device that operates at a frequency of 30-60 kHz non-pulsed ultrasound configured to induce cavitation. In one embodiment, the delivery device 200 is a low frequency ultrasound device that operates at a frequency of 30-60 kHz non-pulsed ultrasound configured to induce cavitation from an unfocused transducer.
  • the delivery device 200 is a GS8.0 low frequency ultrasound device that operates at a frequency of 36 kHz non-pulsed ultrasound with a second harmonic at 55 kHz configured to induce cavitation at depth of approximately 8 mm and 18 mm in water from the face of the unfocused transducer, operating at a power between 2W - 15W, and configured to deliver a composition 100 to a depth of at least 1000 microns.
  • the delivery device 200 is configured to deliver a composition 100 to a depth of 1 - 100 microns, 1-1000 microns, 1-1500 microns, 1-2000 microns, 1-3000 microns, 1-4000 microns, and/or 1-5000 microns.
  • the delivery device 200 is configured to deliver a composition 100 to a depth of 1000 - 1500 microns. In some embodiments, the delivery device 200 is configured to deliver a composition 100 to a depth of 1000 microns. In some embodiments, the delivery device 200 is configured to deliver a composition 100 to a depth of 1500 microns. In some embodiments, the delivery device 200 is configured to deliver a composition 100 to a depth of 2000 microns. In some embodiments, the delivery device 200 is configured to deliver a composition 100 to a depth of 2500 microns.
  • the nanoparticles described herein are formulated to penetrate much deeper— up to several centimeters, or into the panniculus adiposus (hypodermis) layer of subcutaneous tissue.
  • the compositions can be administered by use of a sponge applicator, cloth applicator, spray, aerosol, vacuum suction, high pressure air flow, high pressure liquid flow direct contact by hand ultrasound and other sonic forces, mechanical vibrations, physical manipulation, hair shaft manipulation (including pulling, massaging), physical force, thermal manipulation, or other treatments. Nanoparticle formulation treatments are performed alone, in combination, sequentially or repeated 1-24 times.
  • nanoparticles described may be plasmonic or non-plasmonic.
  • non-plasmonic, photoactive nanoparticles may be used.
  • Acne is caused by a combination of diet, hormonal imbalance, bacterial infection (Propionibacterium acnes), genetic predisposition, and other factors.
  • the nanoparticle-based methods and systems described herein for acne treatment are able to focally target causative regions of the dermis, the sebaceous gland and the hair follicle, and thus have advantages compared to the existing techniques known in the art, including chemical treatment (peroxides, hormones, antibiotics, retinoids, and anti-inflammatory compounds), dermabrasion, phototherapy (lasers, blue and red light treatment, or photodynamic treatment), or surgical procedures.
  • laser-based techniques are becoming an increasingly popular acne treatment, but a substantial limitation is the lack of selective absorptive properties among natural pigments (e.g. fat, sebum) for specific wavelengths of light such that selective heating of one cell, structure, or component of tissue, particularly in the sebaceous glands, infundibulum, and regions of the hair follicle, is not achieved without heating of adjacent off- target tissue.
  • natural pigments e.g. fat, sebum
  • the nanoparticles described herein provide significantly higher photothermal conversion than natural pigments enabling laser energy to be focused to specific cells, structures, or components of tissue within the sebaceous gland, infundibulum, or regions of the hair follicle for selective photothermal damage.
  • Using the materials and techniques described herein may provide acne treatments of greater duration than existing methodologies.
  • tuned selective ablation of the sebaceous gland or infundibulum is achieved as described herein.
  • plasmonic nanoparticles are specifically localized to regions of hair follicles in or proximate to the sebaceous gland or infundibulum.
  • Plasmonic nanoparticles exhibit strong absorption at wavelengths emitted by standard laser hair removal devices (e.g., 755 nm, 810 nm, 1064 nm) and intense pulse light (IPL) devices (e.g., 515-1200 nm range) relative to surrounding epidermal tissue.
  • standard laser hair removal devices e.g., 755 nm, 810 nm, 1064 nm
  • IPL intense pulse light
  • the nanoparticle-based methods and systems described herein for skin treatment have advantages compared to the existing techniques known in the art, including laser-based techniques, chemical techniques, electrolysis, electromagnetic wave techniques, and mechanical techniques (e.g., waxing, tweezers). Such techniques fail to adequately provide permanent hair removal across a breadth of subjects. In particular, subjects having light to medium-pigmented hair are not adequately served by these techniques, which suffer from side-effects including pain and the lack of beneficial cosmetic affects including hair removal.
  • Laser-based techniques are popular in a variety of applications, but a substantial limitation is the lack of selective absorptive properties among natural pigments (e.g.
  • melanin for specific wavelengths of light such that selective heating of one cell, structure, or component of tissue is achieved without heating of adjacent off-target tissues.
  • the nanoparticles described herein provide significantly higher photothermal conversion than natural pigments enabling laser energy to be focused to specific cells, structures, or components of tissue for selective photothermal damage.
  • the methods described herein are useful for hair removal of all types and pigmentations.
  • melanin the predominant hair pigment, is an aggregation of chemical moieties including eumelanin and phaeomelanin. Eumelanin colors hair grey, black, yellow, and brown. A small amount of black eumelanin in the absence of other pigments causes grey hair.
  • Types of eumelanin include black eumelanin and brown eumelanin, with black melanin being darker than brown.
  • black eumelanin predominates in non-European subjects and aged Europeans, while brown eumelanin is in greater abundance in young European subjects.
  • Phaeomelanin predominates in red hair.
  • vellus hair (“peach fuzz") is a type of short, fine, light-colored, and usually barely noticeable hair that develops on much or most of a subject's body (excluding lips, palms of hand, sole of foot, navel and scar tissue). While the density of vellus hair is generally lower than that of other hair types, there is variation from person to person in the density, thickness, and pigmentation.
  • Vellus hair is usually less than 2mm long and the follicle containing the vellus hair is generally not connected to a sebaceous gland.
  • Conditions associated with an overabundance of vellus hair include Cushing's syndrome and anorexia nervosa, such overgrowth being treatable using the methods and compositions described herein.
  • the hair follicles on a subject are in anagen phase (10-14% are in telogen and 1-2% in catagen).
  • the cycle's length is governed by cytokines and hormones, and varies on different parts of the body. For eyebrows, the cycle is completed in around 4 months, while it takes the scalp 3-4 years to finish.
  • the methods and compositions described herein are sufficient to treat hair of all growth stages or phases.
  • plasmonic nanoparticles are specifically localized to regions of hair follicles in or proximate to the bulge region, a stem cell-rich domain of the hair follicle. Moreover, the plasmonic nanoparticles are localized in close approximation of -SOYS % of the hair shaft structure.
  • Plasmonic nanoparticles exhibit strong absorption at wavelengths emitted by standard laser hair removal devices (e.g., 755 nm, 810 nm, 1064 nm) and intense pulse light (IPL) devices (e.g., 515-1200 nm range) relative to surrounding epidermal tissue.
  • IPL intense pulse light
  • irradiation of targeted plasmonic nanoparticles with laser light induces heat radiation from the particles to the adjacent stem cells (or in some cases, the architecture of the hair shaft itself), resulting in cell death and a disruption of the normal regenerative pathway.
  • Laser therapies for the prevention and treatment of non-malignant, malignant, melanoma and non-melanoma skin cancers have been focused largely on photodynamic therapy approaches, whereby photosensitive porphyrins are applied to skin and used to localize laser light, produce reactive oxygen species and destroy cancer cells via toxic radicals.
  • photosensitive porphyrins are applied to skin and used to localize laser light, produce reactive oxygen species and destroy cancer cells via toxic radicals.
  • 5-ALA combined with laser treatment has been FDA-approved for the treatment of non-melanoma skin cancer actinic keratoses, and it is used off-label for the treatment of widely disseminated, surgically untreatable, or recurrent basal cell carcinomas (BCC).
  • nanoparticles described herein provide significantly higher photothermal conversion than natural pigments and dyes, enabling laser energy to be focused to specific cells, structures, or components of tissue for selective thermomodulation [00140]
  • Using the materials and techniques described herein may provide cancer treatments of greater degree and duration than existing methodologies.
  • tuned selective ablation of specific target cells such as Merkel cells or Langerhans cells, as described herein.
  • Plasmonic nanoparticles are specifically localized to regions of hair follicles where follicular bulge stem cells arise to form nodular basal cell carcinomas and other carcinomas. Plasmonic nanoparticles may also be delivered to other target cells that cause tumors, for example, the interfollicular epithelium, which include the cell of origin for superficial basal cell carcinomas.
  • Plasmonic nanoparticles exhibit strong absorption at wavelengths emitted by standard laser hair removal devices (e.g., 755 nm, 810 nm, 1064 nm) and intense pulse light (IPL) devices (e.g., 515-1200 nm range) relative to surrounding epidermal tissue.
  • IPL intense pulse light
  • irradiation of targeted plasmonic nanoparticles with laser light induces heat radiation from the particles to the adjacent keratinocyte, melanocyte, follicular bulge stem cell, cancer cell, or cancer cell precursor, resulting in cell death or inhibited cell growth for cancer prevention and treatment.
  • Target tissues for subdermal applications include the adipose tissue and connective tissue below the integumentary system.
  • Diseases or conditions suitable for treatment with subdermatological applications include wrinkles and tattoos.
  • Other applications include skin rejuvenation and/or resurfacing, the removal or reduction of stretch marks and fat ablation.
  • Target tissues for vascular applications include arteries, arterioles, capillaries, vascular endothelial cells, vascular smooth muscle cells, veins, and venules.
  • Diseases or conditions suitable for treatment with vascular applications include spider veins, leaky valves, and vascular stenosis.
  • vein abnormalities account for a substantial proportion of cosmetic diseases or conditions affecting the vasculature. Individuals with vein abnormalities such as spider veins or faulty venous valves suffer from pain, itchiness, or undesirable aesthetics.
  • ablation of other vessels including arteries, arterioles, or capillaries could provide therapeutic or cosmetic benefit including: 1) ablation of vasculature supplying fat pads and/or fat cells, 2) ablation of vasculature supporting tumors/cancer cells, 3) ablation of vascular birth marks (port-wine stains, hemangiomas, macular stains), and 4) any other indication whereby ablation of vessels mediates the destruction of tissue and apoptosis or necrosis of cells supported by those vessels with therapeutic or cosmetic benefit.
  • Plasmonic nanoparticles are combined with a pharmaceutically acceptable carrier as described above and are introduced into the body via intravenous injection. Nanoparticles diffuse into the blood and, in some embodiments, localize to specific vascular tissues. Subsequently, the nanoparticles are activated with laser or light-based systems as known in the art for treating skin conditions such as hair removal or spider vein ablation. Alternatively, image or non-image guided fiber optic waveguide-based laser or light systems may be used to ablate vessel or blood components in larger veins. In one embodiment, a device with dual functions for both injecting nanoparticles and administering light through on optical waveguide may be used.
  • Activated nanoparticles heat blood and adjacent tissue (vessels, vessel walls, endothelial cells, components on or in endothelial cells, components comprising endothelial basement membrane, supporting mesenchymal tissues, cells, or cell components around the vessel, blood cells, blood cell components, other blood components) to ablative temperatures (38-50 degrees C or higher).
  • compositions comprising a pharmaceutically acceptable carrier and a plurality of plasmonic nanoparticles in an amount effective to induce thermomodulation of a vascular or intravascular target tissue region with which the composition is intravenously contacted.
  • composition of plasmonic nanoparticle may comprise a microvascular targeting means selected from the group consisting of anti-microvascular endothelial cell antibodies and ligands for microvascular endothelial cell surface receptors.
  • thermoablation of a target vascular tissue in a mammalian subject comprising the steps of contacting a region of the target vascular tissue with a composition comprising a plurality of plasmonic nanoparticles and a pharmaceutically acceptable carrier under conditions such that an effective amount of the plasmonic nanoparticles localize to a domain of the target vascular region; and exposing the target tissue region to energy delivered from a surface plasmon resonance excitation sources (e.g., nonlinear excitation surface plasmon resonance source) in an amount effective to induce thermoablation of the domain of the target vascular region.
  • a surface plasmon resonance excitation sources e.g., nonlinear excitation surface plasmon resonance source
  • Target tissues for oral applications include the mouth, nose, pharynx, larynx, and trachea.
  • Diseases or conditions suitable for treatment with vascular applications include oral cancer, polyps, throat cancer, nasal cancer, and Mounier- Kuhn syndrome.
  • Other conditions suitable for treatment include allergies or voice disorders involving vocal chords.
  • Target tissues for endoscopic applications include the stomach, small intestine, large intestine, rectum and anus.
  • Diseases or conditions suitable for treatment with vascular applications include gastrointestinal cancer, ulcerative colitis, Crohn's disease, Irritable Bowel Syndrome, Celiac Disease, Short Bowel Sydrome, or an infectious disease such as giardiasis, tropical sprue, tapeworm infection, ascariasis, enteritis, ulcers, Whipple's disease, and megacolon.
  • thermomodulation Provided are embodiments of methods for performing thermomodulation of a target tissue region.
  • a nanoparticle composition comprising a plurality of plasmonic nanoparticles under conditions such that an effective amount of the plasmonic nanoparticles localize to a domain of the target tissue region; and exposing the target tissue region to energy delivered from a surface plasmon resonance excitation sources (e.g., nonlinear excitation surface plasmon resonance source) in an amount effective to induce thermomodulation of the domain of the target tissue region.
  • a surface plasmon resonance excitation sources e.g., nonlinear excitation surface plasmon resonance source
  • removing nanoparticles localized on the surface of the skin may be performed by contacting the skin with acetone, alcohol, water, air, a debriding agent, or wax. Alternatively, physical debridement may be performed. Alternatively, one can perform a reduction of the plasmonic or other compound.
  • skin is irradiated at a fluence of 1-60 Joules per cm with laser wavelengths of about, e.g., 750 nm, 810 nm, 1064 nm, or other wavelengths, particularly in the range of infrared light.
  • laser wavelengths e.g., 750 nm, 810 nm, 1064 nm, or other wavelengths, particularly in the range of infrared light.
  • Various repetition rates are used from continuous to pulsed, e.g., at 1-10 Hz, 10-100 Hz, 100-1000 Hz. While some energy is reflected, it is an advantage of the subject matter described herein is that a substantial amount of energy is absorbed by particles, with a lesser amount absorbed by skin.
  • Nanoparticles are delivered to the hair follicle, infundibulum, or sebaceous gland at concentration sufficient to absorb, e.g., 1.1-lOOx more energy than other components of the skin of similar volume. This is achieved in some embodiments by having a concentration of particles in the hair follicle with absorbance at the laser peak of 1.1-lOOx relative to other skin components of similar volume.
  • some embodiments of light-absorbing nanoparticles are utilized in conjunction with a laser or other excitation source of the appropriate wavelength.
  • the laser light may be applied continuously or in pulses with a single or multiple pulses of light.
  • the intensity of heating and distance over which photothermal damage will occur are controlled by the intensity and duration of light exposure.
  • pulsed lasers are utilized in order to provide localized thermal destruction.
  • pulses of varying durations are provided to localize thermal damage regions to within 0.05, 0.1, 0.5, 1, 2, 5, 10, 20, 30, 50, 75, 100, 200, 300, 500, 1000 microns of the particles. Pulses are at least femtoseconds, picoseconds, microseconds, or milliseconds in duration.
  • the peak temperature realized in tissue from nanoparticle heating is at least 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, or 500 degrees Celsius.
  • high peak temperatures are realized locally within the hair shaft without raising the macroscopic tissue temperature more than 0.1, 0.5, 1, 2, 3, 4, 5, 7, 9, 12, 15, or 20 degrees Celsius.
  • short pulses (100 nanoseconds- 1000 microseconds) are used to drive very high transient heat gradients in and around the target skin structure (e.g., sebaceous gland and/or hair follicle) from embedded particles to localize damage in close proximity to particle location.
  • longer pulse lengths (1-lOms, or 1-500 ms) are used to drive heat gradients further from the target structure to localize thermal energy to stem cells in the bulge region or other components greater than 100 ⁇ away from the localized particles.
  • Fluences of 1-10 Joules per cm 2 or 1-30 Joules per cm 2 are generally sufficient to thermally ablate follicles that have high particle concentrations and thus higher absorbance than skin (e.g., 1.1-100 times per volume absorbance of skin). These fluences are often lower than what is currently employed (e.g., Diode: 25-40 J/cm 2 , Alexandrite: 20 J/cm2, Nd:YAG: 30-60 J/cm 2 ) and lead to less damage to non-follicular regions, and potentially less pain.
  • Plasmon Resonance Systems containing a surface that includes a plurality of plasmonic nanoparticles, and a nonlinear excitation source.
  • the system contains a means to generate thermal heating of the surface.
  • the surface is a component of skin that is targeted for cosmetic or therapeutic treatment (e.g., bulge region for hair removal, infundibulum or sebaceous gland for acne prevention).
  • a means for delivering plasmonic nanoparticles to the skin surface such as an applicator, a spray, an aerosol, vacuum suction, high pressure air flow, or high pressure liquid flow.
  • Useful surface delivery means include a device that generates high frequency ultrasound, low frequency ultrasound, heat, massage, contact pressure, or a combination thereof.
  • low frequency ultrasound can be applied at frequencies of 1 kHz to 500 kHz, e.g., 1 kHz - 100 kHz, 5 kHz - 45 kHz, 20 kHz - 50 kHz, 30 kHz - 40 kHz, 30 kHz, 40 kHz, and any ranges or frequencies therein.
  • massage e.g., hand massage, vibration, mechanical vibration
  • the removal means includes at least one of acetone, alcohol, water, air, chemical peeling, wax, or a compound that reduces the plasmonic compound.
  • the systems of the present disclosure provide nonlinear excitation source that generates a continuous wave optical source or a pulsed optical source.
  • the nonlinear excitation source is capable of generating electromagnetic radiation, ultrasound, thermal energy, electrical energy, magnetic energy, or electrostatic energy.
  • the nonlinear excitation source is capable of 2
  • the nonlinear excitation source is capable of functioning in a one-photon mode, two-photon mode, multi-photon mode, step-wise mode, or up-conversion mode.
  • a fiber, a waveguide, a contact tip, or a combination thereof may be used in the instant systems.
  • the system contains a monitoring device such as a temperature sensor or a thermal energy detector.
  • the systems also contain a controller means for modulating the nonlinear excitation source (e.g., a "feedback loop controller").
  • the system contains a means for detecting a temperature of the surface or a target tissue adjacent to the surface, wherein the controller means modulates the intensity of the nonlinear excitation source and/or the duration of the excitation.
  • the controller means preferably modulates the intensity of the nonlinear excitation source such that a first component of the hair follicle is selectively thermoablated relative to a second component of the hair follicle.
  • a cooling device is directly contacted with the skin during irradiation to minimize the heating of nanoparticles or skin at the surface, while nanoparticles that have penetrate more deeply into the follicle, skin, or sebaceous gland heat to temperatures that selectively ablate the adjacent tissues.
  • Skin is one embodiment of a target tissue.
  • the skin preferably contains a hair follicle and/or a sebaceous gland, where the nonlinear excitation source generates energy that results in heating the skin in an amount effective to induce thermomodulation of a hair follicle, a infundibulum, a sebaceous gland, or a component thereof, such as by heating sufficient to cause the temperature of the skin to exceed 37°C, such as 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, to about 50°C or greater.
  • nanoparticle compositions are generated by:
  • the exchanging step is optionally performed using liquid chromatography, a solvent exchange system, a centrifuge, precipitation, or dialysis.
  • the nanoparticles are surface modified through a controlled reduction step or an oxidation step. Such surface modification may involve a coating step, such as the adsorbance of a monomer, polymer, or biological entity to a surface of the nanoparticle.
  • the coating step involves contacting the nanoparticles with an oxidative environment. Further, the coating step may include monomer polymerization to create polymer coat.
  • the methods described herein may also include the steps of dissolving the nanoparticles in a non-polar solvent and subsequently mixing the dissolved nanoparticles with a polar solvent so as to encapsulate the nanoparticles in an emulsion.
  • surfactants e.g. sodium dodecyl sulfate, sodium laureth 2-sulfate, ammonium lauryl sulfate, sodium octech-l/deceth-1 sulfate
  • concentrations of 0.1-10% may be used to disrupt the epidermal skin barrier, emulsify the sebum and enable improved mixing of hydrophilic nanoparticles in aqueous solutions.
  • a concentration of the nanoparticles such as centrifugation or lyophilization may be employed. Further, the nanoparticles may be pretreated with heat or radiation. Also provided is the optional step of conjugating a biological entity or plurality of biological entities to the nanoparticles. Such a conjugating step may involve a thiol, amine, or carboxyl linkage of the biological entities to the nanoparticles.
  • Several embodiments of the present disclosure can be used on human (or other animal) skin for the treatment of wrinkles and other changes related to photo-aging or chronologic aging (generally termed skin rejuvenation), for the treatment of diseases including skin diseases, for the reduction of acne and related disorders such as rosacea, folliculitis, pseudofolliculitis barbae or proliferative or papulosquamous disorders such as psoriasis, for the stimulation or reduction of hair growth, and for reduction of cellulite, warts, hypopigmentation such as port- wine stain (PWS; nevus flammeus), birthmarks, hyperhidrosis, varicose veins, pigment problems, tattoos, vitiligo, melasma, scars, stretch marks, fungal infections, bacterial infections, dermatological inflammatory disorders, musculoskeletal problems (for example, tendonitis or arthritis), to improve healing of surgical wounds, burn therapy to improve healing and/or reduce and minimize scar
  • diseases including skin diseases, for
  • Several embodiments of the present disclosure can also be useful in improving wound healing, including but not limited to chronic skin ulcers, diabetic ulcers, gastric ulcers, thermal burn injuries, viral ulcers or disorders, periodontal disease and other dental disease.
  • the present disclosure can be useful in treating the pancreas in diabetes.
  • the present disclosure can be useful for in vitro fertilization enhancement, and the like.
  • the present disclosure in certain embodiments, is also useful in enhancing the effects of devices that create an injury or wound in the process of performing cosmetic surgery including non- ablative thermal wounding techniques for treating skin wrinkles, scars, stretch marks and other skin disorders. Under such circumstances, it may be preferable to use conventional non- ablative thermal treatments in combination with the methods of the present disclosure.
  • the instant application in certain embodiments, are used in conjunction with micro- or surface abrasion, dermabrasion, or enzymatic or chemical peeling of the skin or topical cosmeceutical applications, with or without nanoparticle application to enhance treatment, as the removal of the stratum corneum (and possibly additional epithelial layers) can prove beneficial for some treatment regimen.
  • the methods of the present disclosure are particularly applicable to, but are not limited to, acne treatment, hair removal, hair growth/hair follicle stimulation, reduction/prevention of malignant and non-malignant skin tumors, and skin rejuvenation, as described herein.
  • the dermatologically therapeutic methods described herein may be formed using nanoparticle irradiation alone, nanoparticle irradiation in combination with nano- or microparticles, or nanoparticle irradiation with a composition comprising nano- or microparticles and one or more therapeutic agents.
  • Such nanoparticle irradiation may be produced by any known nanoparticle generator, and is preferably a focused nanoparticle generator capable of generating and irradiating focused nanoparticle waves. Additionally, nanoparticle waves can be focused in tissues to provide damage to local areas with a desirable size and shape.
  • compositions containing photoactive materials for the treatment of small target regions of skin including acne scars and other skin conditions.
  • such compositions are generally applied topically, through an apparatus that provides the composition in a form suitable for contact with and retention at a target region of skin in a manner that encompasses irradiating the skin with light (e.g., electromagnetic radiation) having a wavelength sufficient to ablate or otherwise damage the target region of skin and cause remodeling of the skin tissue.
  • light e.g., electromagnetic radiation
  • thermal injury encompasses cell death in one or more regions of the dermal tissue of interest (“lethal damage”), or stimulation of the release of cytokines, heat shock proteins, and other wound healing factors without stimulating necrotic cell death (“sublethal damage”).
  • Typical dermal scar tissue can result from acne infection or other acute or chronic damage or injuries, such as burns, puncture or abrasive injury, surgery, or from conditions caused by environmental conditions or inherited genetic aberrations.
  • While scars are three dimensional in nature, description of the epidermal surface of the scar on the surrounding skin tissue can be accomplished by provision of a depth, length and a width of the scar, each of which may be, e.g., less than about 1 mm, or about 2, 3, 4, 5, 6, 7, 8, 9, 10mm or greater than 10mm, or provision of the surface area encompassed by the scar, e.g., under about 5mm 2 , such as about 10mm 2 , 15mm 2 , 20mm 2 ,
  • Dermal scars generally have a non-uniform depth, and are generally described as extending from the epidermal layer into the dermis, and optionally through the dermis.
  • an acne scar on the chin, cheek, forehead or other facial area is at least 0.01mm, 0.25mm, 0.50mm, 1mm, 2mm, 3mm, 4mm, or 5mm in median thickness, or any thickness in the range of 0.01mm to 5 mm.
  • a region of skin tissue on a human subject is subjected to the methods provided herein.
  • more than one target region is treated during a treatment regimen, and such treatment regimens may happen once, or more than once, e.g., once or several times per month, once or several times per week, once or several times per day, within hours or within less than one hour.
  • a target region contains an epidermal surface, which contains the skin feature to be treated, such as an acne scar or other dermal scar tissue (also termed a "lesion" herein).
  • the scar tissue may be newly present (e.g., within days, weeks, or a few months of formation following the damage or injury) or may be of longer duration (e.g., several months, or years).
  • a "small target region" is treated, meaning a dermal scar region that does not exceed 25mm , and or does not have a longest surface dimension greater than 5mm; such small target regions are generally located on the face or neck after acne vulgaris infection, or one of many inflammatory diseases such as chicken pox or small pox.
  • Small target regions of dermal scars may be atrophic, hypertrophic, keloidal, or may lay largely within the planar surface of the skin, but have irregular texture, contour, or edges, in various embodiments, small target regions of dermal scars are termed rolling scars, ice-pick scars, and box-car scars.
  • Photoactive materials include chromophores and plasmonic nanoparticles.
  • a chromophore is able to selectively absorb a chosen wavelength of light thereby enhancing the effectiveness of the irradiation, such as laser light.
  • photoactive materials include plasmonic nanoparticles with a nanoparticular metallic structure within which localized surface plasmons are excited by light.
  • These surface plasmons are surface electromagnetic waves that propagate in a direction parallel to the metal/dielectric interface (e.g., metal/air or metal/water).
  • plasmonic nanoparticles are non-linear absorbers of energy, whereby both incident light energy and energy from light not directly incident on the particle is coupled to and absorbed by the particle.
  • nanoparticle compositions, and formulations containing nanoparticle compositions contain from about 10 9 to about 10 16 nanoparticles per ml, such as 10 9 , 10 10 , 10 11 , 10 12 , 10 13 , 10 14 , 10 15 , or 10 16 particles.
  • the compositions contain a sufficient concentration of particles so that the amount of particles localized to an effective 0.01-0.05 ml treatment volumes is from 10 to
  • compositions contain particle concentrations with optical densities (O.D.) of 10 O.D. -1,000 O.D., or optical densities greater than 1,000 O.D. In some embodiments these correspond to concentrations of about 0.01-10% w/w or more of nanoparticles.
  • O.D. optical densities
  • Nanoparticles may be homogenous or heterogeneous in size and other characteristics.
  • a particle size in the range of from about 10 nm to about 200 nm is provided.
  • a particle size in the range of from about 200 nm to about 1000 nm is provided. Modulation of particle size present in the composition is also a useful means of concentrating the composition in a target domain.
  • nanoparticles having a size range of from about 10 nm to about 100 nm can be used as component of a larger molecular structure, generally in the range of from about 100 nm to about 1000 nm or more.
  • photoactive particles such as plasmonic nanoparticles
  • the nanoparticle surface can be coated with a matrix (e.g.
  • silica of 10-100 nm thickness or more in order to increase that dimension or particle to 50-100 nm or more.
  • This increased dimension size can increase the delivery of all nanoparticles to a target region (e.g., scar tissue) and limit delivery to non-target region (e.g. surrounding non-scar epidermis).
  • a metal e.g., gold, silver
  • metallic composite e.g., silver and silica, gold and silica
  • metal oxide e.g. iron oxide, titanium oxide
  • metallic salt e.g., potassium oxalate, strontium chloride
  • intermetallic e.g., titanium aluminide, alnico
  • electric conductor e.g., copper, aluminum
  • electric superconductor e.g., yttrium barium copper oxide, bismuth strontium calcium copper oxide
  • electric semiconductor e.g., silicon, germanium
  • dielectric e.g., silica, plastic
  • a quantum dot e.g., zinc sulfide, cadmium selenium
  • the materials are gold, silver, nickel, copper, platinum, titanium, palladium, silicon, galadium, including any alloys, composites, and amalgams of these metals.
  • the nanoparticle contains a composite including a metal and a dielectric, a metal and a semiconductor, or a metal, semiconductor and dielectric.
  • the composition contains coated particles (e.g., nanoparticles).
  • coatings include a biorecognitive such as an antibody, a bioactive moiety such as a protein, or a biological material that is sourced from living matter.
  • the composition contains an insulator such as silicon, or a thin metal coating such as gold, silver, nickel, platinum, titanium, or palladium.
  • the composition may contain a peptide, a nucleic acid, a protein, or an antibody, or may contain charged moieties, whereby those charges mediate enhanced or diminished binding to the target skin.
  • particles have optical absorption qualities of about 10 nm to about 10,000 nm, e.g., 200-700 nm, 700-1200 nm.
  • the particles have optical absorption useful to excitation by standard laser devices or other light sources.
  • particles absorb at wavelengths of about 755 nm (alexandrite lasers), in the range of about 800-810 nm (diode lasers), or about 1064 nm (Nd: YAG lasers).
  • the particles absorb intense pulsed light (IPL), e.g., at a range of about 500 nm to about 1200 nm
  • chromophore shall be given its ordinary meaning and shall also include compounds having chromophoric groups such as nitro groups, azo, alkylene units, esters, carbonyl groups, aldehydes, alkynes, aromatic rings, heterocyclics, carboxylic acids and the like. Photoactive materials function as therapeutic or cytotoxic agents upon irradiation but are substantially inert prior to irradiation.
  • a photoactive material may be a substance (solid, liquid, or gas) that has color or imparts a color to the intact nanoparticles or microparticles (including when the substance itself lacks color, for example, a clear gas, but scatters electromagnetic waves, for example, light, and thus may appear colored, for example, white, blue, green, or yellow, depending on its scattering properties) under some conditions, for example, all of the time or after exposure to a certain wavelength (such as in a fluorescent substance).
  • a chromophore can be a fluorescent, phosphorescent, wavelength up-converting, or other substance that may normally be substantially invisible, but that emits ultraviolet, visible, or infrared wavelengths during and/or after exposure to wavelengths from a particular region of the electromagnetic spectrum.
  • a chromophore can also be a substance that reversibly or irreversibly changes color spontaneously or in response to any stimulus.
  • the chromophore can be or include rifampin, ⁇ -carotene, tetracycline, indocyanine green, India ink, Evan's blue, methylene blue, FD&C Blue No. 1 (Brilliant Blue FCF), FD&C Green No. 3 (Fast Green FCF), FD&C Red No. 3 (Erythrosine), FD&C Red No. 40, FD&C Yellow No. 5 (Tartrazine), or FD&C Yellow No. 6 (Sunset Yellow FCF).
  • the chromophore can be any colored substance approved by the United States Food and Drug Administration for use in humans.
  • the chromophore can be detected by the naked eye under normal lighting conditions or when exposed to UV, near-UV, IR, or near-IR radiation.
  • photoactive particle e.g., chromophores
  • a microparticle may be a particle of a relatively small size, not necessarily in the micron size range; the term is used in reference to particles of sizes that can be implanted to form tissue markings and thus can be less than 50 nm to 100 microns or greater.
  • a micro- or nanoparticle may be of composite construction and is not necessarily a pure substance; it may be spherical or any other shape.
  • Microparticles include, but are not limited to, (i) an indispersible, biologically inert coating, (ii) a core enveloped within the coating, wherein the core includes the chromophore which is detectable through the coating and is dispersible in the tissue upon release from the microparticle, and, optionally, (iii) an absorption component that absorbs the specific energy and that is located in the coating or the core, or both; and the specific property is the absorption of the specific energy to rupture the microparticle, releasing the chromophore which disperses in the tissue, thereby changing or removing, or both, the detectable marking, wherein the coating, the core, or the optional absorption component, or any combination thereof, provides the specific property.
  • chromophores can be made from any appropriate solid, liquid, or gaseous material that has chromophoric properties.
  • useful chromophores include stains, dyes, colored drugs and proteins, and other materials.
  • chromophores are biologically inert and/or non- toxic (ideally they are non- carcinogenic, non-allergenic, and non-immunogenic) such as those approved by the FDA for use within the body.
  • chromophores may be mixed in combinations before or after optional encapsulation, so that it may only be necessary to select a small number of different chromophores to obtain a broad range of colors for various tissue marking purposes.
  • the pure chromophores can be encapsulated separately and afterwards different colors may be mixed to form intermediate colors and shades (yellow microparticles may be mixed with blue microparticles to form a green mixture).
  • Combinations of two or more unreactive chromophores can be mixed to form desired colors and shades, and then encapsulated to form microparticles.
  • pure chromophores may be separately encapsulated to form sub-microparticles, and then different colored sub-microparticles can be mixed together (or with unencapsulated chromophores) to form desired colors and shades.
  • the mixture can then be encapsulated in coating to form a microparticle having a perceived color resulting from the blend of the differently colored chromophores.
  • useful dispersible chromophores include, but are not limited to: drugs and dyes such as rifampin (red), ⁇ -carotene (orange), tetracycline (yellow), indocyanine green (such as Cardio-GreenTM), India ink, Evan's blue, methylene blue; soluble inorganic salts such as copper sulfate (green or blue), Cu(NH 2+
  • dispersible chromophore nanoparticles can be made from certain inert, normally indispersible colored substances that have been reduced to nanoparticles about 50 nm and smaller (e.g., 0.1-5nm, 5-25nm, 25-50nm, and overlapping ranges therein).
  • diffuse nanoparticles might have different optical properties from the macroscopic material, when concentrated within the confined space of a microparticle core (that is, nanoparticles are closer together than the wavelength of visible light, about 500 nm), they act as a single light scatterer and/or absorber, and thus have the appearance of the original indispersible material from which they are derived.
  • Useful dispersible chromophore nanoparticles may be made from graphite, iron oxides, and other materials with small particle size, for example, less than 50 nm, less than 5 nm, etc.
  • chromophores can be a material, or can include specific absorption components, which strongly absorbs radiation of specific wavelength(s), particularly in the near-infrared spectral region from about 800 to 1800 nm. Absorption properties of the chromophore or specific absorption component allow the microparticle core to be selectively heated by pulses of near-infrared radiation, thus rupturing the microparticle and releasing the previously encapsulated chromophores.
  • Visibly colored near-infrared absorbing materials can be used as the chromophore(s) (to provide the desired detectable color) or as specific absorption component(s) in conjunction with another chromophore (to contribute to the detectable color, if desired).
  • the infrared-absorbing visible chromophore should be rendered invisible upon exposure of the microparticles to the radiation, for example, through dispersal.
  • Examples of useful colored near-infrared absorbing materials include, but are not limited to, graphite and amorphous forms of carbon (black), iron oxides (black or red), silicon (black), germanium (dark gray), cyanine dyes (including indocyanine green and other colors), phthalocyanine dyes (green-blue), and pyrylium dyes (multiple colors). See also U.S. Pat. No. 5,409,797, herein incorporated by reference.
  • Near-infrared absorbing materials used as specific absorption component(s) can also be visibly transparent or nearly transparent at the concentrations and sizes used within the microparticles so that they do not affect the perceived color of the microparticle or of the tissue after microparticle disruption even if the material is indispersible.
  • Useful examples include particles of filter glass (such as those manufactured by Schott, Inc.) and plastics such as polymethylmethacrylate (PMMA), as well as low concentrations of nanoparticulate graphite or other carbon. These materials can be mixed with chromophores having a desired color and then encapsulated.
  • materials with other properties can also be used to construct the photoactive materials.
  • visible materials can be incorporated into the microparticles as chromophores, or as specific absorption components within the chromophore or coating material. Then visible radiation can be applied to rupture the microparticles.
  • Useful materials include, but are not limited to, all of the visible colored dispersible chromophores listed above and other materials rendered invisible upon exposure of the microparticles to the visible radiation, for example, Oil Nile Blue N dyes, fluorescein dyes, porphyrin dyes, and coumarin dyes.
  • chromophores can be materials that are rendered invisible (or whose color changes) upon exposure of the microparticles to specific electromagnetic radiation without necessarily rupturing the microparticle.
  • Bleachable chromophores which react with a bleaching agent released by the radiation
  • photobleachable chromophores altered by the radiation
  • thermolabile chromophores altered by heat produced by radiation absorption
  • Most of the chromophores listed above are suitable, because they can be oxidized and rendered invisible by bleaching agents, for example, peroxides, hypochlorites (such as sodium hypochlorite, or household bleach), excited oxygen species, or free radicals.
  • a microparticle can be constructed with core chromophore FD&C Red No. 40 and sub-microparticle(s) 90 containing sodium hypochlorite as the bleaching agent, which is released upon exposure of the microparticle to specific electromagnetic radiation.
  • the chromophore FD&C Red No. 40 is rendered invisible upon exposure of the microparticle to this radiation and mixing with the bleach.
  • Bleachable chromophores which are pH-sensitive can also be used, because they can be rendered invisible if the pH within the microparticle is changed.
  • a microparticle can be constructed with core chromophore phenolphthalein (pink to red above pH 9) in a basic alcohol solution and sub-microparticle(s) 90 containing hydrochloric acid as bleaching agent 100 which is released upon exposure of the microparticle to specific electromagnetic radiation.
  • the chromophore phenolphthalein is rendered invisible upon exposure of the microparticle to this radiation because of reduction in pH within the microparticle.
  • Photobleachable chromophores that are colored until they are rendered invisible by exposure to a specific type, wavelength, and/or intensity of electromagnetic radiation include, but are not limited to, phthalocyanine (such as the zinc or chloroaluminum complexes which are green or blue); porphycenes which can be green or purple; chlorin which is a chlorophyll derivative; rhodamine dyes which can appear red, yellow, or orange and are bleached upon exposure to near-ultraviolet light; porphyrins (such as porfimer sodium, for example, PHOTOFRINTM (Quadra Logic Technologies, Vancouver, British Columbia, Canada), a green chromophore bleached by near-ultraviolet light); Rose Bengal, bleached upon exposure to near-ultraviolet light or high intensity visible light (such as in the megawatts/cm range); and infrared-bleached dye-paired ion compounds, cationic dye-borate anion complexes, 3
  • photoactive materials may be lipophilic or non-lipophilic.
  • a lipophilic photoactive material is dissolved in a pharmaceutically acceptable oil and applied directly to the area of skin one wishes to treat.
  • a lipophilic photoactive material is dissolved in oil at a final concentration as described herein.
  • the photoactive materials are formulated into a non-dispersive composition in order to retain the photoactive materials at the target region.
  • the non-dispersive composition contains at least one of water, a humectant, a surfactant, a thickener, a dye, an antiseptic, an anti-inflammatory agent, an anti-oxidant, a vitamin, a fragrance, an oil, or a topical anesthetic.
  • the thermal damage to the epidermis resulting from the photoactive material reduces the efficacy of the barrier function of the epidermis, in particular decreasing the stratum corneum. This facilitates the delivery of drugs or other substances to the dermis and epidermis, which can either enhance the effects of the treatment, or decrease the side effects caused by partial damage of the epidermis and/or dermis, or both.
  • beneficial ingredients which may enhance the efficacy of skin remodeling include, but are not limited to, growth factors, collagen byproducts, collagen precursors, hyaluronic acid, vitamins, antioxidants, amino acids, retinoids, retinoid- like compounds, and supplemental minerals among others.
  • Groups of drugs and substances, which may decrease side effects, can be steroidal anti-inflammatory drugs, non-steroidal antiinflammatory drugs, antioxidants, antibiotics, antiviral drugs, antiyeast drugs and antifungal drugs.
  • the vitamins that are used may be vitamin C and/or vitamin E.
  • the supplemental minerals used may be copper and zinc.
  • the antioxidants can be, for example, vitamin C and/or vitamin E.
  • Skin lightening, whitening, or brightening agents are also provided.
  • one or more of the ingredients described herein are included in the same formulation as the photoactive particles.
  • these ingredients are provided after treatment with the photoactive particles.
  • the efficacy of these ingredients are enhanced when used in combination with the photoactive particles.
  • the epidermis may be treated with sealing or bonding agents to restore barrier function on the skin to prevent infection or scarring.
  • bonding agents can be used to tighten, pull, bond, close or otherwise change the mechanical forces within or around the lesion or scar (e.g. reducing tension) during or after treatment to direct the wound healing response, including the deposition of new collagen and re- epithelialization in response to tension.
  • Sealing or bonding agents known in the art include, but are not limited to, cyanoacrylates and other adhesives.
  • the photoactive particles in certain embodiments are formulated in various compositions.
  • the nanoparticles are formulated in compositions containing 1-10% v/v surfactants (e.g. sodium dodecyl sulfate, sodium laureth 2-sulfate, ammonium lauryl sulfate, sodium octech-l/deceth-1 sulfate).
  • surfactants e.g. sodium dodecyl sulfate, sodium laureth 2-sulfate, ammonium lauryl sulfate, sodium octech-l/deceth-1 sulfate.
  • Surfactants disrupt and emulsify sebum or other hydrophobic fluids to enable improved targeting of hydrophilic nanoparticles to a target region of the skin containing a scar or other feature to be targeted for treatment.
  • compositions may also include emulsions of particles at various concentrations (1-20% w/v) in aqueous solutions, silicone/oil solvents, propylene glycol or creams (e.g. comprising alcohols, oils, paraffins, colloidal silicas).
  • the formulation contains a degradable or non-degradable polymer, e.g., synthetic polylactide/co-glycolide co-polymer, porous lauryllactame/caprolactame nylon copolymer, hydroxyethylcellulose, polyelectrolyte monolayers, or alternatively, in natural hydrogels such as hyaluronic acid, gelatin and others.
  • a hydrogel PLGA, PEG-acrylate is included in the formulation.
  • a matrix component such as silica, polystyrene or polyethylene glycol is provided in the formulation.
  • Other formulations include components of surfactants, a lipid bilayer, a liposome, or a microsome.
  • a particle may comprise a larger micron-sized particle.
  • the photoactive materials are formulated for dispensing (including but not limited to from an applicator device 300) in a volume of less than about 1 nanoliter to greater than 100 microliters, such as 1 nanoliters, or 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 300, 350, 400, 450, 500 or above about 500 nanoliters, such as 600, 700, 800, 900 nanoliters, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50 or above about 50 microliters, such as 75, 100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, 1000, or above 1000 microliter
  • such formulations are in viscous compositions (herein termed "non-dispersive compositions") such that lateral movement across the surface of the skin is reduced or prevented.
  • a non-dispersive composition is substantially retained at the epidermal site of application for a period of time sufficient for the light source to be directed to the target region and one or more exposures of the light source to be completed.
  • the apparatus is capable of delivering a volume of a non- dispersive composition of from about 100 nanoliters to about 50 microliters of the liquid formulation on the target area such that the surface area of the target area contacted by the liquid formulation is less than about 50mm 2 , e.g., 25mm 2 or less.
  • the non-dispersive composition in a volume of about 0.1-
  • 2 microliters (e.g., about 0.5 microliters) has a diameter of less than about 2-10 m, (e.g., about 5mm) at the epidermal surface for at least one minute after contacting of the non- dispersive composition with the epidermal surface.
  • the photoactive material does not substantially penetrate the epidermal surface.
  • the non-dispersive composition does not laterally migrate along the epidermal surface upon which it has been applied at a rate greater than about 1mm per minute.
  • a thickener is added to the composition to achieve a viscosity that provides non-dispersive properties to the formulation.
  • the formulations are dispensed using a needle-nose or fine tip applicator, such as those used for dispensing epoxy or other viscous materials.
  • the formulations are dispensed using a pipette, such as a glass or plastic-tipped pipet.
  • an apparatus for delivering a formulation into an acne scar of a human subject contains a supply of a liquid (or semi-liquid such as a gel, or semisolid such as a paste) formulation containing an photoactive material, which, when put in substantial physical contact with a target area of a skin surface of a human subject, is capable of penetrating the skin surface at the target area (such as an acne scar) to denature at least one pathophysiological collagen deposition present in the acne scar.
  • the supply of the formulation containing the photoactive material may contain sufficient material for a single administration or multiple administrations (e.g., to a single target region multiple times or to multiple target regions one or more times).
  • Applicators for the delivery of photoactive material my include, but are not limited to, a pen, pencil, stencil, brush, powder, metered dosing applicator, sponge, cloth, hand, spray device and other applicators known in the field.
  • systems containing an apparatus and a light source.
  • systems are useful for treating acne scars by denaturing collagen present in an acne scar of a human subject, containing a light source (e.g., a laser light) and an apparatus that contains a supply of a liquid formulation containing a photoactive material, which, when a volume of from about 0.01 ml to about 1 ml is applied in substantial physical contact with a target area of a skin surface of a human subject, is retained in the target area and is capable of penetrating the skin surface at the target area to denature at least one pathophysiological collagen deposition present in the acne scar, by delivering sufficient thermal energy to the targeted area such that the temperature of the collagen deposition in the target area is elevated above the denaturation temperature of the collagen deposition.
  • a light source e.g., a laser light
  • an apparatus that contains a supply of a liquid formulation containing a photoactive material, which, when a volume of from about 0.01 ml to about 1 ml is applied
  • systems are useful for treating acne scars by denaturing collagen present in an acne scar of a human subject, containing a light source (e.g., a laser light) and an apparatus that contains a supply of a liquid formulation containing a photoactive material, which, when a volume of from about 0.01 microliters to about 10 microliters is applied in substantial physical contact with a target area of a skin surface of a human subject, is retained in the target area and is capable of penetrating the skin surface at the target area to denature at least one pathophysiological collagen deposition present in the acne scar, by delivering sufficient thermal energy to the targeted area such that the temperature of the collagen deposition in the target area is elevated above the denaturation temperature of the collagen deposition.
  • a light source e.g., a laser light
  • the volume can be 0.01 microliters to about 1ml (e.g., 0.01 - 1 microliters, 0.01 - 10 microliters, 0.01 - 20 microliters, 0.01 - 50 microliters, 0.01 - 100 microliters, 0.01 - 500 microliters).
  • the formulations are applied to larger areas beyond the target area, either by painting, swabbing, spraying, or pouring the photoactive formulations on this larger area, and then the formulation is removed, such as by wiping, blotting, suction, or otherwise, from the non-target regions.
  • an adhesive material is applied to the target skin region in order to enhance retention of the photoactive material at the target skin.
  • a material is applied to a non-target region that diminishes or prevents the photoactive material from adhering to the area outside of the target region.
  • compositions are formulated to enable photoactive compounds to be easily removed from non-target regions or domains after initial application.
  • "non-sticky" surface coatings may be applied to photoactive material to reduce binding to the skin surface and/or components thereof.
  • Coatings include, but not limited to, silica, polyvinyl pyrrolidone, polysulfone, polyacrylamide, polyethylene glycol, polystyrene cellulose, carbopol or other polymers, monolayers, or compounds that modify charge, alter hydrophobicity, render a surface aliphatic, or otherwise change the binding nature of a material with the skin.
  • the carrier solution may be modified by the addition of surfactants or solvents that change the binding properties of photoactive materials within the formulation.
  • a device is used to redistribute photoactive material once applied. This redistribution may include expanding the coverage area of the applied composition, increasing the depth of penetration of material in a small crevice or pitted scar, removing volume from applied composition, removing material from non-target skin areas or other patterns of redistribution.
  • Devices that can be advantageous for redistributing material include, but are not limited to, a swab, brush, sponge, cloth, wipe, knife, fine tip applicator and other devices known in the art.
  • the mixture is contacted with the skin for about 1 minute to about 1 hour prior to irradiation, though embodiments wherein the solution is contacted beyond 1 hour are provided.
  • the radiation is administered using a laser capable of delivering one or more wavelengths.
  • the invention can be performed, according to several embodiments, using intense pulsed light (IPL) systems, in general narrower range(s) of wavelengths are administered by the laser as compared to broad wavelength ranges delivered with intense pulsed light devices.
  • IPL intense pulsed light
  • the administration of more discrete wavelengths permits more accurate control of laser effects than is easily performed when using broad spectrum IPL sources, and moreover, the accurate determination of the proper amount of energy to be provided to a target skin region of a patient is easier with a laser than with and IPL source.
  • the energy can be tuned by monitoring thermal heat gradients on the surface of the skin with a thermal/infrared camera.
  • the methods and systems of the present disclosure provide superior efficacy when a surface plasmon is generated on the nanoparticles by the action of the radiation.
  • the plasmon is generated in a one-photon mode or, alternatively, a two-photon mode, a multi- photon mode, a step-wise mode, or an up-conversion mode.
  • the target region is exposed to light of a frequency, for a duration, and for a number of repetitions to provide an amount of heating of all or a substantial portion of the target region that is sufficient to heat at least a portion of the dermal scar tissue to a temperature of at least 40 degrees Celsius, such as 45, 50, 55, 60, 65, 70, 75, 80 or above 80 degrees Celsius for a period of time sufficient to be effective, meaning to cause lethal damage and/or sublethal damage to surrounding parts of the target region, and to reduce the dermal scar tissue.
  • a frequency for a duration, and for a number of repetitions to provide an amount of heating of all or a substantial portion of the target region that is sufficient to heat at least a portion of the dermal scar tissue to a temperature of at least 40 degrees Celsius, such as 45, 50, 55, 60, 65, 70, 75, 80 or above 80 degrees Celsius for a period of time sufficient to be effective, meaning to cause lethal damage and/or sublethal damage to surrounding parts of the target region, and to reduce the dermal
  • the optical source may be coupled to a skin surface cooling device to reduce heating of particles or structures on the skin surface outside of the target region to thereby focus heating to a target region.
  • the treatment incorporates some form of epidermal cooling, which can be administered to the entire face or entire cosmetic unit (e.g., the cheek, chin, nose, or forehead).
  • cooling devices may include, but are not limited too, refrigerated air, forced air, cryogen spray, cryogen based dynamic cooling, contact cooling (e.g. sapphire window), and other skin surface cooling systems known in the art..
  • the photoactive materials are applied non-dispersively to a target region of skin that has an epidermal surface and dermal scar tissue, which typically contains a single acne scar.
  • the target region does not exceed about 25mm .
  • Energy in the 700nm to about 1200nm range is delivered to the target region in an amount sufficient to heat at least a portion of the dermal scar tissue to a temperature of at least 40 degrees Celsius for a period of time sufficient to reduce the dermal scar tissue.
  • a target region of skin tissue on a human subject where the target region comprises an epidermal surface and dermal scar tissue comprising a pathophysiological collagen deposition, dermal matrix, or epidermal surface, and generally where the target region does not exceed about 25mm .
  • Pre-identification and selection of the target region is a significant advantage to the present invention as it prevents or substantially reduces injury to non-target regions, thus increasing efficacy, patient comfort, and healing time.
  • the epidermal surface of the identified target region is contacted with a non-dispersive composition containing a photoactive material, and energy is delivered to the target region in the 700nm to about 1200nm range in an amount sufficient to heat at least a portion of the dermal scar tissue to a temperature sufficient to cause damage and regeneration, thereby reducing the dermal scar tissue.
  • provided are methods for preventing the formation of dermal scar tissue or reducing its progression that involve identifying target regions of inflammatory acne lesions on a human subject, contacting the region with a non-dispersive composition containing photoactive material, and delivering energy to the target region in the 700nm to about 1200nm range in an amount sufficient to heat at least a portion of the inflammatory acne lesion to a temperature sufficient to cause damage and regeneration, thereby treating the inflammatory lesion and or reducing the dermal scar tissue resulting from the lesion.
  • the method includes i) topically administering to a skin surface of the subject a composition of photoactive particles (e.g., plasmonic particles) ii) providing penetration means to redistribute the plasmonic particles from the skin surface to the sweat glands (e.g. eccrine sweat glands, apocrine sweat glands) and iii) causing irradiation of the skin surface by light to activate photoactive materials and thereby heat, damage, treat or otherwise modulate the sweat gland to reduce excessive sweating.
  • a composition of photoactive particles e.g., plasmonic particles
  • the sweat glands e.g. eccrine sweat glands, apocrine sweat glands
  • the application of the photoactive material and delivery of energy thereto may be performed once or may repeated one or more times on the same target region, or alternatively, to one or more additional target regions. While the target region of skin can be located anywhere on the human subject's body, acne vulgaris scars are most prominent on the face or neck of the human subject.
  • Example 1 Generation of plasmonic nanoparticles for thermomodulation.
  • plasmonic nanoparticles including nanorods, hollow nanoshells, silicon nanoshells, nanoplates, nanorice, nanowires, nanopyramids, nanoprisms, nanoplates and other configurations described herein and known to those skilled in the art, are generated in size ranges from 1-1000 nm under conditions such that surface properties that facilitate deep follicular penetration. Surface properties can be varied on one or multiple (2, 3, or 4) different dimensions to increase nanoparticle concentration in a target tissue domain. Penetration into follicular openings of 10-200 um can be maximized using the nanoparticles described herein.
  • nanoparticles sized in the range of about 10 to about 100 nm are generated, and are preferably assembled or formulated into multiparticle structures having a size in the range of 100-300 nm.
  • a coating e.g., silica
  • a coating is grown on uniparticular structures to increase the particle size to the range of 100-300 nm or more.
  • CTAB-coated nanoparticles are synthesized with stable cetryltrimethylamonium bromide (CTAB) coating and concentrated from an optical density of 1 O.D. to 100, 200, 300, 400, or 500 O.D. through one to three cycles of centrifugation at 16,000 rcf, with supernatant decanting.
  • CTAB-coated nanoparticles are concentrated and resuspended in 250 Amol/L 5-kDa methyl- polyethylene glycol (PEG)-thiol to make PEG-coated nanoparticles.
  • Verification that PEG polymer stocks are fully reduced is performed using spectrophotometry to measure the thiol activity of polymer-thiols with 5,5-dithiobis(2-nitrobenzoic acid) against a DTT gradient.
  • the solution of methy-PEG-thiol and CTAB-coated nanoparticles is mixed at room temperature for 1 h then dialyzed against 5 kDa MWCO in 4 L distilled water for 24 h. Dialyzed samples are processed through 100-kDa filters to remove excess polymer.
  • Quantification of the number of PEG polymers per particle is performed by surface- modifying nanoparticles with amino-PEG-thiol polymer and quantifying the number of amines with an SPDP assay.
  • TEOS tetra-ethyl-ortho-silicate
  • APTS aminopropyletriethoxysilane
  • nanoparticles are embedded (or encapsulated) in materials, which allows for the generation of a diverse range of sizes to tune their size. Particle sizes in the range of 100-2000 nm or 200-2000 nm have been shown to enter the hair follicle without penetrating the dermis.
  • Nanoparticles are encapsulated in silica, a synthetic polylactide/co-glycolide co-polymer, porous lauryllactame/caprolactam nylon copolymer, hydroxyethylcellulose, polyelectrolyte monolayers, or alternatively, in natural hydrogels such as hyaluronic acid, without significantly altering plasmon resonance properties.
  • Nanoparticles are embedded within 100-2000 nm materials or 200-2000 nm materials without covalent attachment or by cross-linking of amines, carboxyls or other moieties on the nanoparticle surface to the polymer structure.
  • the surface of the 100-2000 nm material or 200-2000 nm material may be modified for an optimal zeta potential, hydrophilicity/hydrophobicity, and/or adsorption layer through techniques described herein.
  • the shape of the aspect ratio of the polymer can be modified from low to high to increase concentrations and depths of penetration of the embedded plasmonic nanoparticles.
  • the nanoparticles advantageously have an aspect ratio greater than about 1.
  • Example 2 Formulation of thermoablative plasmonic nanoparticles for topical delivery.
  • nanoparticles are generated as in Example 1 using an appropriate solvent (e.g., water, ethanol, dimethyl sulfoxide).
  • an appropriate solvent e.g., water, ethanol, dimethyl sulfoxide.
  • the mixture comprising a plurality of nanoparticles in water is concentrated to about 100-500 O.D. and exchanged for a new solvent by liquid chromatography, a solvent exchange system, a centrifuge, precipitation, or dialysis.
  • the solvent may include an alcohol (e.g., n-Butanol, isopropanol, n-Propanol, Ethanol, Methanol), a hydrocarbon (e.g., pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-Dioxane), chloroform, Diethyl-ether, water, an acid (e.g., acetic acid, formic acid), a base, acetone, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), acetonitrile (MeCN), tetrahydrofuran (THF), dichloromethane (DCM) or ethylacetate.
  • the new solvent is combined with a cosmetically or pharmaceutically acceptable carrier, thereby forming a nanoparticle composition.
  • the particles and carrier will form an emulsion.
  • nano- and micro- emulsions facilitate partitioning within lipid-rich skin compartments such as the hair follicle.
  • nanoparticles are formulated in compositions containing 0.5-2% v/v surfactants to enable disruption of the epidermal skin barrier, emulsification of sebum, and improved mixing of hydrophilic nanoparticles in hydrophobic solutions or targeting to hydrophobic space in the skin (e.g. between the hair shaft and surrounding follicle).
  • Formulations of nanoparticles are also provided at various concentrations (1-20% w/v) in aqueous solutions, silicone/oil solvents, polypropylene gel, propylene glycol or creams (e.g. containing alcohols, oils, paraffins, colloidal silicas).
  • light- absorbing nanoparticles are utilized in solutions having tailored pH, temperature, osmolyte concentration, viscosity, volatility, and other characteristics to improve light- absorbing nanoparticle entry into hair follicles.
  • Formulations are prepared to maximize nanoparticle stability (degree of aggregation in solution), nanoparticle concentration, and nanoparticle absorbance (degree of laser-induced heating at different concentrations).
  • the temperature increase caused by pulsed 1064 nm laser light was more than 2.5 times greater for the plasmonic solution, compared to conventional clinical dyes used at the same dilution (1: 1000 dilution from clinical concentration, where clinical concentrations are as follows: carbon 20-200 mg/ml, meladine 1 mg/ml, indocyanine green 5 mg/ml).
  • Example 3 Use of plasmonic nanoparticles for thermomodulation of hair.
  • compositions described herein for the selective removal or reduction of untreated blonde, red, gray, or lightly-colored hair.
  • plasmonic nanoparticles generated and formulated as described above are introduced into a target tissue region, generally a skin region, and activated with laser-based hair removal systems as known in the art in order to achieve effective hair removal.
  • an optimal particle size of 30-800 nm (e.g., 100-800nm) containing one or several plasmonic nanoparticles is constructed.
  • Nanoparticles encapsulating plasmonic nanoparticles can be formulated from any number of polymers or matrices.
  • the formulation contains a degradable or non-degradable polymer, e.g., synthetic polylactide/co-glycolide co-polymer, porous lauryllactame/caprolactame nylon co-polymer, hydroxyethylcellulose, polyelectrolyte monolayers, or alternatively, in natural hydrogels such as hyaluronic acid, gelatin and others.
  • a hydrogel PLGA, PEG-acrylate is included in the formulation.
  • a matrix component such as silica, polystyrene or polyethylene glycol is provided in the formulation to improve particle stability and enable facile removal from the skin surface after application and follicle targeting.
  • compositions include component of surfactants (e.g. sodium dodecyl sulfate, sodium laureth 2-sulfate, ammonium lauryl sulfate, sodium octech-l/deceth-1 sulfate), a lipid bilayer, a liposome, or a microsome.
  • surfactants e.g. sodium dodecyl sulfate, sodium laureth 2-sulfate, ammonium lauryl sulfate, sodium octech-l/deceth-1 sulfate
  • a lipid bilayer e.g. sodium dodecyl sulfate, sodium laureth 2-sulfate, ammonium lauryl sulfate, sodium octech-l/deceth-1 sulfate
  • a lipid bilayer e.g. sodium dodecyl sulfate, sodium laureth 2-sulfate, ammonium lauryl sulf
  • Pre-treatment of skin with mechanical or chemical exfoliation is used in some embodiments to remove hair-plugs and "open" the follicle for particle delivery. Additionally, hairs can be shaven or waxed to create a void in the hair follicle for particles to fill.
  • the use of physical or thermal force amplifies or expedites the penetration of light absorbing nanoparticles and conjugates thereof into hair follicles, in part by causing dilation of the hair follicle prior to application of the nanoparticles.
  • ultrasound and other sonic forces, mechanical vibrations, hair shaft manipulation (including pulling), physical force, thermal manipulation, and other treatments are utilized to improve entry of light- absorbing nanoparticles into hair follicles. Nanoparticle formulation treatments are performed alone, in combination, sequentially or repeated 1-24 times.
  • An applicator is used to uniformly apply the composition of nanoparticles into follicles.
  • the applicator can be a sponge, a cloth, direct contact from a finger, a tube, a syringe, a device that applies suction, an aerosol, a spray, or other means known in the art.
  • a formulation of 1ml of plasmonic nanoparticles at a concentration of 100 O O.D. with peak resonance of 810 nm is applied to approximately 200cm area of the skin of an adult human subject with a syringe.
  • a cloth is used to evenly distribute solution across the skin area and into the hair follicles.
  • Deep massage from a mechanical vibrator for 2 minutes with or without 1 MHz ultrasound for 5 minutes is applied to drive particles deep into the follicle.
  • Particles penetrate 50-75% down the full length of the hair shaft at concentrations sufficient to heat skin in a ⁇ radius at incremental temperatures of 5-20-fold greater than is generated in similar volumes of adjacent skin when irradiated by a Diode (810 nm) laser.
  • Acetone, ethanol, or a debriding agent can be used to remove all particles from the surface of the skin that have not deposited in the follicle, in order to reduced or prevent non- follicular heating of the skin.
  • Nanoparticle formulations are tested in ex vivo animal samples, ex vivo human skin samples, and in vivo human skin including the assessment of: 1) depth of nanoparticle penetration into hair follicles; 2) particle concentration achieved; 3) degree of heating achieved at delivered nanoparticle concentrations; and 4) efficacy of photothermal destruction including temporary and permanent hair removal, 5) clearance of nanoparticles after treatment.
  • plasmonic nanoparticles surface- functionalized with fluorescent molecules are visualized by fluorescence microscopy after histological sectioning or follicular biopsy (removal of hair shaft).
  • plasmonic nanoparticles are directly visualized by dark field microscopy after histological sectioning or follicular biopsy.
  • the bulge region is generally localized about midway (-50% down the length of) the hair shaft, permanent hair removal is sufficiently achieved by accumulation of plasmonic nanoparticles to this depth.
  • nanoparticle delivery may also generate a heat gradient emitting further down the hair shaft.
  • Animal studies are useful to demonstrate the efficacy of unpigmented hair removal by comparing heat profiles, thermal ablation of hair shaft, and thermal damage of bulge stem cells in treated hairless rodents, albino rodents and dark-haired rodents. Efficacy on live human skin is measured by measuring hair counts at 3 and 12 month follow ups. Biopsies are taken from select patients at 2, 4, and 6 week follow ups to verify that nanoparticles are cleared from the skin without embedding in the dermis.
  • Figure 3B demonstrates representative confocal images showing that red nanoparticles (548 nm absorbance) are visible within both the superficial and deep follicles, but are not detectable in dermal layers beneath the follicles.
  • Figure 3C shows high- magnification imaging of red nanoparticles localized to and retained within a deep follicle (-400 ⁇ ). Green color indicates tissue autofluorescence (488 nm).
  • mice are treated by pipette with up to 3 nanoparticle formulations, in quadruplicate 5- ⁇ 1 spot sizes per demarcated skin area (up to 12 spots per area or 36 spots per mouse). Precise spot locations are demarcated with pen prior to pipetting. Duplicate treatment spots on the dorsal left side are massaged into skin for 5 minutes, while duplicate treatment spots on the dorsal right side are applied without massage. Thirty minutes after application, mice are sacrificed by carbon dioxide asphyxiation and cervical dislocation, and skin is carefully excised and punched into sections along spot size demarcations. Skin biopsies are fixed in 10% paraformaldehyde, paraffin-embedded, and cut into 5-um sections on a microtome in transverse directions.
  • H&E staining light microscopy and/or dark field microscopy, greater than 50 follicles per formulation are imaged, and scoring is performed for skin sections for visible macroscopic nanoparticle accumulation in the follicle, along the hair shaft, at the site of the putative bulge stem cell niche, and at the depth of the follicle bulb.
  • a silver enhancement staining kit based on sodium thiosulfate may be used to enlarge the plasmonic nanoparticle signal via the precipitation of metallic silver.
  • Phase and dark field micrographs are captured and used to record the depths of follicular penetration for each nanoparticle formulation and method of application. ICP-MS is also performed on skin sections to assess nanoparticle concentrations at various depths along the follicle.
  • Treated areas of pig, human or mouse skin are irradiated with a laser coincident with the peak absorption wavelength of nanoparticles (e.g. 1064 nm YAG laser for 1020 nm plasmonic particles) using clinical parameters (1 s exposure of 30-50 J/cm and a pulse width of 10-50 ms).
  • a laser coincident with the peak absorption wavelength of nanoparticles e.g. 1064 nm YAG laser for 1020 nm plasmonic particles
  • clinical parameters (1 s exposure of 30-50 J/cm and a pulse width of 10-50 ms.
  • To determine microscopic photothermal damage of target skin structures such as the hair follicle and hair follicle bulge stem cells, at ten days after application and irradiation, human subjects receive lidocaine injections to numb treatment areas and skin is carefully excised and punched into sections along spot size demarcations.
  • Fresh human skin biopsies or explanted human and animal skin samples are fixed in 10% paraformaldehyde, paraffin- embedded, and cut into 5-um sections on a microtome in transverse directions, or they are fixed in Zamboni's solution with 2% picric acid and cryosectioned by freezing sliding microtome. Slides with mounted paraffin sections are deparaffinized and stained with hematoxylin and eosin (H&E). Histological sections are examined at various depths for markers of thermal damage and inflammation.
  • H&E hematoxylin and eosin
  • Hematoxylin and eosin is used to image skin and follicle microanatomy and indicate degeneration of hair shafts, atrophy of sebaceous glands, and cell vacuolization (indicating cellular damage).
  • Nitro blue tetrazolium chloride (NBTC) a lactate dehydrogenase stain that is lost upon thermal injury to cells, is used to assess damage to keratinocytes. Cellular damage in follicles of skin samples receiving plasmonic nanoparticle plus laser treatment is scored and compared to those receiving laser treatment alone.
  • Live treated human skin areas are also followed clinically for 2 weeks to 3 months following plasmonic nanoparticle + laser treatment, or during repeated plasmonic nanoparticle + laser treatments, and compared to baseline digital photograph taken prior to first treatment, and to negative control laser only treatments.
  • Clinical observations of hair removal, as well as erythema, edema, discomfort, irritation or scarring, are noted to determine degree of non-specific thermal damage.
  • a matrix component such as silica, polystyrene or polyethylene glycol is provided in the formulation to improve particle stability and enable facile removal from the skin surface after application and follicle targeting.
  • Acetone, ethanol, or a debriding agent can be used to remove all particles from the surface of the skin that have not deposited in the follicle, in order to reduced or prevent non-follicular heating of the skin.
  • live human skin was treated with uncoated plasmonic particles compared to silica-coated plasmonic particles, prior to laser-irradiation and comparison to no particle treatment (laser only) controls.
  • Pre-treatment of skin including shaving with razor and microdermabrasion (15 sec, medium setting) to remove hair-plugs and "open" the follicle for particle delivery, was performed on both forearms.
  • Human forearm skin was irradiated with 810 nm laser pulses (30 J/cm , 30 ms, 2 passes) alone ( Figure 5A), or after treatment with a formulation of 830 nm resonant, Uncoated plasmonic nanoparticles in 20% propylene glycol ( Figure 5B).
  • the plasmonic nanoparticle formulation was applied with 3 minute massage and repeated 3 times, and the skin surface wiped with 3 applications of alternative water and ethanol before laser irradiation.
  • Example 4 Use of plasmonic nanoparticles for acne treatment.
  • compositions described herein for the treatment of acne vulgaris and other acnes and acne-like skin conditions, but the selective targeting of sebaceous follicles, particularly the sebaceous glands and/or hair follicles.
  • Plasmonic nanoparticles generated and formulated as described above are introduced into a target tissue region, generally a skin region, and activated with laser- based systems as known in the art in order to achieve effective hair removal.
  • Nanoparticles encapsulating plasmonic nanoparticles can be formulated from any number of polymers or matrices.
  • the formulation contains a degradable or non-degradable polymer, e.g., synthetic polylactide/co-glycolide co-polymer, porous lauryllactame/caprolactame nylon copolymer, hydroxyethylcellulose, polyelectrolyte monolayers, or alternatively, in natural hydrogels such as hyaluronic acid, gelatin and others.
  • a hydrogel PLGA, PEG-acrylate is included in the formulation.
  • a matrix component such as silica, polystyrene or polyethylene glycol is provided in the formulation to improve particle stability and enable facile removal from the skin surface after application and follicle targeting.
  • formulations include surfactants (e.g. sodium dodecyl sulfate, sodium laureth 2-sulfate, ammonium lauryl sulfate, sodium octech-l/deceth-1 sulfate), components of a lipid bilayer, a liposome, or a microsome.
  • surfactants e.g. sodium dodecyl sulfate, sodium laureth 2-sulfate, ammonium lauryl sulfate, sodium octech-l/deceth-1 sulfate
  • components of a lipid bilayer e.g. sodium dodecyl sulfate, sodium laureth 2-sulfate, ammonium lauryl sulfate, sodium octech-l/deceth-1 sulfate
  • components of a lipid bilayer e.g. sodium dodecyl sulfate, sodium laureth 2-sulfate, ammonium lauryl
  • Plasmonic nanoparticles including nanorods, nanoshells, nanospheres, or nanorice can be encapsulated within the polymer nanoparticle or matrix or deposited on the particle surface.
  • nanoparticles in the size range of 100-250 nm, 250-500 nm, 800 nm-1500 nm, or greater than 1500 nm can be used.
  • the use of physical or thermal force amplifies or expedites the penetration of light absorbing nanoparticles and conjugates thereof into hair follicles and/or sebaceous glands, in part by causing dilation of the hair follicle prior to application of the nanoparticles.
  • ultrasound and other sonic forces, mechanical vibrations, hair shaft manipulation (including pulling), physical force, thermal manipulation, and other treatments are utilized to improve entry of light-absorbing nanoparticles into hair follicles and/or sebaceous glands.
  • Nanoparticle formulation treatments are performed alone, in combination, sequentially or repeated 1-24 times.
  • a pre-treatment step of removing excess sebum from the surface of the skin may be performed using chemical and/or mechanical means.
  • Pre-treatment of skin with mechanical or chemical exfoliation is used in some embodiments to remove hair-plugs and "open" the follicle for particle delivery. Additionally, hairs can be shaven or waxed to create a void in the hair follicle for particles to fill.
  • An applicator is used to uniformly apply the composition of nanoparticles into follicles.
  • the applicator can be a sponge, a cloth, direct contact from a finger, a tube, a syringe, a device that applies suction, an aerosol, a spray, or other means known in the art.
  • a formulation of 1 ml of plasmonic nanoparticles at a concentration of 100 O.D. with peak resonance of 810 nm is applied to approximately 200 cm area of the skin of an adult human subject with a syringe.
  • a cloth is used to evenly distribute solution across the skin area and into the hair follicles.
  • plasmonic nanoparticles to the sebaceous gland determined using human abdominoplasty skin and dark field imaging.
  • the human sebaceous gland exists within the pilosebaceous unit consisting of the hair, hair follicle, arrector pili muscle and sebaceous gland.
  • a human skin biopsy is immunostained with antibodies against Collagen IV (basement membrane marker, blue) and PGP 9.5 (nerve marker, green) to visualize representative pilosebaceous unit microanatomy, including the hair follicle (HF), sebaceous gland (SG) and arrector pili muscle.
  • Collagen IV basement membrane marker, blue
  • PGP 9.5 nerve marker, green
  • compositions of plasmonic nanoparticles with a cosmetically acceptable carrier of 1% SDS/20% PG administered with massage and ultrasound can be delivered 400-600 ⁇ deep into the human follicle and specifically into the sebaceous gland ( Figure 7B).
  • Cosmetic formulations for follicle and sebaceous gland delivery in human skin Preferentially, formulations include surfactants (e.g.
  • Surfactants disrupt the epidermal skin barrier and emulsify the sebum to enable improved mixing of hydrophilic nanoparticles in hydrophobic solutions.
  • Humectants such as propylene glycol are used to help improve topical viscosity and maintain physiological pH.
  • Formulations were contacted with two separate excised human abdominoplasty skin samples, and massage for 3 minutes followed by ultrasound (1 MHz) for 5 min was performed to drive particles deep into the follicles. The procedure was repeated for a total of 3 applications, and surface residue removed with 3-5 applications of alternating water and ethanol.
  • the skin sample was excised, fixed, sectioned along horizontal planes and subjected to dark field imaging to assess particle delivery. As assessed by dark field imaging of horizontal skin sections, compositions of plasmonic nanoparticles with a cosmetically acceptable carrier of 1% SLES/20% administered with massage and ultrasound can be delivered 400-600 ⁇ deep into the human follicle and specifically into the sebaceous gland (Figure 8B).
  • ultrasound and/or other sonic forces, mechanical vibrations, hair shaft manipulation (including pulling), physical force, thermal manipulation, and other treatments are utilized to improve entry of light-absorbing nanoparticles into hair follicles and/or sebaceous glands.
  • Mechanical massage improves follicular penetration through hair shaft 'pumping' mechanisms, while ultrasound enhances transdermal drug delivery through temporary disruption of the skin's lipid bilayer, bubble formation, and liquid microstreaming.
  • plasmonic nanoparticles include nanorods, nanoshells, nanospheres, or nanorice, or plasmonic nanoparticles encapsulated within the polymer nanoparticle or matrix or deposited on the particle surface.
  • a matrix component such as silica, polystyrene or polyethylene glycol is provided in the formulation to improve particle stability and enable facile removal from the skin surface after application and follicle targeting.
  • Formulations were contacted with three separate excised human abdominoplasty skin samples, and massage for 3 minutes followed by ultrasound (1 MHz) for 5 min was performed to drive particles deep into the follicles. The procedure was repeated for a total of 3 applications, and surface residue removed with 3-5 applications of alternating water and ethanol.
  • the skin sample was excised, fixed, sectioned along horizontal planes and subjected to dark field imaging to assess particle delivery. As assessed by dark field imaging of horizontal skin sections, compositions of Polyethylene glycol (PEG)-coated nanorods (gold, 15 x 30 nm dimension) in cosmetically acceptable carrier, administered via ultrasound and massage, were observed within the follicle infundibulum at 200 um deep ( Figure 10A).
  • PEG Polyethylene glycol
  • compositions of plasmonic nanoparticles (Silica-coated nanoplates) at lower concentration (10 O.D.), were apparent at 400-600 um deep in the follicle and in the sebaceous gland (open arrow), albeit at lower concentration than comparable particles in a similar cosmetic carrier at 100 O.D ( Figure 10B).
  • Nanoparticle formulations are tested in ex vivo animal skin samples, ex vivo human skin samples, and in vivo human skin as described in Example 3.
  • human skin is first pre-treated with shaving to remove extruding hair, microdermabrasion (15 sec, medium setting) to remove hair-plugs and corneocytes, and chemical depilation to "open" follicle microwells for particle delivery. Skin is contacted with a 100 O.D.
  • Treated human skin samples are laser irradiated with 810 nm laser (40 J/cm , 30 ms, 5 pulses), and compared to laser only treated human skin.
  • Human skin is biopsied, fixed in Zamboni's solution with 2% picric acid, and cryosectioned by freezing sliding microtome.
  • Hematoxylin and eosin H&E
  • Histological sections are examined at various depths for markers of thermal damage and inflammation.
  • Hematoxylin and eosin H&E is used to image skin and follicle microanatomy and indicate degeneration of hair shafts, atrophy of sebaceous glands, and cell vacuolization (indicating cellular damage).
  • Nitro blue tetrazolium chloride (NBTC) a lactate dehydrogenase stain that is lost upon thermal injury to cells, may also be used to assess damage to keratinocytes vs. sebocytes.
  • Oil-Red-O An intracellular stain, Oil-Red-O, may be used to determine lipid and sebum oil content in treated samples. Sebum excretion rates are measured on in vivo skin at 1-3 months follow up using sebum-absorbant tapes to demonstrate functional change in sebum flow. Clearance and prevention of acne lesions is measured by patient reported outcomes and counting acne lesions at 1-3 months follow up.
  • Example 5 Formulation of thermoablative plasmonic nanoparticles for vascular ablation.
  • formulations are prepared to maximize nanoparticle stability (degree of aggregation in solution), nanoparticle concentration, and nanoparticle absorbance (degree of laser-induced heating at different concentrations) once injected into the blood stream.
  • Nanoparticles are generated as in Example 1 using an appropriate solvent.
  • the mixture comprising a plurality of nanoparticles in water is concentrated to about 100-500 OD at peak absorbance and exchanged for a new solvent by liquid chromatography, a solvent exchange system, a centrifuge, precipitation, or dialysis.
  • Typical exchange solvent is 0.15 mol/L NaCl, 0.1 mol/L Na phosphate buffer (pH 7.2).
  • Example 6 Use of plasmonic nanoparticles for thermoablation of component(s) of vessels and microvessels.
  • nanoparticle-containing compositions are administered, typically intravascularly.
  • a laser matched to the peak plasmonic resonance of the particles e.g., 755nm, 810nm, or 1064nm
  • Pulse widths of 10-lOOns, lOOns-lms, 1-lOms, 10-lOOms, 100-lOOOms or continuous wave irradiation is used to achieve thermal heat gradients and localized heating in the vicinity of particle or particles of 20-200nm. 200 ⁇ -2 ⁇ , 2-20 ⁇ , 20-200 ⁇ , 200 ⁇ -2mm.
  • Thermal gradients of 20-200nm are achieved from individual particles. Supra millimeter thermal gradients are achieved by the collective heat deposition of many particles in veins with diameters of several hundred microns or more. Irradiation is applied from 1 pulse to many pulses over seconds to minutes. A cooling device for epidermal layers is used concomitant to irradiation to reduce pain and prevent thermal damage elsewhere. Laser position, fluence, wavelength, angle of incidence, pattern of irradiation is modified to achieve irradiation of vessels at specific depths between 0-10mm, while avoiding heating of non-target vasculature. Alternatively, laser or light is administered through fiber optic waveguide administered via a catheter to heat the particles in larger veins.
  • a flank of the tissue is irradiated with 2 W/cm , 810 nm, 1 cm beam diameter after injection of PEG-nanorods with peak plasmon resonance at 810nm.
  • Thermographic imaging is used to assess surface temperature of tissue immediately after irradiation.
  • Example 7 Determination of efficiency of conversion of light to thermal energy.
  • a suspension of plasmonic nanoparticles (silica-coated nanoplates having a diameter of about 100-200nm, as described here) was prepared by formulating the plasmonic nanoparticles in 20% propylene glycol in water to a concentration of about 1000 O.D., and the ability of this suspension to convert laser light to thermal energy was determined.
  • Available commercial and research products e.g., stock solutions of carbon lotion (20-200 mg/ml carbon, TelsarSoftLight), Meladine spray (1 mg/ml melanin, Creative Technologies), Indocyanine green (5 mg/ml in water, Sigma Aldrich), and vehicle control (20% propylene glycol in water) were also tested.
  • a series of plasmonic nanoparticle (PNP) formulations (labeled SL-001 and SL-002) exhibited ultra-high absorption compared to existing commercial and research chromophores.
  • Figures 11 A, B Rate of temperature increase over sequential laser pulses for PNP formulation SL-001 ( Figure 11 A, closed circle), resonant at 1064 nm laser wavelength, upon irradiation with 1064 nm laser (A), and SL-002 ( Figure 11B closed circle), resonant at 810 nm laser wavelength, upon irradiation with 810 nm laser (B).
  • Example 8 Quantitation of nanoparticle delivery into target tissues.
  • red fluorescent nanoparticles (Corpuscular Inc., Cold
  • FIGS. 12A-12B the provided formulations of nanoparticles (NPs) deeply and specifically penetrate ex vivo porcine skin.
  • Figure 12A demonstrates representative survey fluorescence image of porcine skin, treated with red fluorescent NPs and histologically sectioned.
  • Red (light contrast) NPs are imaged after penetrating the hair follicle infundibulum (arrows) and deep follicle, but not in the underlying dermis.
  • Figure 12B shows representative confocal images show red NPs within superficial and deep follicle (-870 /-tm) at high and low magnification.
  • Green (dark contrast) is tissue autofluorescence (488 nm emission). Scale bars as labeled 1 mm (A), 10 ⁇ (B, left), 50 ⁇ (B, right).
  • NPs nanoparticles
  • silica coating deeply and specifically penetrate in vivo human skin.
  • a region of an upper arm of a male human subject having skin Type 3 was treated with the red nanoparticles essentially as described above.
  • Shown in Figures 13 A and 13B are representative confocal images of biopsies taken from the in vivo-treated human skin, which were sectioned and immunostained for skin markers.
  • FIG. 13A is 3 color image where red is NPs, blue is collagen IV (staining basement membrane) and green is PGP 9.5 (staining nerve fiber).
  • Figure 13B shows red channel only in black and white. Scale bars as labeled 100 ⁇ .
  • the following treatments were administered to the face of a patient using a ND:YAG laser and a composition containing silica-coated silver plasmonic nanoplates delivered from a needle-nose tube dispenser.
  • Silica-coated silver plasmonic nanoplates were synthesized to have a resonant absorption peak at 1050nm and formulated in a cosmetic carrier containing water, propylene glycol, sodium dodecyl sulfate, aristoflex
  • the solution was dispensed from a needle nose tube dispenser into an ice pick acne scar and a box car chicken pox scar with diameters of ⁇ lmm and ⁇ 3mm respectively and a cosmetic sponge was used to wipe away / soak up material that contacted the skin outside of the target region. Presence of the solution on and within the scars was visualized by its green hue. Electromagnetic radiation (light) was administered to the treatment areas after application of solution to the skin using an ND:YAG laser operating at a 5 ms pulse width, 7mm spot size, and a fluence of 15J / cm .
  • the following treatments were administered to the face of a patient using a 1064nm ND:YAG laser and a composition containing silica-coated silver plasmonic nanoplates delivered from a topical syringe.
  • Silica-coated silver nanoplates were synthesized to have a resonant absorption peak near 1050nm and formulated in a cosmetic carrier containing water, propylene glycol, sodium dodecyl sulfate, aristoflex AVC, and
  • PE9010 Particle concentration was brought to between 10 12 to 1013 particles per ml to achieve an optical density of 100 O.D. at 1050nm.
  • the solution was dispensed from a topical syringe to the cheeks of a patient with multiple atrophic acne scars to disperse the solution into each scar.
  • a wet cloth was used to remove photoactive compound on the surface of the skin, but not localized in the atrophic lesions. Presence of the solution on and within the scars was visualized by its dark hue resulting in a speckled pattern on the face.
  • Electromagnetic radiation was administered to the treatment areas after application of solution to the skin using a 1064nm ND:YAG laser operating at a 5 ms pulse width, 7mm spot size, and a fluence of 15J / cm . Six treatments were administered at 2 weeks apart.
  • Treatment areas initially showed minimal pinkness of the skin, with no purpura after each treatment. After 24 hours the treated spots turned dark immediately around the target region, showing increased pigmentation. Within 3-5 days of each treatment the darker spots scaled off and the skin returned to a normal appearance. After two weeks from the sixth treatment the diameter, depth, and prominence of atrophic scars was significantly reduced.
  • the following treatments were administered to the face of a patient using a 755nm Alexandrite laser and a composition containing PEG-coated gold plasmonic nanoshells delivered from a topical syringe.
  • PEG-coated gold plasmonic nanoshells were synthesized to have a resonant absorption peak near 750nm and formulated in a cosmetic carrier containing water, propylene glycol, aristoflex AVC, and PE9010. Particle concentration was brought to approximately 3x1 ⁇ 11 particles per ml to achieve an optical density of 100 O.D. at 750nm.
  • the solution was dispensed from a needle-nose applicator to individual atrophic acne scars on a patients phase and a sponge was used to wipe away / soak up material in non-target regions. Presence of the solution on and within the scars was visualized by its dark hue resulting in a speckled pattern on the face.
  • Electromagnetic radiation (light) was administered to the treatment areas after application of solution to the skin using a 755nm Alexandrite laser operating at a 5 ms pulse width, 7mm spot size, and a fluence of 15 J / cm . Six treatments were administered at 2 weeks apart.
  • Treatment areas initially showed minimal pinkness of the skin, with no purpura after each treatment. After 24 hours the treated spots turned dark immediately around the target region, showing increased pigmentation. Within 3-5 days of each treatment the darker spots scaled off and the skin returned to a normal appearance. After two weeks from the sixth treatment the diameter, depth, and prominence of atrophic scars was significantly reduced.
  • the following treatments were administered to the arm of a patient using a 755nm alexandrite laser and a composition containing silica-coated silver plasmonic nanoplates delivered from a topical syringe.
  • Silica-coated silver plasmonic nanoplates were synthesized to have a resonant absorption peak at 750nm and formulated in a cosmetic carrier containing water, propylene glycol, sodium dodecyl sulfate, aristoflex AVC, and PE9010. Particle concentration was adjusted to between 10 to 10 particles per ml to achieve an optical density of 100 O.D. at 750nm.
  • the solution was dispensed from a needle nose applicator to 3 individual sun spots / freckles on the arm of a patient. Presence of the solution on the freckles was visualized by its blue hue resulting in a speckled pattern on the arm.
  • Electromagnetic radiation (light) was administered to the treatment areas after application of solution to the skin using an 755nm Alexandrite laser operating at a 0.5 ms, 5ms, and 50ms pulse width for each spot respectively, 7mm spot size, and a fluence of 15J / cm 2 .
  • the following treatments were administered to the arm of a patient using a 755nm alexandrite laser and a composition containing PEG-coated gold plasmonic nanorods delivered from a topical syringe.
  • PEG-coated gold plasmonic nanorods were synthesized to have a resonant absorption peak at 750nm and formulated in a cosmetic carrier containing water, propylene glycol, sodium dodecyl sulfate, aristoflex AVC, and PE9010. Particle concentration was adjusted to achieve an optical density of 50 O.D. at 750nm.
  • the solution was dispensed from a needle nose applicator to 3 individual sun spots / freckles on the arm of a patient.
  • Electromagnetic radiation was administered to the treatment areas after application of solution to the skin using an 755nm Alexandrite laser operating at a 0.5ms, 5ms, and 50ms pulse width for each spot respectively, 7mm spot size, and a fluence of 15J / cm .
  • Example 14 Treatment of Pigmented Lesions / Freckles with Carbon Nanoparticles
  • the following treatments were administered to the arm of a patient using a 1064n ND:YAG laser and a composition containing carbon nanoparticles.
  • Carbon nanoparticles were coated with polyvinyl pyrrolidone and formulated in a cosmetic carrier containing water, propylene glycol, sodium dodecyl sulfate, aristoflex AVC, and PE9010.
  • Particle concentration was brought to l-5mg per ml to achieve an optical density of 100 O.D. at 1050nm.
  • the solution was dispensed from a needle nose applicator to 3 individual sun spots / freckles on the arm of a patient.
  • Electromagnetic radiation was administered to the treatment areas after application of solution to the skin using an 1064nm ND:YAG laser operating at a 0.5ms, 5ms, and 50ms pulse width for each spot respectively, 7mm spot size, and a fluence of 15 J / cm .
  • PE9010 Particle concentration was brought to between 10 12 to 1013 particles per ml to achieve an optical density of 100 O.D. at 1050nm.
  • the solution was dispensed from a needle nose applicator along multiple lines of striae on a patient. Presence of the solution on the striae was visualized by its green hue.
  • Electromagnetic radiation (light) was administered to the treatment areas after application of solution to the skin using an 1064nm ND:YAG laser operating at a 5ms pulse width, 7mm spot size, and a fluence of 15J / cm . Three treatments were administered at 2 weeks apart.
  • Treatment areas initially showed minimal pinkness of the skin, with no purpura after each treatment. After 24 hours the treated areas turned dark immediately around the target region, showing increased pigmentation. Within 3-5 days of each treatment the darker spots scaled off and the skin returned to a normal appearance. Appearance of striae was noticeably reduced two weeks after the third treatment.
  • an embodiment of a composition 100 of nanoparticles was distributed to various target tissue depths with various embodiments of delivery devices 200.
  • an animal skin model (pig ear) comprising hair follicles and sebaceous glands in an epidermis was used to model skin treatment with a composition 100.
  • ultrasound and/or other sonic forces, mechanical vibrations, hair shaft manipulation (including pulling), physical force, thermal manipulation, and other treatments are utilized to improve entry of a composition 100 of light-absorbing nanoparticles into hair follicles and/or sebaceous glands.
  • a composition 100 of plasmonic nanoparticles was contacted with the skin model to produce a semi-quantitative assay for measuring and optimizing delivery efficacy. Through experimentation, evaluation of formulations of the composition 100 in conjunction with testing of individual and/or combinations of embodiments of delivery devices 200.
  • Figure 15 illustrates an embodiment of a delivery device 200 distributing a composition 100 from a skin surface to a target skin depth.
  • the target skin comprises a hair follicle and/or a sebaceous gland.
  • Figure 15 is a schematic side view of a composition being distributed from a skin surface to a target in the tissue with a delivery device according to an embodiment of the invention (left side).
  • composition (100) is applied to the skin followed by the delivery device (200), e.g., massage or ultrasound treatment, (right side) After wiping away excess formulation from the surface of the skin, composition (100) is localized only within the structures of the hair follicle (e.g., infundibulum, lumen, sebaceous gland) and no longer on the surface of the epidermis.
  • the follicle is a plugged follicle.
  • Three embodiments of delivery devices 200 were used. For each of the delivery devices 200, a composition 100 was applied to the surface of the skin model. The delivery device 200 was activated to move the composition 100 from the skin surface to the target tissue depth.
  • Figure 16 includes: (A) an illustration of the skin after targeted delivery of the composition (100). (B) Using common histological protocols, a smaller section of the skin that was treated is fixed and sectioned into horizontal slices between 10-60 microns thick. Areas where the formulation (100) was delivered can be observed within the individual hair follicles contained within these slices. (C) The individual tissue sections are mounted for imaging. (D) Each tissue section is imaged using a high resolution optical scanner. The formulation (100) can be observed (blue color) without staining. (E) Analysis of percent delivery is calculated as the ratio of the formulation (blue color) to the total area of the section and expressed as a percentage.
  • the mounted section of skin is imaged.
  • the composition is
  • composition 100 is blue.
  • the images are analyzed measuring the total blue area as a ratio to the total section area. Delivery measurements are quantified as the ratio of blue area (composition 100) over the total area.
  • the composition 100 can be any color.
  • FIG 17 is a table summarizing experimental results using three embodiments of delivery devices 200 to deliver a composition 100 to various depths in tissue according to various embodiments.
  • the vibraderm (210) is an adjustable vibration device applying a nominal 80 Hz longitudinal vibration.
  • the Acoustic Horn / Sonotrode (220) is a 30-40 kHz ultrasound device employing an acoustic horn or sonotrode to apply the ultrasonic energy into the composition. Ultrasound from an acoustic horn or sonotrode is focused in the volume immediately surrounding the horn or sonotrode and therefore produces cavitation mostly in the formulation and at the surface of the skin.
  • the flat transducer (230) is a 30-40 kHz ultrasound device employing a flat head to deliver the ultrasonic energy into the formulation.
  • the first delivery device 210 is a Vibraderm with 80 Hz longitudinal vibration.
  • the second delivery device 220 is a 30 kHz - 40 kHz low frequency ultrasound device with a sonotrode that operates at a frequency about 32.4 kHz pulsed ultrasound with surface localized energy configured to induce cavitation (IMPACT, Alma Lasers).
  • the third delivery device 230 is a low frequency ultrasound device that operates at a frequency of 40 kHz non-pulsed ultrasound configured to induce cavitation from an unfocused transducer (GS8.0).
  • the first delivery device 210 uses a mechanical mixing mechanism resulting in a 4% of total skin cross-section ratio measurement of composition 100 at a depth of 500 micrometers in porcine ear skin, with a maximum delivery depth of about 1000 microns in porcine ear skin.
  • the second delivery device 220 uses a cavitation mechanism resulting in a 12% of total skin cross-section ratio measurement of composition 100 at a depth of 500 micrometers in porcine ear skin, with a maximum delivery depth of about 1500 microns in porcine ear skin.
  • the third delivery device 230 uses a cavitation mechanism with an unfocused transducer resulting in a variable 4-12% of total skin cross-section ratio measurement of composition 100 at a depth of 500 micrometers in porcine ear skin, with a maximum delivery depth of about 1000 microns in porcine ear skin.
  • Figure 18 illustrates images of delivery of composition 100 to skin models
  • the top panel contains 5x brightfield images looking down at the surface of intact skin models immediately following the delivery of an embodiment of the composition.
  • low frequency ultrasound the formulation (100) is observed to be localized within several hair follicles.
  • the middle and rightmost images of the top panel massage by hand and incubate on skin respectively, no delivery is observed.
  • the lower panel contains 20x brightfield images of vertical cross sections of the skin. The cross sections are cut to expose an individual hair follicle.
  • the formulation (100) is observed clearly localized within the infundibulum, sebaceous gland, and the lumen of the hair follicle.
  • the composition 100 penetrates the deepest with the low frequency ultrasound device, with the composition 100 delivered to the infundibulum (INF), sebaceous gland (SG) and the hair follicle lumen (HFL).
  • the composition 100 penetrates to the infundibulum (INF) with hand massage.
  • the composition 100 penetrates near the skin surface.
  • Figure 19 is a graph plotting data from the experiment, showing the total percent positive area on the y-axis, and depth in microns on the x-axis. Plotted are a negative control (incubation on the skin surface without a delivery device 200), the first delivery device 210 (Vibraderm), and a combination of both the first delivery device 210 (Vibraderm) and the second delivery device 220 (30 kHz - 40 kHz ultrasound device with a sonotrode).
  • Figure 20 is a graph plotting data from the experiment, showing the total percent positive area on the y-axis, and depth in microns on the x-axis.
  • Plotted are a negative control (incubation on the skin surface without a delivery device 200), the first delivery device 210 (Vibraderm), a combination of both the first delivery device 210 (Vibraderm) and the third delivery device 230 (36 kHz non-pulsed ultrasound), and a combination of both the first delivery device 210 (Vibraderm) and the second delivery device 220 (30 kHz - 40 kHz ultrasound device with a sonotrode).
  • Figure 21 includes images from unstained horizontal cross-sections at 720 microns in depth below the skin surface, illustrating the distribution of composition 100 from the experiment.
  • the images include distribution of the composition 100 for a negative control (incubation on the skin surface without a delivery device 200), the first delivery device 210 (Vibraderm), a combination of both the first delivery device 210 (Vibraderm) and the third delivery device 230 (36 kHz non-pulsed ultrasound), and a combination of both the first delivery device 210 (Vibraderm) and the second delivery device 220 (30 kHz - 40 kHz ultrasound device with a sonotrode).
  • Figure 21 is illustrative of images taken of tissue sections at approximately 720 microns deep of composition delivery within tissue samples using various embodiments of delivery devices.
  • a vibration device Vibraderm
  • acoustic horn/sonotrode ultrasound energy there is a markedly increase in the total amount of composition delivered (100) and number of follicles that the composition is delivered to over the other delivery embodiments alone.
  • Figure 22 includes images from unstained horizontal cross-sections at 1060 microns in depth below the skin surface, illustrating the distribution of composition 100 from the experiment.
  • the images include distribution of the composition 100 for a negative control (incubation on the skin surface without a delivery device 200), the first delivery device 210 (Vibraderm), a combination of both the first delivery device 210 (Vibraderm) and the third delivery device 230 (rey), and a combination of both the first delivery device 210 (Vibraderm) and the second delivery device 220 (30 kHz - 40 kHz ultrasound device with a sonotrode).
  • Figure 22 is illustrative of images taken of tissue sections at approximately 1060 microns deep of composition delivery within tissue samples using various embodiments of delivery devices.
  • the methods disclosed herein include certain actions taken by a practitioner; however, they can also include any third-party instruction of those actions, either expressly or by implication.
  • actions such as “identifying a target region of skin tissue” include “instructing the identification of a target region of skin tissue.”
  • the ranges disclosed herein also encompass any and all overlap, sub-ranges, and combinations thereof.
  • Language such as “up to,” “at least,” “greater than,” “less than,” “between,” and the like includes the number recited. Numbers preceded by a term such as “about” or “approximately” or “substantially” include the recited numbers.
  • “about 3 mm” includes “3 mm.”
  • the terms “approximately”, “about”, and “substantially” as used herein represent an amount or characteristic close to the stated amount or characteristic that still performs a desired function or achieves a desired result.
  • the terms “approximately”, “about”, and “substantially” may refer to an amount that is within less than 10% of, within less than 5% of, within less than 1% of, within less than 0.1% of, and within less than 0.01% of the stated amount or characteristic.

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Abstract

L'invention concerne un traitement de tissu de peau à l'aide des matériaux photoactifs et de la lumière, des modes de réalisation concernant le traitement de tissu cicatriciel à l'aide d'un dispositif utilisant des longueurs d'onde de lumière, telles qu'une lumière laser, et des matériaux photoactifs. L'invention concerne une administration améliorée de compositions pour le traitement de tissu cicatriciel à l'aide des nanoparticules plasmoniques photoactives et de la lumière, des modes de réalisation concernant des dispositifs d'administration utilisant, par exemple, les ultrasons. Des traitements sont utiles pour des applications cosmétique, diagnostique et thérapeutique.
PCT/US2014/052266 2013-08-26 2014-08-22 Traitement de surfaces de peau ciblées à administration ciblée de nanoparticules WO2015031189A1 (fr)

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US14/321,509 2014-07-01
US14/321,509 US9572880B2 (en) 2010-08-27 2014-07-01 Ultrasound delivery of nanoparticles

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019086955A3 (fr) * 2017-11-01 2019-08-29 National University Of Singapore Transfert d'énergie de résonance plasmonique quantique et acp photonique ultra rapide
EP3373888A4 (fr) * 2015-11-13 2019-10-23 Sebacia, Inc. Méthodes de traitement d'affections cutanées à l'aide de nanoparticules plasmoniques
CN111729189A (zh) * 2020-06-29 2020-10-02 嘉兴尚牧智能装备有限公司 硅基贴片及其制备方法
CN112512630A (zh) * 2018-06-22 2021-03-16 阿瓦瓦公司 用于对组织进行选择性治疗的装置
CN113304171A (zh) * 2021-05-26 2021-08-27 内蒙古医科大学 一种靶向型硫化汞纳米颗粒药物的制备方法及其应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011013101A1 (fr) * 2009-07-30 2011-02-03 Alma Lasers Ltd. Sonotrode
US20120059307A1 (en) * 2010-08-27 2012-03-08 Sienna Labs, Inc. Compositions and Methods for Targeted Thermomodulation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011013101A1 (fr) * 2009-07-30 2011-02-03 Alma Lasers Ltd. Sonotrode
US20120059307A1 (en) * 2010-08-27 2012-03-08 Sienna Labs, Inc. Compositions and Methods for Targeted Thermomodulation

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3373888A4 (fr) * 2015-11-13 2019-10-23 Sebacia, Inc. Méthodes de traitement d'affections cutanées à l'aide de nanoparticules plasmoniques
AU2016354589B2 (en) * 2015-11-13 2022-06-02 Coronado Aesthetics, Llc Methods of treating skin conditions using plasmonic nanoparticles
WO2019086955A3 (fr) * 2017-11-01 2019-08-29 National University Of Singapore Transfert d'énergie de résonance plasmonique quantique et acp photonique ultra rapide
CN112512630A (zh) * 2018-06-22 2021-03-16 阿瓦瓦公司 用于对组织进行选择性治疗的装置
CN111729189A (zh) * 2020-06-29 2020-10-02 嘉兴尚牧智能装备有限公司 硅基贴片及其制备方法
CN111729189B (zh) * 2020-06-29 2023-01-06 嘉兴尚牧智能装备有限公司 硅基贴片及其制备方法
CN113304171A (zh) * 2021-05-26 2021-08-27 内蒙古医科大学 一种靶向型硫化汞纳米颗粒药物的制备方法及其应用

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