HK1233550A1 - Tissue filler compositions and methods of use - Google Patents
Tissue filler compositions and methods of use Download PDFInfo
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- HK1233550A1 HK1233550A1 HK17107426.0A HK17107426A HK1233550A1 HK 1233550 A1 HK1233550 A1 HK 1233550A1 HK 17107426 A HK17107426 A HK 17107426A HK 1233550 A1 HK1233550 A1 HK 1233550A1
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Description
Cross Reference to Related Applications
This application claims the benefit of U.S. provisional patent application No. 61/973,659, filed 4/1/2014, the contents of which are incorporated by reference in their entirety.
Technical Field
The present invention generally relates to tissue filler compositions and methods of use. In particular, but not exclusively, the invention relates to tissue filler compositions which can be injected or implanted into soft tissue.
Background
Tissue fillers are used in the medical and cosmetic fields for tissue augmentation, regeneration or reshaping. In the cosmetic field, tissue fillers are known as dermal fillers and are injectable materials that can improve the appearance of the skin by filling wrinkles and folds, replacing lost tissue, or contouring the face (e.g., cheek, chin, or chin). Tissue fillers are also used to treat scars by temporarily repairing depressed scars.
It is an object of the present invention to provide new and improved tissue filler compositions and methods of use for use in the medical and cosmetic fields.
Disclosure of Invention
According to various aspects, the present invention provides compositions and methods of use as tissue fillers for medical and cosmetic indications.
According to various aspects, the present invention relates to a method for stimulating collagen synthesis, comprising: administering a composition to an area to be treated within soft tissue, wherein the composition comprises a tissue filler medium and a fluorophore; and irradiating the region with light having a wavelength that is absorbable by the fluorophore, wherein the method stimulates collagen synthesis in the region.
According to various aspects, the present invention relates to a method for cosmetically enhancing soft tissue, comprising: administering intradermally or subcutaneously to the area to be treated a composition, wherein the composition comprises a tissue filler medium and a fluorophore; irradiating the region with light having a wavelength absorbable by the fluorophore, wherein the method stimulates collagen synthesis in the region to cosmetically enhance the soft tissue.
According to various aspects, the present invention relates to a method for skin rejuvenation, comprising: administering intradermally or subcutaneously to the area to be treated a composition, wherein the composition comprises a tissue filler medium and a fluorophore; irradiating the area with light having a wavelength absorbable by the fluorophore, wherein the method stimulates collagen synthesis in the area to cosmetically rejuvenate the skin.
According to various aspects, the present invention relates to a method for inhibiting or treating scarring, the method comprising: applying a composition to an area to be treated within or around a scar or wound, wherein the composition comprises a tissue filler medium and a fluorophore; irradiating the region with light having a wavelength that is absorbable by the fluorophore, wherein the method stimulates collagen synthesis in the region to prevent or reduce scar formation.
According to various aspects, the present invention relates to a method for promoting wound healing, the method comprising: administering a composition to an area to be treated within a wound, wherein the composition comprises a tissue filler medium and a fluorophore; irradiating the region with light having a wavelength that is absorbable by the fluorophore, wherein the method stimulates wound healing in the region.
By certain embodiments of the invention, the light emitted by the fluorophore can induce or stimulate collagen synthesis in soft tissue surrounding the composition where collagen synthesis is absent or may be minimal. For example, in addition to any collagen synthesis inherently induced by the tissue filler medium by mechanical means (e.g., when the tissue filler medium comprises hyaluronic acid) or by a foreign body reaction (e.g., when the tissue filler medium is a non-biodegradable material), collagen synthesis may also be induced by a fluorophore. When the fluorophore is activated to fluoresce or phosphoresce, the surrounding soft tissue is illuminated with a broader spectrum of light than that illuminated from outside the dermis or from a single light source. Also, the surrounding soft tissue may be illuminated with light having a shorter wavelength than can reach the soft tissue through the skin. In this way, soft tissue (e.g., dermis/epidermis/subcutaneous layer) may achieve more efficient and wavelength specific irradiation, which results in a therapeutic or cosmetic effect.
In certain embodiments, the region to be treated is soft tissue. The area to be treated can be on any part of the body, for example on the face, neck, ears, chest, buttocks, arms, armpits, hands, genitals, legs, or feet of the subject. In certain embodiments, the area to be treated is in or around a scar. The scar may be a post-operative scar. The scar may be an old scar or a new scar. In certain embodiments, the area to be treated is within or around a wound. The wound may be an acute wound or a chronic wound, including a burn. In certain embodiments, the area to be treated comprises a stretch mark. The area to be treated may be in or around the stretch mark.
In certain embodiments, the composition is administered by injection. A needle may be used for injection. The gauge of the needle is 27G-40G, specifically 30G or 32G. Administration by injection may be a continuous injection, known as a straight line injection or a continuous puncture, to deposit a droplet. In certain embodiments, the composition is administered by implantation.
In certain embodiments, the composition is a silicone gel. The composition may be a hydrated gel. The composition may be transparent or translucent. In certain embodiments, the tissue filler medium is a silicone gel. The tissue filler medium may be a hydrated gel. The tissue filler medium may be transparent or translucent.
In certain embodiments, the tissue filler medium retains the fluorophore within the composition during administration of the composition and during at least a portion of the irradiation process. Alternatively, in certain embodiments, the tissue filler medium/composition may be such that the fluorophore is separated from the composition/tissue filler medium after administration to tissue.
In certain embodiments, the tissue filler medium is biodegradable. The tissue filler medium may comprise any biodegradable and biocompatible material, such as Hyaluronic Acid (HA), collagen and poly-l-lactic acid. Biodegradation can be completely completed in about 3-18 months. The fluorophore may or may not affect the rate of biodegradation of the tissue filler medium.
In certain embodiments, the tissue filler medium comprises cross-linked hyaluronic acid (cross-linked HA). The cross-linked hyaluronic acid may be about 0.1% -2%, about 2% -30%, about 2% -25%, about 2% -20%, about 2% -15%, about 2% -10%, about 2% -5%, about 4% -30%, about 4% -25%, about 4% -20%, about 4% -15%, about 4% -10%, about 4% -5% of the composition. In certain embodiments, the crosslinked hyaluronic acid is in the form of particles. The particles may be hydratable. The particles may be cohesive. In certain embodiments, the fluorophore is within the crosslinked hyaluronic acid particle.
In certain embodiments, the composition further comprises a particle-loaded injectable medium. The injectable medium may be a fluid. The injectable medium is less viscous and/or cohesive than the particles. For example, the particles may be agglomerated, while the injectable medium is non-agglomerated. The fluorophore may be in the injectable medium or the particle or both. In certain embodiments, the injectable medium comprises hyaluronic acid, which is non-crosslinked or relatively less crosslinked than crosslinked hyaluronic acid particles.
In certain embodiments, the composition further comprises light reflective particles. The light reflective particles may be glass or silica.
In certain embodiments, the fluorophore is a hydrophilic chromophore. The fluorophore may be water soluble. In certain embodiments, the fluorophore is not in liposome form in the composition. In certain embodiments, the fluorophore may be activated by light having a wavelength in the visible range. In certain embodiments, the fluorophore does not absorb light in the ultraviolet range of the electromagnetic spectrum. In certain embodiments, the fluorophore, when activated, can emit light having a wavelength in the visible range. The emitted light may be within one or more of the violet, blue, green, yellow, orange or red portions of the electromagnetic spectrum. Alternatively, the fluorophore emits in the infrared range. In certain embodiments, the fluorophore may be photobleached upon irradiation of the region. In certain embodiments, the fluorophore can be photobleached after 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, or 65 minutes of irradiation. The irradiation may be continuous or pulsed. Irradiation may include re-irradiation of the composition or the area after hours or days. In certain embodiments, photosensitivity is reduced or avoided by photobleaching. In certain embodiments, the fluorophore is not a photosensitizing agent that requires metabolism. For example, in certain embodiments, the fluorophore is not a porphyrin, porphyrinogen, hematoporphyrin, pheophorbide, chlorin, bacteriochlorin, isopulphin, dihydrotetrapyrrole, and tetrahydrotetrapyrrole. In certain embodiments, the fluorophore is not bound to an indigenous cell or cellular structure. In certain embodiments, the area is irradiated upon or immediately following intradermal or subcutaneous administration. In other words, there is no latency between composition application and irradiation.
In certain embodiments, the irradiation is for a time sufficient to activate the fluorophore. In certain embodiments, the irradiation is for a time sufficient to photobleach the fluorophore. In certain embodiments, the irradiation time is 1-30 seconds, 15-45 seconds, 30-60 seconds, 0.75-1.5 minutes, 1-2 minutes, 1.5-2.5 minutes, 2-3 minutes, 2.5-3.5 minutes, 3-4 minutes, 3.5-4.5 minutes, 4-5 minutes, 5-10 minutes, 10-15 minutes, 15-20 minutes, 20-25 minutes, or 25-30 minutes. The treatment time may range up to about 90 minutes, about 80 minutes, about 70 minutes, about 60 minutes, about 50 minutes, about 40 minutes, or about 30 minutes.
In certain embodiments, the composition is illuminated by a light source located outside the dermis. In other words, the irradiation is percutaneous.
In certain embodiments, intradermal or subcutaneous administration provides a track of HA-stimulated cells from the outer surface to the dermis, thereby creating a light conduit from a light source into the dermis or subcutaneous to activate the composition.
In certain embodiments, the method further comprises applying a topical composition to the treatment area, wherein the topical composition comprises a fluorophore. The fluorescent compound may have an emission spectrum that activates a fluorophore within the intradermal/subcutaneous composition. In this way, the soft tissue can be irradiated more deeply. In certain embodiments, the topical composition is applied prior to light irradiation.
According to various aspects, the present invention relates to a method for skin rejuvenation, comprising: administering intradermally or subcutaneously to the area to be treated a composition, wherein the composition comprises a tissue filler medium and a fluorophore; the biophotonic composition is typically topically applied to the skin over the area to be treated; and irradiating the topical biophotonic composition with light having a wavelength that is absorbable by a fluorophore in the topical biophotonic composition to cause the fluorophore to emit light, wherein the fluorophore absorbs the emitted light from the topical biophotonic composition, wherein the method stimulates collagen synthesis in the area to cosmetically rejuvenate the skin. In certain embodiments, the composition is injectable and can be injected through a needle having a gauge of 23G-40G. In certain embodiments, the composition is injected under wrinkles, folds, or scars to immediately repair the defect. Irradiation of the composition may then stimulate collagen synthesis around the injected composition to provide further skin rejuvenation.
From another aspect, there is provided a tissue filler composition comprising: a tissue filler medium; and a fluorophore; wherein the composition is suitable for injection or implantation into the human body.
In some embodiments, the composition is a silicone gel. The composition may be a hydrated gel. The composition may be transparent or translucent.
In certain embodiments, the tissue filler medium retains the fluorophore within the composition during administration of the composition and during at least a portion of the irradiation process. Alternatively, the fluorophore may be separated from the tissue filler medium after administration to the tissue.
In certain embodiments, the tissue filler medium is biodegradable. The tissue filler medium may comprise any biodegradable and biocompatible material, such as hyaluronic acid, collagen and poly-l-lactic acid. Biodegradation can be completely completed in about 3-18 months. The fluorophore may or may not affect the rate of biodegradation of the tissue filler medium.
In certain embodiments, the tissue filler medium comprises cross-linked hyaluronic acid. The cross-linked hyaluronic acid may be about 0.1% -2%, about 2% -30%, about 2% -25%, about 2% -20%, about 2% -15%, about 2% -10%, about 2% -5%, about 4% -30%, about 4% -25%, about 4% -20%, about 4% -15%, about 4% -10%, about 4% -5% of the composition. In certain embodiments, the crosslinked hyaluronic acid is in the form of particles. The particles may be hydratable. The particles may be cohesive. In certain embodiments, the fluorophore is within the crosslinked hyaluronic acid particle.
In certain embodiments, the composition further comprises a particle-loaded injectable medium. The injectable medium may be a fluid. The injectable medium is less viscous and/or cohesive than the particles. For example, the particles may be agglomerated, while the injectable medium is non-agglomerated. The fluorophore may be in the injectable medium or the particle or both. In certain embodiments, the injectable medium comprises hyaluronic acid, which is non-crosslinked or relatively less crosslinked than crosslinked hyaluronic acid particles.
In certain embodiments, the composition further comprises light reflective particles. The light reflective particles may be glass or silica.
In certain embodiments, the fluorophore is a hydrophilic chromophore. The fluorophore may be water soluble. In certain embodiments, the fluorophore is not in liposome form in the composition.
In certain embodiments, the fluorophore may be activated by light having a wavelength in the visible range. In certain embodiments, the fluorophore does not absorb light in the ultraviolet range of the electromagnetic spectrum. In certain embodiments, the fluorophore, when activated, can emit light having a wavelength in the visible range. The emitted light may be within one or more of the violet, blue, green, yellow, orange or red portions of the electromagnetic spectrum. Alternatively, the fluorophore emits in the infrared range.
In certain embodiments, the fluorophore may be photobleached upon irradiation of the region. In certain embodiments, the fluorophore can be photobleached after 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, or 65 minutes of irradiation. In certain embodiments, the fluorophore can be photobleached after 1-30 seconds, 15-45 seconds, 30-60 seconds, 0.75-1.5 minutes, 1-2 minutes, 1.5-2.5 minutes, 2-3 minutes, 2.5-3.5 minutes, 3-4 minutes, 3.5-4.5 minutes, 4-5 minutes, 5-10 minutes, 10-15 minutes, 15-20 minutes, 20-25 minutes, or 25-30 minutes. The treatment time may range up to about 90 minutes, about 80 minutes, about 70 minutes, about 60 minutes, about 50 minutes, about 40 minutes, or about 30 minutes. The irradiation may be continuous or pulsed. Irradiation may comprise re-irradiation of the composition or the area after hours or days.
In certain embodiments, the fluorophore is not a photosensitizing agent that requires metabolism. For example, in certain embodiments, the fluorophore is not a porphyrin, porphyrinogen, hematoporphyrin, pheophorbide, chlorin, bacteriochlorin, isopulphin, dihydrotetrapyrrole, and tetrahydrotetrapyrrole. In certain embodiments, the fluorophore is not bound to an indigenous cell, a cancer cell, or other cellular structure.
In certain embodiments, the composition does not include glucosamine. In certain embodiments where the composition comprises hyaluronic acid, the composition does not comprise glucosamine. In certain embodiments, the composition does not include an oxygen source, such as a peroxide. In certain embodiments, the composition does not include a hydrophobic fluorophore. In certain embodiments, the composition is not photopolymerizable. In certain embodiments, the composition does not include a monomer. In certain embodiments, the composition does not include hyaluronic acid with functionalized chains. In any of the above or below certain embodiments, the composition does not include one or more (e.g., 1, 2, or 3) of Triethanolamine (TEA), N-vinyl pyrrolidone (NVP), or N-vinyl caprolactam (NVC). In certain embodiments, the composition does not include any of Triethanolamine (TEA), N-vinyl pyrrolidone (NVP), or N-vinyl caprolactam (NVC).
In certain embodiments of any of the above or below, the composition is a sterile composition. In certain embodiments, the composition may be sterilized by heat and/or pressure, for example, using an autoclave. In certain embodiments, the composition may be sterilized by gamma irradiation. In certain embodiments of any of the above aspects, the subcutaneously or intradermally placed composition can provide immediate "repair" due in part to its cohesiveness or viscoelasticity. This helps smooth lines and folds on the skin to provide a rejuvenated appearance to the skin. In certain embodiments, the "healing" effect of a subcutaneously or intradermally placed composition decreases as the tissue filler medium degrades, compresses and/or disperses. Thus, by certain embodiments of the present invention, a long lasting skin rejuvenation effect may be obtained by providing an immediate restorative effect to the skin that gradually diminishes over time while simultaneously synthesizing new collagen at or around the intradermal or subcutaneous composition that increases over time. As tissue filler degradation and collagen synthesis engage each other, a substantially continuous skin rejuvenation effect is achieved.
In certain embodiments, the new collagen on or around the in vivo composition substantially matches the extracellular matrix in terms of collagen type, collagen mechanical properties, and collagen fiber orientation. This is different from existing degradable tissue filler media that induce collagen synthesis but do not provide a repair effect (e.g., poly-l-lactic acid based fillers), provide a repair effect but do not induce important collagen synthesis (e.g., hyaluronic acid based dermal fillers), or provide a repair effect and induce collagen synthesis that differs from extracellular matrix properties (e.g., permanent dermal fillers).
According to various aspects, the present invention relates to the use of a composition as described herein for stimulating collagen synthesis in soft tissue. From another aspect, there is provided the use of a composition as described herein for cosmetically enhancing soft tissue. From another aspect, there is provided the use of a composition as described herein for inhibiting or treating scarring. From another aspect, there is provided the use of a composition as described herein for skin rejuvenation. From another aspect, there is provided the use of a composition as described herein, together with a topical biophotonic composition, for skin rejuvenation.
According to various aspects, the present invention relates to the use of a composition comprising a tissue filler medium and a fluorophore in a method for stimulating collagen synthesis, wherein the method comprises the steps of: applying the composition to an area to be treated within the soft tissue, and illuminating the area with light having a wavelength that is absorbable by the fluorophore; and wherein the method stimulates collagen synthesis in the region.
According to various aspects, the present invention relates to the use of a composition comprising a tissue filler medium and a fluorophore in a method for cosmetically enhancing soft tissue, wherein the method comprises the steps of: applying the composition to an area to be treated within the soft tissue, and illuminating the area with light having a wavelength that is absorbable by the fluorophore; and wherein the method cosmetically enhances the soft tissue.
According to various aspects, the present invention relates to the use of a composition comprising a tissue filler medium and a fluorophore in a method for inhibiting or treating scarring, wherein the method comprises the steps of: applying the composition to an area to be treated within the soft tissue, and illuminating the area with light having a wavelength that is absorbable by the fluorophore; and wherein the method cosmetically inhibits or treats scarring.
According to various aspects, the present invention relates to a tissue filler composition comprising more than one tissue filler medium, wherein the composition is suitable for injection or implantation into the human body.
According to various aspects, the present invention relates to a method for stimulating collagen synthesis, comprising: applying a first composition to an area to be treated within soft tissue, wherein the first composition comprises a tissue filler medium; applying a second composition comprising a fluorophore on a surface over the area to be treated; and illuminating the region with light having a wavelength that is absorbable by the fluorophore; wherein the method stimulates collagen synthesis in the region.
Drawings
Fig. 1 is a diagram showing stokes shift.
Fig. 2 is a picture depicting the absorption of light in various layers of the skin (Samson et al evidence report/technical assessment 2004, 111, pages 1-97).
FIG. 3 is a diagram showing absorption and emission spectra of donor and acceptor chromophores. The figure also shows the spectral overlap between the absorption spectrum of the acceptor chromophore and the emission spectrum of the donor chromophore.
FIG. 4 is a schematic of a Jacobian diagram showing the coupling transitions involved between donor emission and acceptor absorption.
Detailed Description
The present invention provides compositions that are useful as tissue fillers and are biophotonic. The tissue filler compositions of the invention include a photosensitizing exogenous chromophore along with a tissue filler medium, and may be injectable, implantable, or delivered to soft tissue in any other manner. The present invention also provides methods for stimulating collagen synthesis; methods for cosmetically enhancing soft tissue, such as soft tissue augmentation, rehabilitation, or reshaping; methods for inhibiting or treating scarring; or methods of promoting wound healing using tissue filler compositions.
Before proceeding with the further detailed description of the present invention, it is to be understood that this invention is not limited to particular compositions or process steps, as these may vary. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.
The word "about" when used in conjunction with a value or range herein means that the value or range is within 20%, preferably within 10% and more preferably within 5% of the value or range specified.
As used herein, "and/or" means that each feature or ingredient of the two specified features or ingredients is specifically disclosed, either concurrently or separately. For example, "A and/or B" means that three instances of (i) A, (ii) B, and (iii) A and B are disclosed, each instance being independent.
"biophotonic" refers to the generation, manipulation, detection, and application of photons in a biologically relevant context. In other words, biophotonic compositions exert their physiological effects primarily due to the generation and manipulation of photons. The biophotonic composition may also generate reactive oxygen species. The "biophotonic composition" of the present invention is a composition for bio-related applications that can generate photons and/or reactive oxygen species by photoactivation.
The words "chromophore", "photoactivating agent" and "photoactivating agent" may be used interchangeably. Chromophores are compounds that absorb light when exposed to light. The chromophore is readily excited by light and then transfers its energy to other molecules and/or allows its energy to be emitted as light. The chromophore can be a synthetic chromophore or a naturally occurring chromophore.
As used herein, "fluorophore" refers to a chromophore that emits light when excited by light (e.g., by fluorescence, phosphorescence, or any other means).
As used herein, "tissue filler" refers to a material suitable for or generally used for tissue augmentation, regeneration or reshaping, for example, a material suitable for or used in the dermal region, such as dermal fillers, or a material suitable for or used as a scaffold or delivery material in any other soft tissue. Tissue fillers include biodegradable and non-biodegradable materials, as well as natural and synthetic materials, including hydrogels. The tissue filler may be administered by any means, such as injection or implantation. The tissue filler may be administered to any soft tissue site, such as subcutaneous, subcutaneous or intradermal. By "dermal filler" is meant a material that can be used in the dermal region, e.g., beneath the epidermis and/or above or below the subcutaneous tissue, e.g., for tissue augmentation, regeneration or reshaping. The dermal filler may be delivered by subcutaneous or intradermal injection or by any other method (e.g., implantation).
The term "soft tissue" as used herein refers to tissue, rather than bone, that connects, supports, or surrounds other structures and organs of the body. Soft tissues include tendons, ligaments, fascia, skin, fibrous tissue, fat and synovium (all of which are connective tissue), and muscles, nerves and blood vessels (which are non-connective tissue). It is sometimes defined by what it is not. Soft tissue is defined as "non-epithelial, extra-skeletal mesenchyme except for the reticuloendothelial system and glia".
As used herein, "injectable" refers to a flowable material that can be drawn into or pushed out through a needle and injected into soft tissue by a syringe. Soft tissues include tendons, ligaments, fascia, skin, dermis, fibrous tissue, fat, synovium, muscles, nerves and blood vessels.
As used herein, "inhibiting or treating scarring" refers to preventing or minimizing scarring or reducing existing scarring. The scar may be the result of any wound, such as a burn or surgical incision.
"photobleaching" refers to the photochemical destruction of chromophores.
The term "light" or "actinic light" refers to light energy emitted by a particular light source (e.g., a lamp, LED, or laser) and capable of being absorbed by a substance (e.g., a chromophore or photoactivator as defined above). In a preferred embodiment, the light has a peak wavelength in the visible range of the electromagnetic spectrum, such as: 360nm-760 nm.
"wound" refers to any tissue injury, including, for example, acute, subacute, delayed-healing or difficult-to-heal wounds, as well as chronic wounds. Examples of wounds include open wounds and closed wounds. Wounds include, for example, amputations, burns, incisions, resections, injuries, lacerations, abrasions, puncture or perforation wounds, surgical wounds, abrasions, hematomas, pressure wounds, ulcers (e.g., pressure, venous, arterial or diabetic), wounds caused by periodontitis (periodontal inflammation).
"skin rejuvenation" refers to the process of reducing, eliminating, delaying or reversing one or more symptoms of skin aging or skin damage. Skin rejuvenation also generally refers to improving the cosmetic appearance of skin or the cosmetic beautification of skin. For example, it includes increasing skin brightness; shrinking pores; reducing fine lines or wrinkles; improving skin thinning and transparency; the compactness is improved; the fullness is improved; improving tissue loss or skin sagging due to potential fat or bone loss; improvement of dry skin (possibly itching); reducing or reversing blotchiness, age spots, spider veins, or blotchy skin; improving rough and leathery skin; or improve the fine lines that disappear when pulled apart. According to the present invention, one or more of the above-described symptoms of aging may be reduced, eliminated, delayed or even reversed by certain embodiments of the compositions, methods and uses of the present invention.
In some embodiments, the present invention provides biophotonic compositions that can be injected or implanted into soft tissue as a tissue filler. The present invention provides a biophotonic composition. A biophotonic composition is, in a broad sense, a composition that is activated by light of a particular wavelength (e.g., photons). These compositions comprise at least one exogenous chromophore which can be activated by light of an appropriate wavelength, thereby causing the chromophore to emit light. The activation and/or emitted light may have a therapeutic effect on itself. The activated chromophore and/or light may also cause photochemical activation of other agents contained in the composition or located at the treatment site. For example, in the presence of an oxygen-releasing agent, such agents may be activated, resulting in the formation of oxygen radicals, such as pure oxygen. The oxygen-releasing agent may be an internal source of oxygen, such as blood.
In some aspects, the present invention provides biophotonic compositions comprising at least one first chromophore and a tissue filler medium. Upon absorption of a photon of a certain wavelength, the chromophore is excited. This is an unstable state and the molecule will try to return to the ground state, releasing excess energy. For some chromophores, it is desirable to emit excess energy in the form of light when it returns to the ground state. This process is called fluorescence, and these chromophores are also called "fluorophores". As the conversion process loses energy, the peak wavelength of the emitted fluorescence is shifted towards longer wavelengths compared to the absorption wavelength. This phenomenon is called stokes shift, as shown in fig. 1. In a suitable environment (e.g., in a biophotonic composition), much of the energy is transferred to other components of the composition or directly to the treatment site.
It is believed that the light activated chromophores possess therapeutic properties because the emitted fluorescence has femtosecond, picosecond, or nanosecond emission characteristics that are recognized by biological cells and tissues, resulting in beneficial biological modulation. However, it is not limited to this theory. In addition, the emitted fluorescence is longer in wavelength and therefore penetrates deeper into the tissue than the activating light (fig. 2). Irradiating intradermal, subcutaneous, or other soft tissue with such a wide range of wavelengths, including in some embodiments activating light through the composition, can have different and complementary effects on cells and tissue.
In certain embodiments, the tissue surrounding the biophotonic composition will be irradiated with light of different wavelengths, which, if irradiated percutaneously, will not normally reach the soft tissue site due to the short wavelength and depth from the skin. In certain embodiments, in use, this may result in a therapeutic or cosmetic benefit for the soft tissue surrounding the biophotonic composition, such as stimulation of collagen production. This may be in addition to any physical filling and repair effects typical of tissue fillers, and in addition to any collagen production induced by stresses locally applied from tissue fillers. Furthermore, by observing the foreign body response with some existing tissue fillers, the collagen produced can be more closely matched to the collagen of the extracellular collagen matrix of the area being treated than fibrous collagen formation. That is, the type of collagen, the mechanical properties of the collagen, and the orientation of the collagen fibers will more closely match that of native collagen.
In certain instances, the biophotonic compositions of the present invention may be capable of triggering an alteration in cellular signaling to increase collagen deposition by stimulation of fibroblasts, thereby locally altering the extracellular matrix.
The biophotonic compositions of the present disclosure may be substantially transparent/translucent and/or have a relatively high degree of light transmittance to allow light to be emitted into and through the composition. Thus, the tissue region surrounding the composition can be treated with both the fluorescent light emitted by the composition and the light activated by irradiating the composition with light. For example, the% transmittance of the biophotonic composition is measured at a wavelength ranging from 250nm to 800nm using a Perkin-Elmer Lambda9500 series UV-visible spectrophotometer. In some embodiments, the light transmittance in the visible range is measured and the data averaged. In some other embodiments, the light transmittance of the biophotonic material is measured with the chromophore removed. In some embodiments, the light transmittance of the compositions of the present invention is measured at 460 nm. Since the light transmittance is dependent on the thickness, the thickness of each sample was measured using a caliper before the samples were loaded into the spectrophotometer. The light transmission values are normalized to a thickness of 100 μm (or any thickness) according to the following equation:
in the formula, t1Actual thickness of the sample, t2Normalized thickness is measured as light transmittance. In the prior art, the transmittance measurements are typically normalized to 1 cm. In some embodiments, the biophotonic composition has a light transmittance in the visible range of greater than about 15%, about 20%, about 30%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, or about 85%. In some embodiments, the light transmittance is greater than about 70%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% in the visible range of the electromagnetic spectrum (e.g., 400-700 nm).
The biophotonic compositions of the present invention may be injected, implanted, or delivered in vivo to a soft tissue site in any other manner.
These compositions can be described in terms of the ingredients that make up the composition. Additionally or alternatively, the compositions of the present invention have functional and structural properties, which properties may also be used to define and describe the compositions. The respective components of the composition of the present invention will be described in detail below.
The compositions of the present invention include one or more chromophores which may be considered exogenous, e.g., not naturally present in skin or tissue. Suitable chromophores may be fluorophores or fluorochromes, such as fluorescent dyes (or colorants), although other dye sets or dyes (biological and histological dyes, food colors, carotenoids, naturally occurring fluorescence and other dyes) may also be used. Suitable photoactivators may be those Generally Regarded As Safe (GRAS). A bleaching agent that is not well tolerated by the skin or other tissue may be included in the biophotonic composition in an encapsulated or chemically modified form.
In certain embodiments, biophotonic compositions of the present disclosure include a first chromophore that is partially or fully photobleached upon application of light. Photobleaching refers to the photochemical destruction of chromophores, which is often visually manifested as discoloration. In some embodiments, the absorption wavelength of the first chromophore is in the visible spectral range, such as at a wavelength of about 380-800nm, about 380-700nm, about 400-700nm, or about 380-600 nm. In these embodiments, the first chromophore is not activated by ultraviolet light. In other embodiments, the first chromophore absorption wavelength is at about 200-. In one embodiment, the first chromophore absorption wavelength is at about 200-600 nm. In some embodiments, the first chromophore absorbs light at a wavelength of about 200-.
It will be appreciated by those skilled in the art that the optical properties of a particular chromophore may vary depending on the surrounding medium of the chromophore. Thus, as described herein, the absorption and/or emission wavelengths (or spectra) of a particular chromophore correspond to the wavelengths (or spectra) measured in the biophotonic compositions of the present invention.
The biophotonic compositions of the present invention comprise at least one additional chromophore. The combination chromophore can increase light absorption by combining dye molecules and enhance the selectivity of absorption and photo-biological modulation. This creates several possibilities for creating new mixtures of photosensitive and/or selective chromophores.
When such multichromophoric materials are irradiated with light, energy transfer occurs between the chromophores. This process is known as resonance energy transfer and is a photophysical process by which a "donor" chromophore (also referred to herein as a first chromophore) is excited to transfer its excitation energy to an "acceptor" chromophore (also referred to herein as a second chromophore). The efficiency and directionality of resonance energy transfer depends on the spectral characteristics of the donor and acceptor chromophores. In particular, the energy flow between chromophores depends on the spectral overlap reflecting the relative position and shape of the absorption and emission spectra. To allow energy transfer to occur, the emission spectrum of the donor chromophore should overlap with the absorption spectrum of the acceptor chromophore (FIG. 3). Both the reduction or quenching of the donor emission and the shortening of the excited state lifetime with the increase in acceptor emission intensity demonstrate that energy transfer has occurred. FIG. 4 is a jabronsted graph illustrating the coupling transitions involved between donor emission and acceptor absorption. To improve the efficiency of energy transfer, the donor chromophore should have good ability to absorb and emit photons. Furthermore, it is believed that the more overlap between the emission spectrum of the donor chromophore and the absorption spectrum of the acceptor chromophore, the better the donor chromophore can transfer energy to the acceptor chromophore.
In certain embodiments, the biophotonic compositions of the present disclosure further comprise a second chromophore. In some embodiments, the emission spectrum of the first chromophore overlaps at least about 80%, about 50%, about 40%, about 30%, about 20%, or about 10% with the absorption spectrum of the second chromophore. In one embodiment, the emission spectrum of the first chromophore overlaps at least about 20% with the absorption spectrum of the second chromophore. In some embodiments, the emission spectrum of the first chromophore overlaps with the absorption spectrum of the second chromophore by at least about 1-10%, at least about 5-15%, at least about 10-20%, at least about 15-25%, at least about 20-30%, at least about 25-35%, at least about 30-40%, at least about 35-45%, at least about 50-60%, at least about 55-65%, or at least about 60-70%.
% spectral overlap as used herein refers to the% overlap of the emission wavelength range of the donor chromophore with the absorption wavelength range of the acceptor chromophore measured at one-quarter full width maximum (FWQM) of the spectrum. For example, fig. 2 shows normalized absorption and emission spectra for a donor chromophore and an acceptor chromophore. The spectrum FWQM of the absorption spectrum of the acceptor chromophore is about 60nm (515nm to about 575 nm). The overlap between the spectrum of the donor chromophore and the absorption spectrum of the acceptor chromophore is about 40nm (from 515nm to about 555 nm). Thus, the% overlap can be calculated as 66.6% 40nm/60nm x 100.
In some embodiments, the second chromophore absorbs at a wavelength in the visible spectrum. In certain embodiments, the absorption wavelength of the second chromophore is relatively longer than the absorption wavelength of the first chromophore, with the wavelength being in the range of about 50-250nm, about 25-150nm, or 10-100 nm.
As described above, irradiation of light with the compositions of the present invention results in an energy transfer cascade between the chromophores. In certain embodiments, this cascade of energy transfer causes photons from within the soft tissue to be emitted, the photons moving deeper than they would move transcutaneously. In some embodiments, this cascade of energy transfer is not accompanied by the generation of heat. In some embodiments, the cascade of energy transfer does not result in tissue damage.
Alternatively, when the biophotonic composition includes a first chromophore and a second chromophore, the first chromophore is present in an amount of about 0.001 to about 40% by weight of the composition and the second chromophore is present in an amount of about 0.001 to about 40% by weight of the composition. In certain embodiments, the total weight of the chromophore or combination of chromophores is about 0.001-40.001% by weight of the composition. In certain embodiments, the first chromophore comprises about 0.001-0.01%, about 0.001-0.05%, about 0.005-0.01%, about 0.01-1%, about 0.01-2%, about 0.05-1%, about 0.05-2%, about 1-5%, about 2.5-7.5%, about 5-10%, about 7.5-12.5%, about 10-15%, about 12.5-17.5%, about 15-20%, about 17.5-22.5%, about 20-25%, about 22.5-27.5%, about 25-30%, about 27.5-32.5%, about 30-35%, about 32.5-37.5%, or about 35-40% by weight of the composition. In certain embodiments, the second chromophore comprises about 0.001-1%, about 0.001-2%, about 0.001-0.01%, about 0.01-0.1%, about 0.1-1.0%, about 1-2%, about 1-5%, about 2.5-7.5%, about 5-10%, about 7.5-12.5%, about 10-15%, about 12.5-17.5%, about 15-20%, about 17.5-22.5%, about 20-25%, about 22.5-27.5%, about 25-30%, about 27.5-32.5%, about 30-35%, about 2.5-37.5%, or about 35-40% by weight of the composition. In certain embodiments, the total weight of the chromophore or combination of chromophores is about 0.001-1%, about 0.01-2%, about 0.05-2%, about 0.5-1%, about 0.5-2%, about 1-5%, about 2.5-7.5%, about 5-10%, about 7.5-12.5%, about 10-15%, about 12.5-17.5%, about 15-20%, about 17.5-22.5%, about 20-25%, about 22.5-27.5%, about 25-30%, about 27.5-32.5%, about 30-35%, about 32.5-37.5%, or about 35-40.05% by weight of the composition.
In some embodiments, the one or more chromophores are selected such that upon photoactivation their emitted fluorescence is one or more of in the green, yellow, orange, red and infrared portions of the electromagnetic spectrum, e.g., with a peak wavelength in the range of about 450nm to about 500nm, about 490nm to about 800nm, or about 470nm to about 700 nm. In certain embodiments, the peak power density of the emitted fluorescence is from 0.005 to about 10mW/cm2Or about 0.5 to about 5mW/cm2。
Suitable chromophores that may be used in the biophotonic compositions of the present invention include, but are not limited to:
chlorophyll dyes-exemplary chlorophyll dyes include, but are not limited to, chlorophyll a; chlorophyll b; chlorophyllin; oil-soluble chlorophyll; a bacteriochlorophyll a; bacteriochlorophyll b; a bacteriochlorophyll c; a bacteriochlorophyll d; a primary chlorophyll; a primary chlorophyll a; amphiphilic chlorophyll derivative 1; and amphiphilic chlorophyll derivative 2.
Xanthene derivatives-exemplary xanthene dyes include, but are not limited to, eosin B (4 ', 5' -dibromo-2 ', 7' -dinitro-fluorescein dianion); eosin Y; eosin Y (2 ', 4', 5 ', 7' -tetrabromo-fluorescein dianion); eosin (2 ', 4', 5 ', 7' -tetrabromo-fluorescein dianion); eosin (2 ', 4', 5 ', 7' -tetrabromo-fluorescein dianion) methyl ester; eosin (2 ', 4', 5 ', 7' -tetrabromo-fluorescein monovalent anion) p-isopropylbenzyl ester; eosin derivatives (2 ', 7' -dibromo-fluorescein dianion); eosin derivatives (4 ', 5' -dibromo-fluorescein dianion); eosin derivatives (2 ', 7' -dichloro-fluorescein dianion); eosin derivatives (4 ', 5' -dichloro-fluorescein dianion); eosin derivatives (2 ', 7' -diiodo-fluorescein dianion); eosin derivatives (4 ', 5' -diiodo-fluorescein dianion); eosin derivatives (tribromofluorescein dianion); eosin derivatives (2 ', 4', 5 ', 7' -tetrachloro-fluorescein dianion); eosin; eosin dihexadecyl pyridine chloride ion pair; erythrosin B (2 ', 4', 5 ', 7' -tetraiodo-fluorescein dianion); erythrosine; erythrosine dianion; erythrosine B; fluorescein; a fluorescein dianion; fluorescent pink B (2 ', 4', 5 ', 7' -tetrabromo-3, 4, 5, 6-tetrachloro-fluorescein dianion); phloxine B (tetrachloro-tetrabromo-fluorescein); phloxine B; rose bengal (3, 4, 5, 6-tetrachloro-2 ', 4', 5 ', 7' -tetraiodofluorescein dianion); perhexiline G, perhexiline J, perhexiline Y; rhodamine dyes, such as rhodamine include 4, 5-dibromo-rhodamine methyl ester; 4, 5-dibromo-rhodamine n-butyl ester; rhodamine 101 methyl ester; rhodamine 123; rhodamine 6G; rhodamine 6G hexyl ester; tetrabromo-rhodamine 123; and tetramethyl-rhodamine ethyl ester.
Methylene blue derivatives-exemplary methylene blue derivatives include, but are not limited to, 1-methyl methylene blue; 1, 9-dimethylmethylene blue; methylene blue; methylene blue (16 μ M); methylene blue (14 μ M); methylene violet; bromomethylene violet; 4-iodomethylene violet; 1, 9-dimethyl-3-dimethyl-amino-7-diethyl-amino-phenothiazine; and 1, 9-dimethyl-3-diethylamino-7-dibutyl-amino-phenothiazine.
Azo dyes-exemplary azo (or disazo-) dyes include, but are not limited to, methyl violet, neutral red, para-red (pigment red 1), amaranth (azorubine S), acid red (azorubine, food red 3, acid red 14), allura red AC (FD & C40), tartrazine (FD & C yellow 5), orange G (acid orange 10), ponceau 4R (food magenta 7), methyl red (acid red 2), and ammonium taurocide-ammonium rhodanate.
In certain aspects of the invention, one or more chromophores of the biophotonic compositions of the invention may be independently selected from any of: acid black 1, acid blue 22, acid blue 93, acid magenta, acid green 1, acid green 5, acid magenta, acid orange 10, acid red 26, acid red 29, acid red 44, acid red 51, acid red 66, acid red 87, acid red 91, acid red 92, acid red 94, acid red 101, acid red 103, acid magenta, acid violet 19, acid yellow 1, acid yellow 9, acid yellow 23, acid yellow 24, acid yellow 36, acid yellow 73, acid yellow S, acridine orange, acridine yellow, alcian blue, alcian yellow, an alcohol-soluble red, alizarin blue 2RC, alizarin carmine, alizarin cyanine BBS, alizarin cyanine R, alizarin red S, alizarin red violet, try alunite, amido black 10B, aminoblack, aniline blue nin, anthracene blue SWR, auramine O, azodye B, azokagakagac G, azo (azo 5, azo) 48, azo 48, Azure A, azure B, azure C, basic Blue 8, basic Blue 9, basic Blue 12, basic Blue 15, basic Blue 17, basic Blue 20, basic Blue 26, basic brown 1, basic fuchsin, basic green 4, basic orange 14, basic red 2(Saffranin O), basic red 5, basic red 9, basic violet 2, basic violet 3, basic violet 4, basic violet 10, basic violet 14, basic yellow 1, basic yellow 2, brisbane, bismarcel Brown Y, brilliant crystalline scarlet 6R, calc, carmine, carminic acid (acid 4), azure Blue B, Chinese Blue, vermilion, azure Blue (Coelestine), chrome violet CG, chrome variolin 2R, chrome cyanine R, congo corinth, congo red, cotton Blue, cotton red, crocein, safranin, crystal purplish 6R, crystal purplish Blue, macrochroman B, DiOC6, mazinan Blue 14, direct indigo 14, indigo 58, direct purplish Blue 14, indigo, Direct red 10, direct red 28, direct red 80, direct yellow 7, eosin B, blue eosin, eosin Y, yellow eosin, Eosinol, illipe garnet B, chrome cyanine R, erythrosine B, ethyl eosin, ethyl green, ethyl violet, evans blue, fast blue B, fast green FCF, fast red B, fast yellow, fluorescein, food green 3, pyrogallophthalein, glamine blue, betacyanin, gentian violet, hematoxylin oxide, hematoxylin violet, daylight fast magenta BBL, methyl blue, hematoxylin violet, huffman violet, royal red, indocyanine green, alisnew blue 1, alisnew yellow 1, INT, carmine, kernehirot, shellac, laccaic acid, lausuran violet, malachite green, SF, leukin green, Luxol blue, fuchsin II, manchester yellow I, chester green, chester yellow B, mauve blue, mauve, fusceau yellow, mauve blue, mauve, fusceva, fuschin yellow, fuchsin, mauve, ma, Mercurobromine, mercurochrome, acid metamine yellow, methylene sky blue a, methylene sky blue B, methylene sky blue C, methylene blue, methylene green, methyl violet 2B, methyl violet 10B, mordant blue 3, mordant blue 10, mordant blue 14, mordant blue 23, mordant blue 32, mordant blue 45, mordant red 3, mordant red 11, mordant violet 25, mordant violet 39, naphthol blue black, naphthol green B, naphthol yellow S, natural black 1, natural red 3, natural red 4, natural red 8, natural red 16, natural red 25, natural red 28, natural yellow 6, NBT, natural red, neofuchsin, nilgara blue 3B, night blue, nile blue a, nile red, nile blue sulfate, nile red, nitro BT, nitro blue tetrazolium, nuclear blue, fast red O, orange G, lichen red, parafuchsin, fluorescein B, phycoerythrin B, phycobilin, orcein, orchin blue C, orchin blue C blue, Phycoerythrin. Phycoerythrin (PEC), phthalocyanine, picric acid, ponceau 2R, ponceau 6R, ponceau B, xylidine ponceau, ponceau S, primrose, purpurin, peyronin B, peyronin G, peyronin Y, rhodamine B, rosaniline, rose bengal, safranine, safranin O, scarlet R, shellac, purplish red F3B, salococyanin R, soluble blue, solvent black 3, solvent blue 38, solvent red 23, solvent red 24, solvent red 27, solvent red 45, solvent yellow 94, prolamine, sudan III, sudan IV, sudan black B, sulfur S, Swiss blue, tartrazine S, thioflavin T, thionine violet, toluidine blue, toluidine red, aniline yellow G, acridine, trypanosoma blue, fluorescein sodium, victoria blue 4R, victoria blue B, victoria blue I, water-soluble red B, rhodamine I, rhodamine B, Xylidine ponceau or eosin yellow.
In certain embodiments, the compositions of the present invention include any one of the chromophores listed above, or a combination thereof, to provide a biophotonic effect at the treatment site. This is a completely different application of these agents, as opposed to the use of chromophores as simple colorants or as catalysts for photopolymerization. In certain embodiments, the compositions do not include compounds that can be polymerized or crosslinked by chromophore activation.
The synergistic effect of a chromophore combination refers to a biophotonic effect greater than the sum of its respective effects, but is not limited to any particular theory. Advantageously, this may translate into increased reactivity of the biophotonic material, faster speed or improved treatment times. Furthermore, no changes in treatment conditions, such as time of exposure to light, power of the light source used and wavelength of light used, are required to achieve the same or better treatment results. In other words, the same or better treatment may be achieved using a synergistic chromophore combination without necessarily requiring prolonged exposure to the light source, increased power of the light source, or the use of a light source of a different wavelength.
In some embodiments, the biophotonic material includes eosin Y as a first chromophore and one or more of rose bengal, fluorescein, erythrosine, phloxine B, chlorophyllin as a second chromophore. It is believed that these combinations have a synergistic effect in that they can transfer energy from one chromophore to another chromophore when they are activated in part by overlapping or proximity to their absorption and emission spectra. This transferred energy then gives off or generates reactive oxygen in the form of fluorescence. This absorbed and re-emitted light is believed to be transmitted throughout the composition, and also into the treatment site.
In a further embodiment, the material comprises the following synergistic combination: eosin Y and fluorescein; fluorescein and rose bengal; erythrosin and eosin Y, rose bengal or fluorescein; phloxine B and one or more of eosin Y, rose bengal, fluorescein, and erythrosine. Other synergistic chromophore combinations may also be employed.
Chromophores that are not normally activated by activating light (e.g., the blue light of an LED) can be activated by the synergistic effect of the combination of chromophores in the material by energy transfer from the chromophores activated by the activating light. In this way, photoactivated chromophores of different nature can be utilized and tailored according to the desired cosmetic or medical treatment.
For example, rose bengal, when activated in the presence of molecular oxygen, can produce higher yields of singlet oxygen. However, the quantum yield of rose bengal is low in terms of emission of fluorescence. The peak absorption of rose bengal is around 540nm, so it can be activated with green light. The quantum yield of eosin Y is high and can be activated with blue light. The combination of rose bengal and eosin Y results in a composition that, when activated by blue light, emits therapeutically useful fluorescence and produces singlet oxygen. In this case, blue light photoactivates eosin Y, which transfers part of its energy to rose bengal and emits part of the energy in the form of fluorescence.
The present invention provides a biophotonic composition comprising at least a first chromophore and a tissue filler medium. The tissue filler medium may be a dermal filler. In some embodiments, the tissue filler medium is characterized by its source. In some embodiments, the source may be natural, biological, or synthetic. Biological tissue filler media may be those derived from an organism. In some embodiments, the tissue filler medium can be characterized by the ability of the body to clean the product without external intervention (e.g., biodegradable versus non-biodegradable). The tissue filler medium and/or biophotonic composition is typically biocompatible. The tissue filler medium and/or biophotonic composition is generally non-toxic. The tissue filler medium may comprise a polymer. The polymer may be selected from the group consisting of: proteins, peptides, polypeptides, polylysines, collagen, procollagen, elastin, and laminin. The polymer may be selected from the group consisting of: synthetic polymers with hydroxyl, amine and carboxyl functional groups: polyethylene (vinyl alcohol), polyethylene glycol, polyvinylamine, polyallylamine, deacetylated polyacrylamide, polyacrylic acid, and polymethacrylic acid. The polymer may be selected from the group consisting of: dendritic or branched polymers including dendritic polyols and dendritic polyamines. The polymer may be selected from the group consisting of: a solid surface polymer having hydroxyl, amine and carboxyl functional groups. The polymer may be, for example, a polysaccharide selected from the group consisting of polysaccharides including starch and derivatives thereof; dextran and its derivatives, cellulose and its derivatives; chitin and chitosan, alginate and their derivatives. In some embodiments, the tissue filler medium is a cross-linked biocompatible polysaccharide gel.
In some embodiments, the polymer is a glycosaminoglycan. The tissue filler medium may further comprise two or more different mucopolysaccharide polymers. The term "mucopolysaccharide" as used herein is synonymous with "GAG" and "mucopolysaccharide" and refers to a long linear polysaccharide consisting of repeating disaccharide units. The repeat unit is composed of a hexose (six carbon sugar) or a hexuronic acid linked to an hexosamine (nitrogen containing six carbon sugar) and pharmaceutically acceptable salts thereof. Members of the GAG family vary in the type of hexosamine, hexose or hexuronic acid units (including e.g. glucuronic acid, iduronic acid, galactose, galactosamine, glucosamine) and also in the geometry of the glycosidic linkages. Non-limiting examples of mucopolysaccharides include chondroitin sulfate, dermatan sulfate, keratan sulfate, and hyaluronan. Non-limiting examples of acceptable salts of mucopolysaccharides include sodium, potassium, magnesium, calcium salts, and combinations thereof. Mucoadhesive for use in the compositions and methods disclosed hereinSugars and their resulting polymers are described, for example, in Piron and Tholin, polysaccharide cross-linking, hydrogel preparation, the resulting polysaccharides and hydrogels, their uses, U.S. patent publication No. 2003/0148995; lebreton, crosslinking of low molecular weight and high molecular weight polysaccharides of injectable single-phase hydrogels; lebreton, a viscoelastic solution containing sodium hyaluronate and hydroxypropyl methylcellulose, methods of preparation, and uses, U.S. patent publication No. 2008/0089918; lebreton, a hyaluronic acid-based gel containing lidocaine, U.S. patent publication No. 2010/0028438; and the polysaccharides and hydrogels thus obtained, U.S. patent publication nos. 2006/0194758; and Di Napoli, compositions and methods for intradermal soft tissue augmentation, international patent publication No. 2004/073759, the entire contents of which are incorporated herein by reference. GAGs for use in the methods disclosed herein are commercially available, for example hyaluronic acid-based dermal filler JUVEDERMTM、JUVEDERMTM30、JUVEDERMTMUltra、JUVEDERMTMUltra Plus、JUVEDERMTMUltra XC、JUVEDERMTMUltra Plus XC、JUVEDERM VOLUMATMXC and JUVEDERM VOLUMATM(Ailanthigen pharmaceutical Co., Europe, Calif.).
Examples of biological and biodegradable tissue filler media are media comprising materials derived from organism, human and/or animal tissue and/or products. Examples of such media include: hyaluronic Acid (HA) (e.g., avian HA, bovine HA, and non-animal stable HA ("NASHA") (e.g., avian HA, bovine HA, and non-NASHA "))Andinjectable dermal fillers)), collagen (e.g., type I collagen, type II collagen, type III collagen, cross-linked and/or non-cross-linked bovine, porcine, human, and autologous collagen). Additional examples of collagen-based fillers include(collagen derived from bovine tissue),Type I (bovine tissue-derived collagen),Type II (bovine tissue-derived collagen), EVOLENCETM(collagen derived from pig) and FIBRETM(collagen from pig). Collagen-based tissue fillers are typically derived from animals and are associated with a higher incidence of allergic reactions than non-animal based fillers. NASHA tissue fillers, for example, are of bacterial origin and have a lower incidence of allergic reactions than collagen-based fillers. Many NASHA tissue fillers provide an immediate filling effect, but may also induce minimal collagen formation due to local mechanical deformation of fibroblasts at the soft tissue site. As will be appreciated by those of ordinary skill in the art, in some embodiments, the filler medium is self-replicating and may include living cells (e.g., collagen-producing cells or fibroblasts). Thus, in some embodiments, the composition includes a biological and biodegradable tissue filler medium.
Synthetic biodegradable tissue filler media include RADIANCETMAnd RADIIESSETM(calcium and phosphate-based microspheres),(carboxymethyl cellulose and polyethylene oxide),(poly-L-lactic acid microspheres), other polyacids, polyethers and polymers. Calcium and phosphate based microspheres include calcium hydroxyapatite particles suspended in a water-based gel that acts as a scaffold for new collagen growth. Over time, the particles degrade into calcium and phosphate ions that can be removed by normal metabolic processesAnd (4) adding the active ingredients. Degradation typically takes 18 months or even longer. Fillers based on poly-L-lactic acid are considered "stimulating" as they are believed to stimulate collagen production over time. Therefore, no immediate filling effect is seen. Moreover, they have been associated with granuloma formation and nodule formation.
Synthetic non-biodegradable tissue filler media include compounds that do not immediately decompose in the body. The synthetic non-biodegradable tissue filler medium may include biological components (or vice versa). In some embodiments, at least a portion of the product is not significantly degraded by different bodily operations. Examples of synthetic non-biodegradable filler media include: ARTEFILTMAnd ARTECOLTMPolymethyl methacrylate (PMMA) microspheres suspended in a bovine collagen carrier,(liquid medical grade silicone), DERMALIVETMAnd DERMADEEPTM(stabilized hyaluronic acid plus acrylic hydrogel hydroxyethyl methacrylate (HEMA) and Ethyl Methacrylate (EMA) interpolymer particles) and various other polymers, polyacids, and polyethers. In some embodiments, the carrier has a rapid biodegradation effect. Some of these non-degradable fillers stimulate fibroblast deposition of collagen around the non-degradable material as part of the body's immune response. In some cases, the newly formed collagen does not match the body's native collagen matrix to a high degree in terms of type, fibril arrangement, and/or mechanical properties. Moreover, complications may arise and may last longer due to the non-degradable nature of the material and are more difficult to treat than with degradable fillers. In addition, permanent fillers have also been associated with severe fibrotic reactions, leading in some cases to scar formation.
As can be appreciated by one of ordinary skill in the art, in some embodiments, any one or combination of the above-described components of the filler can be combined with other fillers (or optional fillers) in different embodiments and for particular results.
In some embodiments, the tissue filler medium is selected from: collagen, fat, human or animal derived collagen, bovine collagen, type I collagen, type II collagen, type III collagen, 3.5% bovine dermal collagen crosslinked by glutaraldehyde to form a lattice structure, native human collagen, autologous collagen, polymethylmethacrylate microspheres (optionally suspended in bovine collagen), a suspension of collagen fibers formulated from the tissue of a subject, cadaver-derived dermis, a human tissue collagen matrix of polyacids and polyethers (e.g., carboxymethylcellulose (CMC) and polyethylene oxide), lyophilized acellular human cadaver dermis, lyophilized micronized acellular human cadaver dermis, artificially cultured autologous fibroblasts, hyaluronic acid, non-animal derived stable hyaluronic acid derivatives, microspheres of calcium hydrocarbyl apatite suspended in an aqueous gel carrier, Dextran beads (e.g., 40-60mu in diameter) suspended in a non-animal source of Hailan gel, solubilized elastin peptides with bovine collagen, silicone, solubilized elastin peptides with bovine collagen, poly-L-lactic acid, Polytetrafluoroethylene (PTFE), glycosylated collagen, PMMA, osteogenic calcium apatite, cultured human cells, expanded polytetrafluoroethylene (e-PTFE), or ePTFEOr some combination thereof. Further examples of injectable filler media include:(including water and crosslinked polymers),(PMMA microspheres suspended in bovine collagen),Dermal fillers (synthetic biocompatible polymers, non-HA gels including absorbable medical polymers),(PMMA microspheres suspended in bovine collagen),BIO-ALCAMIDTM(synthetic network polymers (polyalkylimides), CAPTIQUE)TM(non-animal hyaluronic acid), COSMODERMTM(human collagen dermal filler), COMOPLASTTM、Self-body collagen,FASCIANTM(bandages), bandages, fats, HylaformTM(hyaluronic acid for poultry),JUVEDERM VOLBELLA、JUVEDERM VOLUMA、JUVADERM ESTHELIS、JUVADERMFORTELIS、(Biochemically synthesized non-animal hyaluronic acid), RADIIESSETM(calcium and phosphorus based microspheres),(poly-L-lactic acid (PLLA)), collagen, hyaluronic acid,(collagen derived from bovine tissue),(hyaluronic acid and acrylic acid hydrogel particles),(hyaluronic acid and acrylic acid hydrogel particles),(artificially cultured autologous human fibroblasts),(carboxymethyl cellulose (CMC) and polyethylene oxide (PEO) fillers), PURAGENTM(fillers comprising double cross-linked hyaluronic acid molecules),INTRA (a filler comprising flexible dextran microbeads suspended in supercoiled stable hyaluronic acid), SCULPTRATM(Formerly NEW-FILLTMFillers of poly (L-lactic acid), Teosyal,(hyaluronic acid fillers relating to 3D hyaluronic acid matrix technology),Cosmetic tissue fillers (CTA of Anika), and combinations thereof.
Other examples of tissue fillers include: of AllerganOf GaldermOf Anika TherapeuticsOf Neogenesis
In some embodiments, the additive may be combined with a tissue filler medium. The agent associated with the polymer may include an anesthetic or analgesic (e.g., lidocaine) or a vitamin (e.g., vitamin C). Additives may include bioactive ingredients such as growth factors, peptides and cells.
In some embodiments, the tissue filler medium is substantially stable at room temperature for, e.g., about 3 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, about 21 months, about 24 months, about 27 months, about 30 months, about 33 months, or about 36 months. In other aspects of this embodiment, the dermal filler composition is substantially stable at room temperature for, e.g., about at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months, at least 24 months, at least 27 months, at least 30 months, at least 33 months, or at least 36 months. In other aspects of this embodiment, the tissue filler composition is substantially stable at room temperature for, e.g., about 3-12 months, about 3-18 months, about 3-24 months, about 3-30 months, about 3-36 months, about 6-12 months, about 6-18 months, about 6-24 months, about 6-30 months, about 6-36 months, about 9-18 months, about 9-24 months, about 9-30 months, about 9-36 months, about 12-18 months, about 12-24 months, about 12-30 months, about 12-36 months, about 18-24 months, about 18-30 months, or about 18-36 months.
In some embodiments, the tissue filler medium is degradable and degrades in vivo at about 1 month, 2 months, 3 months, about 3-12 months, about 3-18 months, about 3-24 months, about 6-12 months, about 6-18 months, about 9-12 months, about 9-18 months, about 12-18 months.
In certain embodiments, the tissue filler medium comprises cross-linked hyaluronic acid. Hyaluronic acid may be derived non-animal, e.g. by a streptococcal fermentation process, which is then stabilized by cross-linking. Such bacteria-derived hyaluronic acid has a chain length and molecular weight (about 1-3 megadaltons compared to 4-6 megadaltons) smaller than animal-derived hyaluronic acid.
Crosslinking of hyaluronic acid can be accomplished using crosslinking agents such as 1, 4-butanediol diglycidyl ether (BDDE) (e.g., Restylane, Juvederm, and Boletero dermal fillers), vinyl sulfone (DVS) (e.g., hylarorm, Captique, and Prevelle dermal fillers), 2, 7, 8-Diepoxyoctane (DEO), polyethylene glycol-based crosslinking agents described in U.S. patent application publication No. 2014/0039062, the contents of which are incorporated herein by reference, and bis-carbodiimides in the presence of pH buffers described in U.S. patent No. 8,124,120, the contents of which are incorporated herein by reference. Crosslinking results in slower degradation of hyaluronic acid. The type and extent of crosslinking will determine the rate of degradation, viscoelasticity, and stability of the tissue filler medium. However, possible limitations on the degree of crosslinking may be a reduction in biocompatibility (e.g., an increased inflammatory response and granuloma formation in vivo) and high viscosity that renders the filler non-injectable.
The tissue filler medium may include a relatively insoluble crosslinked hyaluronic acid component of a soluble fluid component. The crosslinked hyaluronic acid component may comprise adherent particles. The soluble fluid component may include free hyaluronic acid (non-crosslinked) or any other fluid component that facilitates delivery of the tissue filler composition through the fine needle. The concentration of hyaluronic acid (including both the crosslinked hyaluronic acid component and the non-crosslinked hyaluronic acid component) may be about 4.5-40mg/mL, about 4.5-35mg/mL, about 4.5-30mg/mL, about 4.5-25mg/mL, about 4.5-20mg/mL, about 4.5-15mg/mL, about 4.5-10 mg/mL. The concentration of hyaluronic acid (including both the crosslinked hyaluronic acid component and the non-crosslinked hyaluronic acid component) may be about 10mg/mL, about 12mg/mL, about 14mg/mL, about 16mg/mL, about 18mg/mL, about 20mg/mL, about 22mg/mL, or about 24 mg/mL. The non-crosslinked hyaluronic acid component may comprise about 30-100% of the total hyaluronic acid, or about 40-100%, about 40-99%, about 40-98%, about 40-95%, about 40-90%, about 40-85%, about 40-80%, about 40-75%, about 40-70%, about 40-65%, about 40-60%, about 40-55%, about 40-50%, about 40-45%, about 50-100%, about 50-99%, about 50-98%, about 50-95%, about 50-90%, about 50-85%, about 50-80%, about 50-75%, about 50-70%, about 50-65% of the total hyaluronic acid content of the composition, About 50-60%, about 50-55%, about 60-100%, about 60-99%, about 60-98%, about 60-95%, about 60-90%, about 60-85%, about 60-80%, about 60-75%, about 60-70%. The cross-linked hyaluronic acid component may comprise about 1% -20% of the total hyaluronic acid content of the composition. In certain embodiments, the crosslinked hyaluronic acid component comprises about 1% -15%, about 1% -14%, about 1% -13%, about 1% -12%, about 1% -11%, about 1% -10%, about 1% -9%, about 1% -8%, about 1% -7%, about 1% -6%, about 1% -5%, about 1% -4%, about 1% -3%, about 1% -2%. In certain embodiments, the crosslinked hyaluronic acid component comprises about 1% -12%, about 3% -10%, or about 4% -10%.
In certain embodiments, the tissue filler medium comprises crosslinked hyaluronic acid particles within the fluid component, which may be the same size or different sizes. The particles are sized so that they can pass through a fine needle hole, such as a 27-40 gauge needle. The particle size range may be 100-1000 μm, or about 200-1000 μm, about 250-1000 μm, about 300-1000 μm, about 350-1000 μm, about 400-1000 μm, about 450-1000 μm, about 500-1000 μm, about 550-1000 μm, about 600-1000 μm, about 650-1000 μm, about 700-1000 μm, about 200-900 μm, about 250-900 μm, about 300-900 μm, about 350-900 μm, about 400-900 μm, about 450-900 μm, about 500-900 μm, about 550-900 μm, about 600-900 μm, about 650-900 μm, about 700-900 μm, about 200-800 μm, about 250-800 μm, About 300-800 μm, about 350-800 μm, about 400-800 μm, about 450-800 μm, about 500-800 μm, about 550-800 μm, about 600-800 μm, about 650-800 μm, or about 700-800 μm.
The cohesiveness of the tissue filler composition may be a desired property in applications where it is desired to mechanically repair soft tissue surrounding the implantation or injection site. The elastic modulus G' is often used to characterize the firmness of the gel and represents the ability of the material to resist deformation. In hyaluronic acid, the degree of crosslinking and the concentration of hyaluronic acid affect the modulus of the composition. Increasing the hyaluronic acid concentration and crosslinking increases the filler modulus. In some embodiments, the elastic modulus G' of the tissue filler medium is in the range of 100-800Pa, about 100-700Pa, about 100-600Pa, about 100-500Pa, about 200-600Pa, or about 200-500 Pa.
In certain embodiments, the tissue filler medium is hydrated. The degree of hydration is a factor used to determine how much medium will swell once applied to soft tissue.
The biophotonic compositions of the present invention have a variety of uses. The biophotonic compositions of the present invention may be used for skin rejuvenation, but are not limited to any particular theory. The biophotonic compositions of the present invention may promote wound healing or tissue repair, but are not limited by this theory. The biophotonic compositions of the present invention may cosmetically enhance soft tissue. The biophotonic compositions of the present invention may inhibit or treat scarring. The biophotonic compositions of the present invention can stimulate collagen synthesis. The collagen synthesis can be used for tissue repair, skin restoration, or cosmetic enhancement of soft tissue. It is therefore an object of the present invention to provide a method by which a wound may be treated with biophotonic therapy, wherein the method promotes wound healing. It is an object of the present invention to provide a method for treating wounds that can be treated with biophotonic therapy, wherein the method promotes collagen synthesis. It is an object of the present invention to provide a method for treating wounds with biophotonic therapy, wherein the method prevents scar formation. It is also an object of the present invention to provide a method of treating skin tissue with biophotonic therapy, wherein the method is used to promote skin rejuvenation. It is also an object of the present invention to provide a method for treating skin tissue with biophotonic therapy, wherein the method is used to promote collagen synthesis.
In certain embodiments, the present invention provides a method of treating a wound with biophotonic therapy, the method comprising: administering a composition to an area to be treated within a wound, wherein the composition comprises a tissue filler medium and a fluorophore; illuminating the region with light having a wavelength that is absorbable by the fluorophore; wherein the method stimulates wound healing in the area.
In yet another aspect, the present invention provides a method of promoting skin rejuvenation. In certain embodiments, the present invention provides a method of promoting skin rejuvenation, the method comprising: administering a composition to an area to be treated within soft tissue, wherein the composition comprises a tissue filler medium and a fluorophore; illuminating the region with light having a wavelength that is absorbable by the fluorophore; wherein the method stimulates collagen synthesis in the region. The tissue filler medium provides an immediate filling effect and the composition induces collagen synthesis.
In yet another aspect, the present invention provides a method for cosmetically enhancing soft tissue. In certain embodiments, the present invention provides a method for cosmetically enhancing soft tissue, comprising: administering intradermally or subcutaneously to the area to be treated a composition, wherein the composition comprises a tissue filler medium and a fluorophore; illuminating the region with light having a wavelength that is absorbable by the fluorophore; wherein the method stimulates collagen synthesis in the region to cosmetically augment the soft tissue.
In yet another aspect, the present invention provides a method for inhibiting or treating scarring. In certain embodiments, the present invention provides a method for inhibiting or treating scarring, the method comprising: applying a composition to an area to be treated within or around a scar or wound, wherein the composition comprises a tissue filler medium and a fluorophore; illuminating the region with light having a wavelength that is absorbable by the fluorophore; wherein the method stimulates collagen synthesis in the region to prevent or reduce scar formation.
In the methods disclosed herein, the biophotonic composition may be administered into or under (e.g., subcutaneously, intradermally, subdermally) soft tissue at the treatment site by injection or implantation (e.g., using a syringe, needle, etc.). One skilled in the art can select the appropriate size of the needle hole depending on the soft tissue to be treated. In intradermal applications, 27G-40G gauge needles, typically 30 or 32G, may be used. The higher the gauge size, the finer the pinhole. The biophotonic compositions of the present invention may also be injected or implanted superficially, for example, into the papillary layer of the dermis, or may be injected or implanted into the reticular layer of the dermis.
The biophotonic composition may be administered intradermally or subcutaneously into the dermis by a continuous means (e.g., a straight line injection) or using a needle (e.g., a serial puncture technique) to form discrete patches of the biophotonic composition intradermally or subcutaneously. The biophotonic composition is irradiated simultaneously with or after application of the composition to the soft tissue site.
In certain embodiments, about 1mL of the biophotonic composition is administered intradermally or subcutaneously. In certain embodiments, less than about 1mL of the biophotonic composition is administered intradermally or subcutaneously. In certain embodiments, about 0.1-0.2mL, about 0.2-0.3mL, about 0.3-0.4mL, about 0.4-0.5mL, about 0.5-0.6mL, about 0.6-0.7mL, about 0.7-0.8mL, about 0.8-0.9mL, about 0.9-1.0mL of the biophotonic composition is administered intradermally or subcutaneously.
Suitable biophotonic compositions for use in the methods of the present invention are selected from any of the embodiments of the biophotonic compositions described above. For example, the biophotonic compositions used in the methods of the present disclosure may include a first chromophore that undergoes at least partial photobleaching upon application of light. The first chromophore absorption wavelength is at about 200-800nm, about 200-700nm, about 200-600nm, or about 200-500 nm. In one embodiment, the first chromophore absorption wavelength is at about 200-600 nm. In some embodiments, the first chromophore absorbs light at a wavelength of about 200-. In other examples, biophotonic compositions suitable for the methods of the present disclosure further include at least one other chromophore (e.g., a second chromophore). The absorption spectrum of the second chromophore overlaps at least about 80%, about 50%, about 40%, about 30%, or about 20% of the emission spectrum of the first chromophore. In some embodiments, the emission spectrum of the first chromophore overlaps with the absorption spectrum of the second chromophore by at least about 1-10%, at least about 5-15%, at least about 10-20%, at least about 15-25%, at least about 20-30%, at least about 25-35%, at least about 30-40%, at least about 35-45%, at least about 50-60%, at least about 55-65%, or at least about 60-70%.
Irradiation of the biophotonic composition with light may result in energy transfer from the first chromophore to the second chromophore. Subsequently, the second chromophore can emit energy as fluorescence and/or generate reactive oxygen species. In certain embodiments of the methods of the present invention, the energy transfer resulting from the application of light is not accompanied by the generation of heat, or results in tissue damage.
In the methods of the invention, the biophotonic composition may be irradiated transdermally (from outside the body) or from inside the soft tissue (e.g., using an optical fiber or light tunnel). In certain embodiments, the biophotonic composition itself may form a light conduit from the skin surface to the composition. To form such a light tunnel, a composition trajectory is formed from the skin puncture to the composition within the soft tissue. In the methods of the present invention, the biophotonic composition is simultaneously irradiated while or immediately after the composition is applied to the intra-donor region.
Any source of actinic light may be used in the process of the present invention. Any type of halogen lamp, LED or plasma arc lamp or laser is suitable. A key feature of a suitable source of actinic light is that it emits light at a wavelength(s) suitable for activating one or more photoactivators in the composition. In one embodiment, an argon laser is used. In another embodiment, a potassium titanyl phosphate (KTP) laser (e.g., Greenlight) is usedTMA laser). In another embodiment, sunlight may be employed. In yet another embodiment, the source of actinic light is an LED light curing device. In yet another embodiment, the source of actinic light is a source of light having a wavelength of about 200 and 800 nm. In another embodiment, the source of actinic light is a source of visible light having a wavelength of about 400-600nm or about 400-700 nm. In yet another embodiment, the source of actinic light is blue light. In yet anotherIn an embodiment, the source of actinic light is red light. In yet another embodiment, the source of actinic light is green light. In addition, the source of actinic light should have a suitable power density. Suitable power densities for the non-collimated light source (LED, halogen lamp or plasma lamp) are about 1mW/cm2-200mW/cm2. A suitable power density for the laser light source is about 0.5mW/cm2-0.8mW/cm2。
In some embodiments of the methods of the invention, the energy of the light source at the skin, wound or mucosal surface of the subject is about 1mW/cm2-500mW/cm2、1-300mW/cm2Or 1-200mW/cm2Wherein the energy applied is dependent on at least the treatment condition, the wavelength of the light, the distance of the subject's skin from the light source, and the thickness of the biophotonic composition. In certain embodiments, the light at the skin of the subject is about 1-40mW/cm2Or 20-60mW/cm2Or 40-80mW/cm2Or 60-100mW/cm2Or 80-120mW/cm2Or 100-140mW/cm2Or 120-160mW/cm2Or 140 ion power of 180mW/cm2Or 160 ion power of 200mW/cm2Or 110-240mW/cm2Or 110-150mW/cm2Or 190 ion power 240mW/cm2。
In some embodiments of the methods of the present invention, the topical biophotonic composition may be an additional illumination source or the only illumination source. In these embodiments, the topical biophotonic composition may include a fluorophore such that when illuminated with activating light (e.g., from an LED or laser source) it emits light having a longer wavelength (stokes shift). Light from the activating light and/or topical biophotonic composition can activate a fluorophore within the tissue filler composition. Thus, the tissue surrounding the tissue filler composition is irradiated with broad band light of different intensities. The topical biophotonic composition may be described in one of WO2010/051636, WO2010/051641 and WO2013/155620, the contents of which are incorporated herein by reference.
In certain embodiments, the chromophore in the composition may be photoexcited by ambient light including sunlight and overhead illumination. In some embodiments, the chromophore can be activated by light in the visible range of the electromagnetic spectrum. Such light may be emitted by any light source, such as daylight, a light bulb, an LED device, an electronic display screen, such as a television, a computer, a telephone, a mobile device, a flashlight on a mobile device. Any light source may be used in the method of the invention. For example, ambient light and direct light or artificial direct light may be used in combination. Ambient light includes overhead lighting, such as LED bulbs, fluorescent lamps, etc., and indirect sunlight.
The desired duration of exposure to actinic light will depend on the depth below the skin surface of the biophotonic composition; intervening in tissue thickness, density and composition; the type of intervening tissue, the concentration of chromophores within the tissue filler composition, the power density, wavelength and bandwidth of the light source, the thickness of the biophotonic composition, and the therapeutic distance to the light source. Fluorescence irradiation of the treatment area may occur within seconds or even less than one second, however, it is beneficial to extend the irradiation time in order to take advantage of the synergistic effect of absorbed, reflected and re-emitted light on the composition of the invention and its interaction with the treated tissue.
In one embodiment, the tissue to which the biophotonic composition is applied is exposed to actinic light for a period of 1-5 minutes. In another embodiment, the tissue to which the biophotonic composition is applied is exposed to actinic light for a period of 1 to 5 minutes. In some other embodiments, the biophotonic composition is irradiated for 1-3 minutes. In certain embodiments, the light is applied for a time period of 1 to 30 seconds, 15 to 45 seconds, 30 to 60 seconds, 0.75 to 1.5 minutes, 1 to 2 minutes, 1.5 to 2.5 minutes, 2 to 3 minutes, 2.5 to 3.5 minutes, 3 to 4 minutes, 3.5 to 4.5 minutes, 4 to 5 minutes, 5 to 10 minutes, 10 to 15 minutes, 15 to 20 minutes, 20 to 25 minutes, or 20 to 30 minutes. The treatment time may range up to about 90 minutes, about 80 minutes, about 70 minutes, about 60 minutes, about 50 minutes, about 40 minutes, or about 30 minutes. It should be understood that the treatment time may be adjusted to maintain the dosage by adjusting the rate of delivery of the energy density delivered to the treatment site. For example, the integrated energy transmitted is about 4 to about 60J/cm2About10-60J/cm2About 10 to 50J/cm2About 10-40J/cm2About 10-30J/cm2About 20-40J/cm2About 15J/cm2-25J/cm2Or about 10-20J/cm2。
In yet another embodiment, the source of actinic light is continuously moved over the treatment site for an appropriate exposure time. In yet another embodiment, the biophotonic composition and the actinic light are applied multiple times. In some embodiments, the biophotonic composition or tissue is exposed to actinic light at least two, three, four, five, or six times. In some embodiments, the biophotonic composition is applied fresh prior to exposure to actinic light or application of the fresh biophotonic composition to soft tissue.
The process can be repeated as desired. For example, in certain embodiments where the tissue filler medium is a biodegradable material, the method may be repeated after the tissue filler medium is nearly completely degraded or completely degraded. The tissue filler medium degradation time depends on the type of filler medium and its inherent degradation characteristics, such as viscosity, the amount of filler in the soft tissue, its location within the soft tissue, and the depth of the tissue. The period of repeating the method according to certain embodiments of the invention may range from about 2-24 months. In certain embodiments, the fluorophore does not degrade upon irradiation, in which case the composition may be re-irradiated until photobleached.
The method may further comprise: massage is applied to the area once the composition has been applied.
The epidermis and dermis are the first and second layers of skin, respectively. The dermis contains the structural element connective tissue of the skin. Within the dermis are various types of connective tissue with different functions. Elastic fibers give the skin elasticity, and collagen gives the skin strength.
The junction between the dermis and epidermis is a very important structure. The dermal-epidermal junction joins to form an epidermal ridge similar to a finger. Epidermal cells receive their nutrients from blood vessels within the dermis. The epidermal ridges increase the surface area of the epidermis exposed to these blood vessels and nutrients required.
Aging of the skin is accompanied by significant physiological changes in the skin. The production of new skin cells slows and the epidermal ridges at the dermal-epidermal junction flatten out. Although the number of elastic fibers increases, the structure and cohesiveness thereof decrease. In addition, the amount of collagen and the thickness of the dermis decrease as the skin ages.
Collagen is a major component of the skin extracellular matrix, providing a structural framework. During the aging process, collagen synthesis decreases and collagen fibers become insoluble, resulting in thinning of the dermis and loss of the biomechanical properties of the skin.
Physiological changes in the skin lead to the appearance of significant symptoms of aging, commonly referred to as chronological aging, intrinsic aging, and photoaging. The skin becomes drier, rough and has increased desquamation, and becomes duller in appearance, with visible fine lines and wrinkles. Other symptoms of skin aging include, but are not limited to: thinning and transparency of the skin, loss of underlying fat (leading to depression of the cheeks and deep eyes, and significant loss of tightness in the hands and neck), osteoporosis (due to osteoporosis, separation of bone from the skin, leading to skin laxity), dry skin (which may be itchy), inability to perspire enough to cool the skin, facial hair growth, freckles, age spots, spider veins, rough and leathery skin, fine lines that disappear when pulled apart, skin laxity, or lentigines.
The dermal-epidermal junction is the basement membrane, separating keratinocytes in the epidermis from the extracellular matrix located beneath the epidermis. The base film is composed of two layers: a basal layer in contact with keratinocytes and a lower reticular layer in contact with extracellular matrix. The basal layer is rich in type IV collagen and laminin, which molecules play a role in providing a structural network and bioadhesive characteristics for cellular connectivity.
Laminins are glycoproteins that are only present in the basal membrane. It consists of three polypeptide chains (α, β and γ) arranged in an asymmetric cross shape, held together by disulfide bonds. These three chains exist in different isoforms, resulting in twelve different isoforms of laminin, including laminin-1 and laminin-5.
The dermis is anchored by collagen type VII fibers at the hemidesmosome of basement membrane keratinocytes, a specific junction located on keratinocytes, consisting of α -integrins and other proteins. Laminins, and in particular laminin-5, constitute the actual anchor point between the hemidesmoplasmic transmembrane protein and collagen type VII in basal keratinocytes.
It has been demonstrated that laminin-5 synthesis and collagen type VII expression are reduced in aging skin. This results in a loss of contact between the dermis and epidermis, resulting in loss of elasticity and relaxation of the skin.
Another type of wrinkle, commonly referred to as expression lines, requires a loss of elasticity, particularly in the dermis, so that when facial muscles producing facial expressions apply stress to the skin, the skin is no longer able to recover its original state, resulting in expression lines.
The compositions and methods of the present invention promote skin rejuvenation. In some embodiments, the biophotonic compositions and methods of the present disclosure promote collagen synthesis. In some embodiments, the compositions and methods of the present invention may reduce, eliminate, delay, or even reverse one or more symptoms of skin aging, including, but not limited to, the appearance of fine lines or wrinkles, thinning and transparency of the skin, loss of underlying fat (resulting in depressions in the cheeks and deep eyes, and significant loss of firmness in the hands and neck), osteoporosis (due to osteoporosis, separation of bones from the skin resulting in skin laxity), dry skin (which may be itchy), inability to perspire to sufficiently cool the skin, facial hair, freckles, age spots, spider veins, rough and leathery skin, fine lines that disappear when pulled apart, skin laxity, or lentigines. In some embodiments, the compositions and methods of the present invention can induce pore reduction, enhance the firmness of various portions of the skin, and/or enhance skin translucency. In addition, the compositions and methods of the present invention can enhance the aesthetic appearance of skin by, for example, increasing brightness and texture, decreasing pore size, and tightening the skin.
The biophotonic materials and methods of the present disclosure may be used to treat wounds, promote wound healing, promote tissue repair, and/or eliminate or reduce the need for cosmetic treatment, including improving motor function (e.g., joint movement). Wounds that can be treated by the biophotonic materials and methods of the present invention include, for example, wounds of the skin and subcutaneous tissue that are initiated in different ways (e.g., pressure ulcers caused by prolonged periods of bed rest, wounds caused by trauma, wounds caused by symptoms such as periodontitis), and wounds with different characteristics. In certain embodiments, the present invention provides biophotonic materials and methods for treating and/or promoting healing of, for example, burns, incisions, resections, tears, abrasions, puncture or penetrating wounds, surgical wounds, contusions, hematomas, pressure wounds, sores and ulcers.
The biophotonic compositions and methods of the present invention may be used to treat and/or promote healing of chronic skin ulcers or wounds that fail to achieve a durable structural, functional, and aesthetic closure through a series of ordered, timely events. The vast majority of chronic wounds can be classified into three categories according to their etiology: pressure ulcers, neuropathic (diabetic foot) ulcers and vascular (venous or arterial) ulcers.
For example, the present invention provides biophotonic compositions and methods for treating and/or promoting healing of diabetic ulcers. Diabetic patients are prone to foot and other ulcers due to neurological and vascular complications. Peripheral neuropathy can lead to altered or complete loss of sensation in the foot and/or leg. Diabetic patients with advanced neuropathy completely lose the ability to discern severe pain. When any wounds or traumas occur in the feet of patients suffering from neuropathy, they may be completely unnoticed for days or weeks. Patients with advanced neuropathy lose the ability to sense sustained pressure stimulation and, as a result, tissue ischemia and gangrene may occur, resulting in, for example, plantar ulcers. Microvascular disease is one of the significant complications of diabetes and can also lead to ulcers. In certain embodiments, the present invention provides biophotonic materials and methods for treating chronic wounds characterized by diabetic foot ulcers and/or ulcers resulting from diabetic neuropathy and/or vascular complications.
In other examples, the present invention provides biophotonic compositions and methods for treating and/or promoting healing of pressure ulcers. Pressure ulcers include pressure sores, decubitus ulcers and ischial tuberosity ulcers, which can cause significant pain and discomfort to the patient. Pressure ulcers are caused by pressure applied to the skin for a prolonged period of time. Thus, pressure may be applied to the patient's skin due to the weight or mass of the individual. Pressure ulcers form when the blood supply to an area of the skin is occluded or otherwise interrupted for more than two or three hours. The affected skin area becomes red, painful and necrotic. If left untreated, the skin may become exposed and infected. Thus, pressure ulcers are skin ulcers that develop in an area of the skin under pressure caused by prolonged bed rest, wheelchair and/or cast wear. Pressure ulcers occur when a person is bedridden, unconscious, unable to feel pain or immobilized. Pressure ulcers typically occur in bony prominences of the body, such as the hip region (sacrum or iliac crest) or heel.
Other types of wounds that may be treated with the biophotonic materials and methods of the present disclosure include those disclosed in U.S. patent application publication No. 20090220450, which is incorporated herein by reference.
The wound healing process has three distinct phases. First, during the inflammatory phase, usually from the wound appearance to two to five days, platelets aggregate to deposit creutzfeldt-jakob, promote fibrin deposition and stimulate the release of growth factors. The white blood cells migrate to the wound site and begin to digest and transport debris away from the wound site. During this inflammatory phase, monocytes are also converted into macrophages, which release growth factors, stimulating the formation of blood vessels and the production of fibroblasts.
Second, in the hyperplastic stage, which typically occurs between two and three weeks, the pulp-tooth tissue forms and begins to epithelialize and contract. Fibroblasts are a key cell type at this stage, filling the wound by proliferating and synthesizing collagen, providing a strong matrix for epithelial cell growth. When fibroblasts produce collagen, blood vessels are formed extending from nearby blood vessels, resulting in the formation of crenular tooth tissue. The pulp tooth tissue usually grows from the bottom of the wound. Epithelialization involves the migration of epithelial cells from the wound surface, thereby sealing the wound. Epithelial cells are driven by the need to contact similar cells and are guided by a network of fibrin chains that act as a lattice on which these cells migrate. Contractile cells called myofibroblasts appear at the wound site to help close the wound. These cells show collagen synthesis and contractility and are relatively common in meat dental wounds.
Again, the remodeling stage, the final stage of wound healing, is from three weeks to several years where the collagen in the scar undergoes repeated degradation and re-synthesis. At this stage, the tensile strength of the newly formed skin increases.
However, as the rate of wound healing increases, there is generally a corresponding increase in scar formation. Scarring is the result of the healing process of most adult animal and human tissues. Scar tissue, unlike the tissue it replaces, is generally of poorer functional quality. Types of scars include, but are not limited to, atrophic scars, hypertrophic scars and keloids, and scar contractures. Atrophic scars are flat with the surface below the surrounding skin, forming valleys or holes. Hypertrophic scars are raised scars that remain within the boundaries of the original lesion and usually contain excess collagen laid out in an abnormal manner. A fleck tumor is an elevated scar that spreads out of the margins of the original wound, invading the vicinity of normal skin in a site-specific manner, usually containing collagen helices arranged in an abnormal manner.
In contrast, normal skin is composed of collagen fibers arranged in a basket-like manner, contributing to the strength and elasticity of the dermis. Therefore, in order to make the wound healing process smoother, a method is needed that not only stimulates the production of collagen, but also stimulates the production of collagen in a manner that reduces scar formation.
The biophotonic compositions and methods of the present invention promote wound healing by promoting substantially uniform epithelialization, promoting collagen synthesis, promoting controlled contraction, and/or reducing scar tissue formation. In certain embodiments, the biophotonic compositions and methods of the present disclosure may promote wound healing by promoting substantially uniform epithelialization. In some embodiments, the biophotonic compositions and methods of the present disclosure promote collagen synthesis. In some other embodiments, the biophotonic compositions and methods of the present disclosure promote controlled contraction. In certain embodiments, the biophotonic compositions and methods of the present disclosure promote wound healing, for example, by reducing the formation of scar tissue. In certain embodiments, the biophotonic composition may be used during or after wound closure for optimizing scar repair.
The biophotonic composition may be administered periodically, for example, once a week, or at intervals deemed appropriate by a physician. Alternatively, once administered, the biophotonic composition may be photoactivated at regular intervals until the chromophore is depleted.
Local or systemic adjunctive therapy, such as antibiotic therapy, may be used. Negative pressure may also be used to assist wound closure and/or to remove the composition.
In some examples, the frequency of administration of the biophotonic compositions specified herein may depend on the type and/or amount of filler initially administered. Depending on its thickness, viscosity and elasticity, the filler can be applied as early as several months and as late as 2 years. Likewise, the problem of the amount applied per unit time may depend on the type of filler, the location, the depth of the tissue site and the amount applied.
The invention also provides kits for preparing and/or administering any of the compositions of the invention. The kit may comprise a container comprising the biophotonic composition of the present invention. The container may be light-tight, air-tight, and/or leak-proof. Exemplary containers include, but are not limited to, syringes, vials, or bags. In some embodiments, the tissue filler medium and the chromophore composition are placed in separate containers for mixing by the user prior to administration. In some embodiments, the tissue filler medium and the chromophore composition are placed in a single pre-mix composition. In some embodiments, the kit comprises a handheld injection device.
In other embodiments, the kit includes a systemic or topical medicament for enhancing the therapeutic effect of the composition. For example, the kit includes systemic or topical antibiotic or hormonal therapy drugs for the treatment of acne or wound healing.
Written instructions on how to use the biophotonic compositions according to the present invention may be included in the kit, or may be included on or with the container containing the compositions of the present invention.
In certain embodiments of the kit, the kit can further comprise a light source, such as a portable lamp having a wavelength suitable for activating a chromophore in the biophotonic composition. The portable light may be battery powered or may be rechargeable.
In certain embodiments, the kit may further comprise one or more waveguides.
In certain embodiments, the kit may further comprise a topical biophotonic composition described in one of WO2010/051636, WO2010/051641, and WO2013/155620, the contents of which are incorporated herein by reference.
Identifying equivalent compositions, methods and kits will be familiar to those skilled in the art in light of the teachings of this invention, and no further experimentation will be required beyond routine experimentation. The invention will be more fully understood from the following examples, which are given by way of illustration only and should not be construed as limiting the invention in any way.
Examples of the invention
Examples are given below to illustrate the results of practicing the present invention. They are not intended to limit or define the full scope of the invention.
Example 1
A composition comprising a fluorophore and dermal filler according to the invention is prepared. The following combination of dermal fillers and fluorophores was used.
1) JUVEDERM volbal + fluorescein + eosin Y;
2) JUVEDERMVOLBELLA + eosin Y + eosin B;
3) JUVEDERM volbal + eosin Y;
4) JUVEDERM VOLUMA + fluorescein + eosin Y;
5) JUVEDERM VOLUMA + eosin Y;
6) JUVEDERM VOLUMA + eosin Y + eosin B;
7) estelois + eosin Y + fluorescein;
8) FORTELIS + eosin Y + fluorescein;
9)+ fluorescein + eosin Y;
10)+ eosin Y + eosin B;
11)+ eosin Y;
12)+ fluorescein + eosin Y;
13)+ eosin Y + eosin B; and
14)+ eosin Y.
For example, compositions 7) and 8) were prepared as follows:
7)0.75g of FORTELIS was mixed with 9.38. mu.l of eosin Y (9.6mg/ml) and 9.38. mu.l of fluorescein (9.6mg/ml) such that the final concentration of eosin Y was 0.012% and the final concentration of fluorescein was 0.012%.
8)0.75g of ESTHELIS was mixed with 9.38. mu.l of eosin Y (9.6mg/ml) and 9.38. mu.l of fluorescein (9.6mg/ml) such that the final concentration of eosin Y was 0.012% and the final concentration of fluorescein was 0.012%.
Example 2
Dermal filler-mediated effects on type I and type III collagen gene expression levels were evaluated in human dermal fibroblasts (DHF). Dermal filler gels were evaluated in vitro to assess their potential effect on collagen synthesis. Collagen is a major component of the skin extracellular matrix (ECM) and an increase in collagen synthesis is beneficial in skin rejuvenation.
JUVEDERM VOLUMA(VB)、JUVADERM VOLBELLA(V15)、(RL), ESTHELIS (EB) and JUVADERM VOLBELLA (V15),The mixture of (RL) and estheelis (eb) (gel a) was used as a dermal filler gel in the study. The effect of dermal fillers on collagen synthesis was tested in human dermal fibroblasts (DHF). Type I and type III collagen mrnas were quantified by qRT-PCR. DHF was cultured on glass-bottom dishes. The dermal filler gel being applied to a glass dish (2mm thick)The other side and using blue visible light (KLOX THERA)TMLamp) was irradiated at a distance of 5cm for 5 minutes (300 seconds). The dermal filler gels tested contained only eosin Y or a combination of both eosin Y and fluorescein (0.011% each). A dermal filler gel without chromophore was used as a control.
DHF cells were also treated with light alone without the gel to assess the effect of blue light irradiation on the collagen expression pattern. After 16 hours of irradiation, cells were collected for RNA extraction, and cDNA synthesis was performed. Collagen mRNA levels under different conditions were assessed by qRT-PCR. TGF-beta 1(5ng/ml) was used to trigger collagen gene expression and was used as a positive control in all experiments. The results were expressed as folded mRNA expression levels compared to untreated controls.
The data are summarized in Table 1.
Table 1: type I and type III collagen mRNA expression in DHF after 16 hours of treatment was compared to untreated controls.
Gel a + eosin Y + fluorescein showed a positive effect on collagen type I and type III gene expression (up to 2.9 and 2.33 fold increase, respectively) compared to untreated controls. Interestingly, a slight induction of gene expression of collagen type I and collagen type III was also observed for gel a rather than chromophore samples (2.3 and 1.57, respectively), which could be attributed to the higher ability of gel a to transmit blue light, which exerts its effect on DHF cells leading to collagen mRNA expression.
The mixture of tissue filler media including EB, RL and V15 (gel a) stimulated higher mRNA expression of type I collagen in DHF cells than the levels of tissue filler media smeared alone and compared to light alone. Stimulation of mRNA expression of type I collagen and type III collagen in DHF cells increased when chromophore was added to gel a when compared to gel a lacking chromophore.
Example 3
This technique is carried out under sterile conditions. The skin in the upper lip area is cleansed with 0.5% chlorhexidine (or similar antiseptic). At that time, a slow dermal or subcutaneous injection was performed with the HA filler. Note that the respective regions are overflowed. After the injection is completed, the area is gently massaged to achieve the desired result. A chromophore gel was applied to each partition of the upper lip and the area was illuminated using an LED lamp for 5 minutes. After light treatment, the gel was wiped off with saline.
Example 4
The composition comprising a fluorophore and a dermal filler (including hyaluronic acid) according to the invention may be injected intradermally under the folds on the patient's face. The composition may be irradiated with light that overlaps the absorption spectrum of the fluorophore to photosensitize the fluorophore in situ. The fluorophore may fluoresce towards the surrounding soft tissue.
Example 5
The composition comprising a fluorophore and a dermal filler (including hyaluronic acid) according to the invention may be injected intradermally under the folds on the patient's face. A thin layer of topical biophotonic composition may be placed immediately over the fold above the injected composition. The topical composition may be irradiated with light that overlaps the absorption spectrum of the fluorophore in the topical composition to photosensitize the fluorophore and may cause it to emit light having an emission spectrum that may overlap the absorption spectrum of the fluorophore within the injected composition of the present invention. The fluorophore may fluoresce towards the surrounding soft tissue.
While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth, as follows in the scope of the appended claims.
All documents mentioned in the specification are herein incorporated by reference.
Claims (69)
1. A method for stimulating collagen synthesis, comprising:
-administering a composition to an area to be treated within soft tissue, wherein the composition comprises a tissue filler medium and a fluorophore;
-illuminating said area with light having a wavelength that is absorbable by said fluorophore;
wherein the method stimulates collagen synthesis in the region.
2. A method for cosmetically augmenting soft tissue, comprising:
-administering a composition intradermally or subcutaneously to the area to be treated, wherein the composition comprises a tissue filler medium and a fluorophore;
-illuminating said area with light having a wavelength that is absorbable by said fluorophore;
wherein the method stimulates collagen synthesis within the region to cosmetically enhance the soft tissue.
3. A method for inhibiting or treating scarring, the method comprising:
-applying a composition to an area to be treated within or around a scar or wound, wherein the composition comprises a tissue filler medium and a fluorophore;
-illuminating said area with light having a wavelength that is absorbable by said fluorophore;
wherein the method stimulates collagen synthesis in the region to prevent or reduce scar formation.
4. The method of claim 2 or claim 3, wherein the region to be treated is soft tissue.
5. The method of any one of claims 1-4, wherein the area to be treated is on the face, neck, ear, chest, hip, arm, armpit, hand, leg, or foot of the subject.
6. The method of any one of claims 1-5, wherein the area to be treated is in or around a scar.
7. The method of any one of claims 1-5, wherein the area to be treated is within or around a wound.
8. The method of any one of claims 1-7, wherein the area to be treated comprises a stretch mark.
9. The method of any one of claims 1-8, wherein the composition is administered by injection.
10. The method of any one of claims 1-8, wherein the composition is administered by implantation.
11. The method of any one of claims 1-10, wherein the composition is a silicone gel.
12. The method of any one of claims 1-11, wherein the composition is a hydrated gel.
13. The method of any one of claims 1-12, wherein the composition is transparent or translucent.
14. The method of any one of claims 1-13, wherein the tissue filler medium retains the fluorophore within the composition during administration of the composition and during at least a portion of the irradiation.
15. The method of any one of claims 1-14, wherein the tissue filler medium is biodegradable.
16. The method of any one of claims 1-15, wherein the tissue filler is a dermal filler.
17. The method of any of claims 1-15, wherein the tissue filler medium comprises a polymer.
18. The method of claim 17, wherein the polymer is selected from the group consisting of: proteins, peptides, polypeptides, polylysines, collagen, procollagen, elastin, and laminin.
19. The method of claim 17, wherein the polymer is selected from the group consisting of: polyethylene (vinyl alcohol), polyethylene glycol, polyvinylamine, polyallylamine, deacetylated polyacrylamide, polyacrylic acid, and polymethacrylic acid.
20. The method of any one of claims 1-15, wherein the tissue filler medium comprises collagen, fat, collagen derived from humans or animals, bovine collagen, type I collagen, type II collagen, type III collagen, 3.5% bovine dermal collagen crosslinked by glutaraldehyde to form a lattice structure, native human collagen, autologous collagen, polymethylmethacrylate microspheres, a suspension of collagen fibers formulated from the tissue of a subject, dermis derived from cadavers, a polyacid and polyether human tissue collagen matrix, lyophilized non-fineDermis of a human cadaver of a cell, dermis of a micronized, acellular human cadaver that has been lyophilized, autologous fibroblasts cultured artificially, hyaluronic acid, a non-animal derived stable hyaluronic acid derivative, microspheres of calcium hydrocarbyl apatite suspended in an aqueous gel carrier, dextran beads suspended in a gel of cymbidium of non-animal origin, dissolved elastin peptide with bovine collagen, silicone, collagen with bovine collagen, poly-L-lactic acid, Polytetrafluoroethylene (PTFE), glycosylated collagen, PMMA, osteogenic calcium apatite, human cells cultured artificially, expanded polytetrafluoroethylene (e-PTFE), or expanded polytetrafluoroethyleneOr any combination thereof.
21. The method of any one of claims 1-15, wherein the tissue filler medium comprises cross-linked hyaluronic acid.
22. The method of claim 21, wherein the cross-linked hyaluronic acid is in particulate form.
23. The method of claim 22, wherein the composition further comprises an injectable medium loaded with the particles.
24. The method of claim 23, wherein the injectable medium comprises hyaluronic acid which is relatively less cross-linked than hyaluronic acid in particle form.
25. The method of any one of claims 1-24, wherein the composition further comprises light reflective particles.
26. The method of any one of claims 1-25, wherein the fluorophore is a hydrophilic chromophore.
27. The method of any one of claims 1-26, wherein the fluorophore is activatable by light having a wavelength in the visible range.
28. The method of any one of claims 1-27, wherein the fluorophore can emit light having a wavelength in the visible range when activated.
29. The method of any one of claims 1-28, wherein the fluorophore is photobleachable upon irradiation of the region.
30. The method of any one of claims 1-29, wherein the fluorophore is not in a liposome form in the composition.
31. The method of any one of claims 1-25, wherein the fluorophore is not a photosensitizing agent.
32. The method of any one of claims 1-25, wherein the chromophore is a xanthene dye.
33. The method of claim 32 wherein said xanthene dye is selected from the group consisting of: eosin B, eosin Y, eosin derivatives, erythrosine, fluorescein, phloxine B and rose bengal.
34. The method of any one of claims 1-3, further comprising a second fluorophore.
35. The method of claim 34, wherein the second fluorophore is a xanthene dye.
36. The method of claim 35 wherein said xanthene dye is selected from the group consisting of: eosin B, eosin Y, eosin derivatives, erythrosine, fluorescein, phloxine B and rose bengal.
37. The method according to any one of claims 1-36, wherein the area is irradiated upon or immediately following intradermal or subcutaneous administration.
38. The method of any one of claims 1-37, wherein the irradiation is for a time sufficient to activate a fluorophore.
39. The method of any one of claims 1-37, wherein the irradiation is for a time sufficient to photobleach a fluorophore.
40. The method of any one of claims 1-39, wherein the composition is illuminated by a light source located outside the dermis.
41. The method according to any one of claims 1-40, wherein the intradermal or subcutaneous administration comprises providing a track of the composition from the exterior to the dermis to the composition.
42. The method of any one of claims 1-41, wherein the method further comprises applying a topical composition to the treatment area, wherein the topical composition comprises a fluorophore.
43. The method of claim 42 wherein the fluorescent compound has an emission spectrum of a fluorophore that activates an intradermal composition.
44. The method of claim 42 or claim 43, wherein the topical composition is applied prior to light irradiation.
45. A tissue filler composition comprising:
a tissue filler medium; and
at least one fluorophore;
wherein the composition is suitable for injection or implantation into the human body.
46. The composition of claim 45, wherein the composition is a silicone gel.
47. The composition of claim 45 or claim 46, wherein the composition is a hydrated gel.
48. The composition of any one of claims 45-47, wherein the composition is transparent or translucent.
49. The composition of any one of claims 45-48, wherein the tissue filler medium retains the fluorophore within the composition during administration of the composition and during at least a portion of irradiation.
50. The composition of any one of claims 45-49, wherein the tissue filler medium is biodegradable.
51. The composition of any one of claims 45-50, wherein the tissue filler medium comprises cross-linked hyaluronic acid.
52. The composition of any one of claims 45-51, wherein the cross-linked hyaluronic acid is in particulate form.
53. The composition of any one of claims 45-52, wherein the composition further comprises an injectable medium loaded with the particles.
54. The composition of any one of claims 45-53, wherein the injectable medium comprises hyaluronic acid that is relatively less cross-linked than hyaluronic acid in particle form.
55. The composition of any one of claims 45-54, wherein the composition further comprises light reflective particles.
56. The composition of any one of claims 45-55, wherein the fluorophore is a hydrophilic chromophore.
57. The composition of any one of claims 45-56, wherein the fluorophore is activatable by light having a wavelength in the visible range.
58. The composition according to any one of claims 45-57, wherein the fluorophore, when activated, emits light having a wavelength in the visible range.
59. The composition according to any one of claims 45-58, wherein the fluorophore is photobleachable upon irradiation of the region.
60. The composition of any one of claims 45-59, wherein the fluorophore is not in the form of a liposome in the composition.
61. Use of a composition comprising a tissue filler medium and a fluorophore in a method for stimulating collagen synthesis, wherein the method comprises the steps of: applying the composition to an area to be treated within soft tissue, and illuminating the area with light having a wavelength that is absorbable by the fluorophore; and wherein the method stimulates collagen synthesis in the region.
62. Use of a composition comprising a tissue filler medium and a fluorophore in a method for cosmetically enhancing soft tissue, wherein the method comprises the steps of: applying the composition to an area to be treated within soft tissue, and illuminating the area with light having a wavelength that is absorbable by the fluorophore; and wherein the method cosmetically enhances the soft tissue.
63. Use of a composition comprising a tissue filler medium and a fluorophore in a method for inhibiting or treating scarring, wherein the method comprises the steps of: applying the composition to an area to be treated within soft tissue, and illuminating the area with light having a wavelength that is absorbable by the fluorophore; and wherein the method cosmetically inhibits or treats scarring.
64. The tissue filler composition of any of claims 51-60, wherein the composition comprises more than one tissue filler medium.
65. A tissue filler composition comprising one or more tissue filler media, wherein the composition is suitable for injection or implantation into the human body.
66. The tissue filler composition according to claim 65, further comprising at least one fluorophore.
67. A method for stimulating collagen synthesis, comprising:
-applying a first composition to an area to be treated within soft tissue, wherein the first composition comprises a tissue filler medium;
-applying a second composition comprising a fluorophore on a surface above the area to be treated; and
-illuminating said area with light having a wavelength that is absorbable by said fluorescence;
wherein the method stimulates collagen synthesis in the region.
68. The method of claim 67, wherein the first composition comprises more than one tissue filler medium.
69. The method of claim 67 or claim 68, wherein the second composition comprises more than one fluorophore.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US61/973,659 | 2014-04-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK1233550A1 true HK1233550A1 (en) | 2018-02-02 |
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